bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022‒04‒24
123 papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development
  1. Recent advances in nanogold as a promising nanocarrier for curcumin delivery.
  2. Therapeutic Targeting Hypoxia-Inducible Factor (HIF-1) in Cancer: Cutting Gordian Knot of Cancer Cell Metabolism.
  3. Recent Advances in Near Infrared Upconverting Nanomaterials for Targeted Photodynamic Therapy of Cancer.
  4. Delivery of triptolide: a combination of traditional Chinese medicine and nanomedicine.
  5. Photodynamic Therapy of Up-Conversion Nanomaterial Doped with Gold Nanoparticles.
  6. Application of Self-Assembly Nanoparticles Based on DVDMS for Fenton-Like Ion Delivery and Enhanced Sonodynamic Therapy.
  7. Recent patents on plant derived nanoparticles and their potential application towards various cancer therapeutics.
  8. Iron phthalocyanine-derived nanozyme as dual reactive oxygen species generation accelerator for photothermally enhanced tumor catalytic therapy.
  9. Drug-delivery nanoparticles for bone-tissue and dental applications.
  10. Near-Infrared Light-Triggered Nitric Oxide Nanogenerators for NO-Photothermal Synergistic Cancer Therapy.
  11. [Anti-cancer properties of dichloroacetate].
  12. Multiple health benefits of curcumin and its therapeutic potential.
  13. Combination of Immunotherapy and Photo-Pyroptosis as Novel Anticancer Strategy.
  14. Natural Products for the Prevention and Treatment of Oral Mucositis-A Review.
  15. Hyperthermia Treatment as a Promising Anti-Cancer Strategy: Therapeutic Targets, Perspective Mechanisms and Synergistic Combinations in Experimental Approaches.
  16. Synthesis and Characterization of Curcumin Incorporated Multi component Nano-Scaffold with Enhanced Anti-bacterial and Wound Healing Properties.
  17. Mitochondrial and metabolic alterations in cancer cells.
  18. Cyclodextrin-Derived ROS-Generating Nanomedicine with pH-Modulated Degradability to Enhance Tumor Ferroptosis Therapy and Chemotherapy.
  19. Folic Acid-Functionalized Carbon Dot-Enabled Starvation Therapy in Synergism with Paclitaxel against Breast Cancer.
  20. Crossing the Blood-Brain Barrier: Advances in Nanoparticle Technology for Drug Delivery in Neuro-Oncology.
  21. Exosome-based nanomedicine for cancer treatment by targeting inflammatory pathways: Current status and future perspectives.
  22. The development of a redox-sensitive curcumin conjugated chitosan oligosaccharide nanocarrier for the efficient delivery of docetaxel to glioma cells.
  23. Formulation and Evaluation of Apigenin-Loaded Hybrid Nanoparticles.
  24. Estrone-targeted PEGylated Liposomal Nanoparticles for Cisplatin (DDP) Delivery in Cervical Cancer.
  25. Leukemia inhibitory factor drives glucose metabolic reprogramming to promote breast tumorigenesis.
  26. β-Lactoglobulin-Modified Mesoporous Silica Nanoparticles: A Promising Carrier for the Targeted Delivery of Fenbendazole into Prostate Cancer Cells.
  27. Combinatorial epigenetic mechanisms of sulforaphane, genistein and sodium butyrate in breast cancer inhibition.
  28. Unique Properties of Surface-Functionalized Nanoparticles for Bio-Application: Functionalization Mechanisms and Importance in Application.
  29. Iron Oxide Nanoparticles-Plant Insignia Synthesis with Favorable Biomedical Activities and Less Toxicity, in the "Era of the-Green": A Systematic Review.
  30. Curcumin and Derivatives in Nanoformulations with Therapeutic Potential on Colorectal Cancer.
  31. Development of a Novel Methotrexate-Loaded Nanoemulsion for Rheumatoid Arthritis Treatment with Site-Specific Targeting Subcutaneous Delivery.
  32. Receptor-Mediated Targeting in Breast Cancer through Solid Lipid Nanoparticles and Its Mechanism.
  33. Mucoadhesive Nanocarriers as a Promising Strategy to Enhance Intracellular Delivery against Oral Cavity Carcinoma.
  34. Deep Tumor Penetrating Gold Nano-Adjuvant for NIR-II-Triggered In Situ Tumor Vaccination.
  35. Phytosterol-Loaded Surface-Tailored Bioactive-Polymer Nanoparticles for Cancer Treatment: Optimization, In Vitro Cell Viability, Antioxidant Activity, and Stability Studies.
  36. Current Advances of Nanomedicines Delivering Arsenic Trioxide for Enhanced Tumor Therapy.
  37. Biomedical applications of metallic nanoparticles in cancer: Current status and future perspectives.
  38. Cell membrane-based biomimetic nanosystems for advanced drug delivery in cancer therapy: A comprehensive review.
  39. Water-Extracted Prunella vulgaris Alleviates Endometriosis by Reducing Aerobic Glycolysis.
  40. Light-Activated Monomethyl Auristatin E Prodrug Nanoparticles for Combinational Photo-Chemotherapy of Pancreatic Cancer.
  41. Effects of Glucose Metabolism, Lipid Metabolism, and Glutamine Metabolism on Tumor Microenvironment and Clinical Implications.
  42. KRAS: A Druggable Target in Colon Cancer Patients.
  43. Chitosan-coated nanostructured lipid carriers for transdermal delivery of tetrahydrocurcumin for breast cancer therapy.
  44. Nanocarriers for Drug Delivery: An Overview with Emphasis on Vitamin D and K Transportation.
  45. Recent development of aptamer conjugated chitosan nanoparticles as cancer therapeutics.
  46. Drug Nanocrystals for Active Tumor-Targeted Drug Delivery.
  47. Natural Bioactive Compounds Targeting Histone Deacetylases in Human Cancers: Recent Updates.
  48. Nutraceutical Concepts and Dextrin-Based Delivery Systems.
  49. Application of Ultrasound Combined with Microbubbles for Cancer Therapy.
  50. Cannabis sativa L. Bioactive Compounds and Their Protective Role in Oxidative Stress and Inflammation.
  51. Bioactive Compounds and Their Derivatives: An Insight into Prospective Phytotherapeutic Approach against Alzheimer's Disease.
  52. Vascular Co-Option and Other Alternative Modalities of Growth of Tumor Vasculature in Glioblastoma.
  53. Molecular Pathways Involved in the Anti-Cancer Activity of Flavonols: A Focus on Myricetin and Kaempferol.
  54. A neutrophil-mediated carrier regulates tumor stemness by inhibiting autophagy to prevent postoperative triple-negative breast cancer recurrence and metastasis.
  55. Nanoliposomes in Cancer Therapy: Marketed Products and Current Clinical Trials.
  56. Insight into the cellular interactions and molecular mechanisms of ketogenic diet for comprehensive management of epilepsy.
  57. Recent Advances in the Treatment of Alzheimer's Disease Using Nanoparticle-Based Drug Delivery Systems.
  58. Role of Plant-Derived Active Constituents in Cancer Treatment and Their Mechanisms of Action.
  59. Advancements in cell membrane camouflaged nanoparticles: A bioinspired platform for cancer therapy.
  60. Resveratrol Augments Doxorubicin and Cisplatin Chemotherapy: A Novel Therapeutic Strategy.
  61. Cruciferous Vegetables and Their Bioactive Metabolites: from Prevention to Novel Therapies of Colorectal Cancer.
  62. Using Chitosan-Coated Polymeric Nanoparticles-Thermosensitive Hydrogels in association with Limonene as Skin Drug Delivery Strategy.
  63. Drug delivery through nanoparticles in solid tumors: a mechanistic understanding.
  64. Antiosteoporosis Effects, Pharmacokinetics, and Drug Delivery Systems of Icaritin: Advances and Prospects.
  65. Reprogramming of Fatty Acid Metabolism in Gynaecological Cancers: Is There a Role for Oestradiol?
  66. Evening Primrose Oil Improves Chemotherapeutic Effects in Human Pancreatic Ductal Adenocarcinoma Cell Lines-A Preclinical Study.
  67. Cannabis Biomolecule Effects on Cancer Cells and Cancer Stem Cells: Cytotoxic, Anti-Proliferative, and Anti-Migratory Activities.
  68. Tumor Glucose and Fatty Acid Metabolism in the Context of Anthracycline and Taxane-Based (Neo)Adjuvant Chemotherapy in Breast Carcinomas.
  69. Self-Assembled Nanomicellar Formulation of Docetaxel as a Potential Breast Cancer Chemotherapeutic System.
  70. Liposomal Drug Delivery And Its Potential Impact On Cancer Research.
  71. A Flavonoid on the Brain: Quercetin as a Potential Therapeutic Agent in Central Nervous System Disorders.
  72. 3D-Printable Oxygen- and Drug-Carrying Nanocomposite Hydrogels for Enhanced Cell Viability.
  73. Tailored protein-conjugated DNA nanoplatform for synergistic cancer therapy.
  74. CD44-Targeted Nanocarrier for Cancer Therapy.
  75. Health Benefits of Quercetin in Age-Related Diseases.
  76. Caspase-3 mediated switch therapy of self-triggered and long-acting prodrugs for metastatic TNBC.
  77. Carbon Nanotubes-Based Assays for Cancer Detection and Screening.
  78. pH/reduction dual-responsive hyaluronic acid-podophyllotoxin prodrug micelles for tumor targeted delivery.
  79. The Result of Vitamin C Treatment of Patients with Cancer: Conditions Influencing the Effectiveness.
  80. Emerging Fabrication Strategies of Hydrogels and Its Applications.
  81. A review of the ethnomedicinal uses, chemistry, and pharmacological properties of the genus Acanthus (Acanthaceae).
  82. Molecular Switches-Tools for Imparting Control in Drug Delivery Systems.
  83. Physiological Effects and Human Health Benefits of Hibiscus sabdariffa: A Review of Clinical Trials.
  84. Repurposing disulfiram as a chemo-therapeutic sensitizer: molecular targets and mechanisms.
  85. Delivery of Molecules Using Nanoscale Systems for Cancer Treatment and/or Diagnosis.
  86. Effect of Solvents, Stabilizers and the Concentration of Stabilizers on the Physical Properties of Poly(d,l-lactide-co-glycolide) Nanoparticles: Encapsulation, In Vitro Release of Indomethacin and Cytotoxicity against HepG2-Cell.
  87. Carbohydrates Used in Polymeric Systems for Drug Delivery: From Structures to Applications.
  88. Metabolic Vulnerabilities in Multiple Myeloma.
  89. Does a Hypertrophying Muscle Fibre Reprogramme its Metabolism Similar to a Cancer Cell?
  90. Nanocarrier Drug Delivery Systems: Characterization, Limitations, Future Perspectives and Implementation of Artificial Intelligence.
  91. Anchoring β-CD on simvastatin-loaded rHDL for selective cholesterol crystals dissolution and enhanced anti-inflammatory effects in macrophage/foam cells.
  92. Evening Primrose Oil Enhances Tamoxifen's Anticancer Activity against Breast Cancer Cells by Inducing Apoptosis, Inhibiting Angiogenesis, and Arresting the Cell Cycle.
  93. Interactions between Nanoparticles and Intestine.
  94. Recent literature review on Coumarin hybrids as potential anti-cancer agents.
  95. Advances of podophyllotoxin and its derivatives: patterns and mechanisms.
  96. Oxygen and Drug-Carrying Periodic Mesoporous Organosilicas for Enhanced Cell Viability under Normoxic and Hypoxic Conditions.
  97. Making waves: how ultrasound-targeted drug delivery is changing pharmaceutical approaches.
  98. Niosomal Nanocarriers for Enhanced Dermal Delivery of Epigallocatechin Gallate for Protection against Oxidative Stress of the Skin.
  99. Applications of Metal-Organic Frameworks as Drug Delivery Systems.
  100. Ionic Liquids: Promising Approach for Oral Drug Delivery.
  101. Microbial torularhodin - a comprehensive review.
  102. Bacterial cellulose as a potential biopolymer in biomedical applications: a state-of-the-art review.
  103. Photothermal-enhanced antibacterial and antioxidant hydrogel dressings based on catechol-modified chitosan-derived carbonized polymer dots for effective treatment of wound infections.
  104. In situ injectable nano-complexed hydrogel based on chitosan/dextran for combining tumor therapy via hypoxia alleviation and TAMs polarity regulation.
  105. Solid dispersion technology as a formulation strategy for the fabrication of modified release dosage forms: A comprehensive review.
  106. Energetic metabolic reprogramming in Jurkat DFF40-deficient cancer cells.
  107. Egg Allergy in Children and Weaning Diet.
  108. Hyaluronic acid functionalization improves dermal targeting of polymeric nanoparticles for management of burn wounds: In vitro, ex vivo and in vivo evaluations.
  109. Tailoring of Selenium-Plated Novasomes for Fine-Tuning Pharmacokinetic and Tumor Uptake of Quercetin: In Vitro Optimization and In Vivo Radiobiodistribution Assessment in Ehrlich Tumor-Bearing Mice.
  110. Recent Advances in the Antiproliferative and Proapoptotic Activity of Various Plant Extracts and Constituents against Murine Malignant Melanoma.
  111. Targeting pancreatic cancer with combinatorial treatment of CPI-613 and inhibitors of lactate metabolism.
  112. Phytoplankton Toxins and Their Potential Therapeutic Applications: A Journey toward the Quest for Potent Pharmaceuticals.
  113. Dietary behavior and urinary gallic acid concentration differences among underserved elder racial and ethnic minorities in New York City.
  114. Extracellular Vesicle-Mediated Mitochondrial Reprogramming in Cancer.
  115. Application of γ-Cyclodextrin-lysozyme as host materials for encapsulation of curcumin: characterization, stability and controlled release properties.
  116. How Did Conventional Nanoparticle-Mediated Photothermal Therapy Become "Hot" in Combination with Cancer Immunotherapy?
  117. Development of Astaxanthin-Loaded Nanosized Liposomal Formulation to Improve Bone Health.
  118. Emerging Albumin-Binding Anticancer Drugs for Tumor-Targeted Drug Delivery: Current Understandings and Clinical Translation.
  119. Transdermal Glipizide Delivery System Based on Chitosan-Coated Deformable Liposomes: Development, Ex Vivo, and In Vivo Studies.
  120. Dual Responsive poly(vinyl caprolactam)-Based Nanogels for Tunable Intracellular Doxorubicin Delivery in Cancer Cells.
  121. Polymerized β-Cyclodextrin-Based Injectable Hydrogel for Sustained Release of 5-Fluorouracil/Methotrexate Mixture in Breast Cancer Management: In Vitro and In Vivo Analytical Validations.
  122. Drug Repurposing in Cancer Therapy: Influence of Patient's Genetic Background in Breast Cancer Treatment.
  123. Ferroptosis in plants: regulation of lipid peroxidation and redox status.
  1. Colloids Surf B Biointerfaces. 2022 Mar 26. pii: S0927-7765(22)00164-3. [Epub ahead of print]215 112481
    Recent advances in nanogold as a promising nanocarrier for curcumin delivery.
    Ali Mahmoudi, Prashant Kesharwani, Muhammed Majeed, Yong Teng, Amirhossein Sahebkar.
      Curcumin is a natural polyphenolic compound that has promising therapeutic benefits. However, curcumin suffers from low aqueous solubility and poor bioavailability following oral administration, which are severe constraints to its full therapeutic potential. An exciting approach to resolving such challenges has been to incorporate curcumin into gold nanoparticles (AuNPs) to improve its unfavorable physicochemical and biopharmaceutical properties. Growing evidence shows that AuNPs increase cytotoxicity and apoptotic effect of curcumin on cancer cells. Moreover, AuNPs has the potential to enhance curcumin's cellular uptake and antioxidant properties. In addition, numerous benefits have been suggested for exploiting the curcumin's gold (Au) NPs as simple preparation and functionalization. Therefore, we can take advantage of the nanogold combination with curcumin in several therapeutic methods like photothermal therapy and theranostic nanocarrier. Here, we focus on the therapeutic properties of Au/curcumin NPs and the way to improve biocompatibility and bioavailability for curcumin encapsulation, intending to enhance their anticancer and antioxidant capacities. The present review also discusses the utilization and impact of Au NPs as a drug/gene delivery system/platform and various methods for the synthesis of Au/curcumin NPs.
    Keywords:  Bioavailability; Curcumin; Drug delivery; Gold nanoparticles; Solubility
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112481
  2. Front Genet. 2022 ;13 849040
    Therapeutic Targeting Hypoxia-Inducible Factor (HIF-1) in Cancer: Cutting Gordian Knot of Cancer Cell Metabolism.
    Abhilasha Sharma, Sonam Sinha, Neeta Shrivastava.
      Metabolic alterations are one of the hallmarks of cancer, which has recently gained great attention. Increased glucose absorption and lactate secretion in cancer cells are characterized by the Warburg effect, which is caused by the metabolic changes in the tumor tissue. Cancer cells switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis due to changes in glucose degradation mechanisms, a process known as "metabolic reprogramming". As a result, proteins involved in mediating the altered metabolic pathways identified in cancer cells pose novel therapeutic targets. Hypoxic tumor microenvironment (HTM) is anticipated to trigger and promote metabolic alterations, oncogene activation, epithelial-mesenchymal transition, and drug resistance, all of which are hallmarks of aggressive cancer behaviour. Angiogenesis, erythropoiesis, glycolysis regulation, glucose transport, acidosis regulators have all been orchestrated through the activation and stability of a transcription factor termed hypoxia-inducible factor-1 (HIF-1), hence altering crucial Warburg effect activities. Therefore, targeting HIF-1 as a cancer therapy seems like an extremely rational approach as it is directly involved in the shift of cancer tissue. In this mini-review, we present a brief overview of the function of HIF-1 in hypoxic glycolysis with a particular focus on novel therapeutic strategies currently available.
    Keywords:  cancer; cancer therapies; clinical outcomes; genomic alterations; hypoxia-induced tumor microenvironment; metabolic reprogramming; metabolism; warburg effect
    DOI:  https://doi.org/10.3389/fgene.2022.849040
  3. Methods Appl Fluoresc. 2022 Apr 21.
    Recent Advances in Near Infrared Upconverting Nanomaterials for Targeted Photodynamic Therapy of Cancer.
    Carla Arnau Del Valle, Thomas Hirsch, Maria Marin.
      Photodynamic therapy (PDT) is a well-established treatment of cancer that uses the toxic reactive oxygen species, including singlet oxygen (1O2), generated by photosensitiser drugs following irradiation of a specific wavelength to destroy the cancerous cells and tumours. Visible light is commonly used as the excitation source in PDT, which is not ideal for cancer treatment due to its reduced tissue penetration, and thus inefficiency to treat deep-lying tumours. Additionally, these wavelengths exhibit elevated autofluorescence background from the biological tissues which hinders optical biomedical imaging. An alternative to UV-Vis irradiation is the use of near infrared (NIR) excitation for PDT. This can be achieved using upconverting nanoparticles (UCNPs) functionalised with photosensitiser (PS) drugs where UCNPs can be used as an indirect excitation source for the activation of PS drugs yielding to the production of singlet 1O2 following NIR excitation. The use of nanoparticles for PDT is also beneficial due to their tumour targeting capability, either passively via the enhanced permeability and retention (EPR) effect or actively via stimuli-responsive targeting and ligand-mediated targeting (ie. using recognition units that can bind specific receptors only present or overexpressed on tumour cells). Here, we review recent advances in NIR upconverting nanomaterials for PDT of cancer with a clear distinction between those reported nanoparticles that could potentially target the tumour due to accumulation via the EPR effect (passive targeting) and nanoparticle-based systems that contain targeting agents with the aim of actively target the tumour via a molecular recognition process.
    Keywords:  cancer; near infrared; photodynamic therapy; targeting agents; upconverting nanoparticles
    DOI:  https://doi.org/10.1088/2050-6120/ac6937
  4. J Nanobiotechnology. 2022 Apr 20. 20(1): 194
    Delivery of triptolide: a combination of traditional Chinese medicine and nanomedicine.
    Rui Sun, Jingyue Dai, Mingjian Ling, Ling Yu, Zhiqiang Yu, Longguang Tang.
      As a natural product with various biological activities, triptolide (TP) has been reported in anti-inflammatory, anti-tumor and anti-autoimmune studies. However, the narrow therapeutic window, poor water solubility, and fast metabolism limit its wide clinical application. To reduce its adverse effects and enhance its efficacy, research and design of targeted drug delivery systems (TDDS) based on nanomaterials is one of the most viable strategies at present. This review summarizes the reports and studies of TDDS combined with TP in recent years, including passive and active targeting of drug delivery systems, and specific delivery system strategies such as polymeric micelles, solid lipid nanoparticles, liposomes, and stimulus-responsive polymer nanoparticles. The reviewed literature presented herein indicates that TDDS is a multifunctional and efficient method for the delivery of TP. In addition, the advantages and disadvantages of TDDS are sorted out, aiming to provide reference for the combination of traditional Chinese medicine and advanced nano drug delivery systems (NDDS) in the future.
    Keywords:  Active targeting; Nanomedicine; Passive targeting; Stimuli-responsive targeting; Traditional Chinese medicine; Triptolide
    DOI:  https://doi.org/10.1186/s12951-022-01389-7
  5. Int J Mol Sci. 2022 Apr 13. pii: 4279. [Epub ahead of print]23(8):
    Photodynamic Therapy of Up-Conversion Nanomaterial Doped with Gold Nanoparticles.
    Wei Zhang, Yang Zang, Yanli Lu, Jinghui Han, Qingyun Xiong, Jinping Xiong.
      Two key concerns exist in contemporary cancer chemotherapy: limited therapeutic efficiency and substantial side effects in patients. In recent years, researchers have been investigating the revolutionary cancer treatment techniques of photodynamic therapy (PDT) and photothermal therapy (PTT) proposed by many scholars. A photothermal treatment of cancer was synthesized using the hydrothermal method which has high photothermal conversion efficiency and can generate reactive oxygen species (ROS) in cells. Photothermal treatment of tumors has a good short-term effect and photodynamic therapy lasts longer. However, both PTT and PDT have their inevitable shortcomings and it is difficult to completely eradicate a tumor using a single mode of treatment. PTT and PDT synergistic treatment not only inherits the advantages of low toxicity and side effects of phototherapy but also enables the two treatment methods to complement each other. It is an effective strategy to improve curative effects and reduce toxic and side effects. Furthermore, gold doped UCNPs have an exceptionally high target recognition for tumor cells. The gold doped UCNPs, in particular, are non-toxic to normal tissues, endowing the as-prepared medications with outstanding therapeutic efficacy and exceptionally low side effects. These findings may encourage the creation of fresh, effective imaging-guided approaches to meet the goal of photothermal cancer therapy.
    Keywords:  nanomaterials; photodynamic; photothermal; up-conversion
    DOI:  https://doi.org/10.3390/ijms23084279
  6. Biosensors (Basel). 2022 Apr 18. pii: 255. [Epub ahead of print]12(4):
    Application of Self-Assembly Nanoparticles Based on DVDMS for Fenton-Like Ion Delivery and Enhanced Sonodynamic Therapy.
    Jinqiang Liu, Shiying Fu, Jiaxuan Xie, Jianzhong Zhang, Jintao Pan, Chengchao Chu, Gang Liu, Shenghong Ju.
      Upon harnessing low-intensity ultrasound to activate sonosensitizers, sonodynamic therapy (SDT) induces cancer cell death through the reactive oxygen species (ROS) mediated pathway. Compared with photodynamic therapy (PDT), SDT possesses numerous advantages, including deeper tissue penetration, higher accuracy, fewer side effects, and better patient compliance. Sinoporphyrin sodium (DVDMS), a sonosensitizer approved by the FDA, has drawn abundant attention in clinical research, but there are some deficiencies. In order to further improve the efficiency of DVDMS, many studies have applied self-assembly nanotechnology to modify it. Furthermore, the combined applications of SDT/chemodynamic therapy (CDT) have become a research hotspot in tumor therapy. Therefore, we explored the self-assembly of nanoparticles based on DVDMS and copper to combine SDT and CDT. A cost-effective sonosensitizer was synthesized by dropping CuCl2 into the DVDMS solution with the assistance of PVP. The results revealed that the nanostructures could exert excellent treatment effects on tumor therapy and perform well for PET imaging, indicating the potential for cancer theranostics. In vitro and in vivo experiments showed that the nanoparticles have outstanding biocompatibility, higher ROS production efficiency, and antitumor efficacy. We believe this design can represent a simple approach to combining SDT and CDT with potential applications in clinical treatment and PET imaging.
    Keywords:  DVDMS; chemodynamic therapy; self-assembly; sonodynamic therapy; theranostics
    DOI:  https://doi.org/10.3390/bios12040255
  7. Recent Pat Anticancer Drug Discov. 2022 Apr 20.
    Recent patents on plant derived nanoparticles and their potential application towards various cancer therapeutics.
    S B Santhosh, Santny Shanmugarama, Nimma Ramesh, A Mohamed Sheik Tharik, Veera Vijaya Basamshetty.
      BACKGROUND: Nanotechnology plays a vital role in the field of medicine. Especially various nanoparticles such as silver, gold, platinum were involved in the treatment of different type of cancer. The effective nanoparticles were synthesized using techniques like chemical, physical, electrochemical and biological methods. In order to overcome the limitations existing in the synthesis of nanoparticles, researchers turned their attention towards the biological single step nanoparticle synthesis method by using plant and plant products.OBJECTIVE: To overcome the side effects encountered in the existing anti cancer agents like non specificity and fast excretion, plant derived nanoparticles that are ecofriendly, cost effective and biologically active could serve as a promising alternative.
    CONCLUSION: From the thorough literature review and recent patents, it is understood that the plant derived nanoparticles exhibited an excellent anti proliferation, anti tumor activity towards different types of cancers without affecting the normal cells. Especially, the traditional chemotherapeutic drugs obtained from the plant source incorporated with the nanoparticles shows remarkable results against anti cancer studies. The present review focused on some of the existing herbal plant derived nanoparticles, formulations and its potential application towards cancer therapeutics.
    Keywords:  Herbal plants; anticancer; cytotoxicity.; nanoparticles; patents; treatments
    DOI:  https://doi.org/10.2174/1574892817666220420122426
  8. Biomaterials. 2022 Apr 08. pii: S0142-9612(22)00134-X. [Epub ahead of print]284 121495
    Iron phthalocyanine-derived nanozyme as dual reactive oxygen species generation accelerator for photothermally enhanced tumor catalytic therapy.
    Fuchun Nan, Qingyan Jia, Xiaokuang Xue, Shuai Wang, Weimin Liu, Jian Wang, Jiechao Ge, Pengfei Wang.
      Nanozymes are artificial enzymes that mimic natural enzyme-like activities and show great promise for tumor catalytic therapy. However, new nanozymes with multiple catalytic activities for multifunctional nanotheranostic use remain challenging to design. Herein, for the first time, iron phthalocyanine (Fe(II)Pc) was assembled with poly(l-lactide-co-glycolide)-block-poly(ethylene glycol) to prepare an Fe(II)Pc assembly (denoted as Fe(II)Pc-A). The obtained Fe(II)Pc-A could be applied as a smart near-infrared (NIR) light-responsive nanotheranostic for simultaneous photoacoustic imaging-guided photothermal therapy. Notably, Fe(II)Pc-A possessed peroxidase, catalase, and oxidase mimicking activities, which could not only catalyze the conversion of intratumoral H2O2 to •OH, but also degrade H2O2 to generate O2 and continuously catalyze the conversion of O2 to cytotoxic O2•-. Impressively, the dual reactive oxygen species (ROS) generation of Fe(II)Pc-A was further remarkably enhanced by the endogenous acidity of the tumor microenvironment and the exogenous NIR light-responsive photothermal effect. Moreover, the O2 self-supplying ability of Fe(II)Pc-A led to increased generation of O2•- for enhancing catalytic therapy in hypoxic tumor. These collective properties of Fe(II)Pc-A nanozyme enabled it to be a dual ROS generation accelerator for photothermally enhanced tumor catalytic therapy. Thus, a new type of high-performance nanozyme for multifunctional nanotheranostic use toward cancer was presented.
    Keywords:  Hypoxia relieving; Nanozymes; Photothermal therapy; Reactive oxygen species; Tumor catalytic therapy
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121495
  9. Biomed Phys Eng Express. 2022 Apr 19.
    Drug-delivery nanoparticles for bone-tissue and dental applications.
    Taisa Higino, Rodrigo França.
      The use of nanoparticles as biomaterials with applications in the biomedical field is growing every day. These nanomaterials can be used as contrast imaging agents, combination therapy agents, and targeted delivery systems in medicine and dentistry. Usually, nanoparticles are found as synthetic or natural organic materials, such as hydroxyapatite, polymers, and lipids. Besides that, they are could also be inorganic, for instance, metallic or metal-oxide-based particles. These inorganic nanoparticles could additionally present magnetic properties, such as superparamagnetic iron oxide nanoparticles. The use of nanoparticles as drug delivery agents has many advantages, for they help diminish toxicity effects in the body since the drug dose reduces significantly, increases drugs biocompatibility, and helps target drugs to specific organs. As targeted-delivery agents, one of the applications uses nanoparticles as drug delivery particles for bone-tissue to treat cancer, osteoporosis, bone diseases, and dental treatments such as periodontitis. Their application as drug delivery agents requires a good comprehension of the nanoparticle properties and composition, alongside their synthesis and drug attachment characteristics. Properties such as size, shape, core-shell designs, and magnetic characteristics can influence their behavior inside the human body and modify magnetic properties in the case of magnetic nanoparticles. Based on that, many different studies have modified the synthesis methods for these nanoparticles and developed composite systems for therapeutics delivery, adapting, and improving magnetic properties, shell-core designs, and particle size and nanosystems characteristics. This review presents the most recent studies that have been presented with different nanoparticle types and structures for bone and dental drug delivery.
    Keywords:  Biomaterials; Bone treatment materials; Dental Materials; Nanoparticles; Nanosystems
    DOI:  https://doi.org/10.1088/2057-1976/ac682c
  10. Nanomaterials (Basel). 2022 Apr 14. pii: 1348. [Epub ahead of print]12(8):
    Near-Infrared Light-Triggered Nitric Oxide Nanogenerators for NO-Photothermal Synergistic Cancer Therapy.
    Weiwei Liu, Farouk Semcheddine, Zengchao Guo, Hui Jiang, Xuemei Wang.
      Cancer is still one of the major health issues faced by human beings today. Various nanomaterials have been designed to treat tumors and have made great progress. Herein, we used amino-functionalized metal organic framework (UiO-66-NH2) as superior templates and successfully synthesized the UiO-66-NH2@Aushell composite nanoparticles (UA) with high loading capacity and excellent photothermal properties through a simple and gentle method. In addition, due to the rich pore structure and excellent biocompatibility of the as-prepared composite nanoparticles, the hydrophobic NO donor BNN6 (N,N'-Di-sec-butyl-N,N'-dinitroso-1, 4-phenylenediamine) molecule was efficiently delivered. Based on the phenomenon where BNN6 molecules can decompose and release NO at high temperature, when UiO-66-NH2@Aushell-BNN6 composite nanoparticles (UA-BNN6) entered tumor cells and were irradiated by NIR, the porous gold nanoshells on the surface of composite nanoparticles induced an increase in temperature through the photothermal conversion process and promoted the decomposition of BNN6 molecules, releasing high concentration of NO, thus efficiently killing HeLa cells through the synergistic effect of NO-photothermal therapy. This effective, precise and safe treatment strategy controlled by NIR laser irradiation represents a promising alternative in the field of cancer treatment.
    Keywords:  BNN6; MOF; NO-photothermal therapy; gold nanoshells
    DOI:  https://doi.org/10.3390/nano12081348
  11. Pol Merkur Lekarski. 2022 Apr 19. 50(296): 145-147
    [Anti-cancer properties of dichloroacetate].
    Małgorzata Latocha, Luiza Żyrek.
      One of the hallmarks of cancer cells is aerobic glycolysis (the Warburg effect). The effect of dichloroacetate (DCA) is to switch glucose metabolism (cellular respiration) to a more efficient process involving oxygen, reduce the production of lactic acid, activate the respiratory chain, change the potential of the mitochondrial membrane, and release pro-apoptotic mediators (cytochrome c and AIF) into the cytosol. As a result, the control over the mutated cells is improved, their sensitivity to various drugs or radiotherapy and their sensitivity to apoptosis increase. In the study the review of data on the mechanism of action of DCA on neoplastic cells was performed to indicate the side effects associated with the possible introduction of this compound to cancer therapy.
    Keywords:  cancer; dichloroacetate
  12. Environ Sci Pollut Res Int. 2022 Apr 20.
    Multiple health benefits of curcumin and its therapeutic potential.
    Muddaser Shah, Waheed Murad, Sidra Mubin, Obaid Ullah, Najeeb Ur Rehman, Md Habibur Rahman.
      Turmeric, or Curcuma longa as it is formally named, is a multifunctional plant with numerous names. It was dubbed "the golden spice" and "Indian saffron" not only for its magnificent yellow color, but also for its culinary use. Turmeric has been utilized in traditional medicine since the dawn of mankind. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin, which are all curcuminoids, make up turmeric. Although there have been significant advancements in cancer treatment, cancer death and incidence rates remain high. As a result, there is an increasing interest in discovering more effective and less hazardous cancer treatments. Curcumin is being researched for its anti-inflammatory, anti-cancer, anti-metabolic syndrome, neuroprotective, and antibacterial properties. Turmeric has long been used as a home remedy for coughs, sore throats, and other respiratory problems. As a result, turmeric and its compounds have the potential to be used in modern medicine to cure a variety of diseases. In this current review, we highlighted therapeutic potential of curcumin and its multiple health benefits on various diseases.
    Keywords:  Anti-cancer; Antimicrobial properties; Curcuma longa; Health benefits; Neuroprotective activity; Therapeutic potential
    DOI:  https://doi.org/10.1007/s11356-022-20137-w
  13. Chembiochem. 2022 Apr 19.
    Combination of Immunotherapy and Photo-Pyroptosis as Novel Anticancer Strategy.
    Anyi Dao, Ashish Kumar Yadav, Li Wei, Samya Banerjee, Huaiyi Huang.
      Immunotherapy has made great progress in clinical cancer treatment in recent years, but the therapeutic efficacy was significantly limited by the lack of immunogenicity in the tumor microenvironment. Pyroptosis is a kind of programmed cell death in which the dying cancer cells produce inflammatory cytokines to relieve immuno-suppressive microenvironment and thus increase anti-tumor immunity. Reactive oxygen species (ROS) produced during photodynamic therapy (PDT) is one of the efficient activators to induce pyroptosis. Recently, a few photosensitizers have emerged with the ability to induce immunogenic cancer cell death via pyroptosis, opening up a new field for PDT. This highlight introduces the latest research on anti-tumor strategies achieved by the combination of immunotherapy and photodynamic therapy through photo-pyroptosis.
    Keywords:  Anticancer strategy; Immunotherapy; Photo-pyroptosis; Photodynamic therapy
    DOI:  https://doi.org/10.1002/cbic.202200201
  14. Int J Mol Sci. 2022 Apr 15. pii: 4385. [Epub ahead of print]23(8):
    Natural Products for the Prevention and Treatment of Oral Mucositis-A Review.
    Ana Sofia Ferreira, Catarina Macedo, Ana Margarida Silva, Cristina Delerue-Matos, Paulo Costa, Francisca Rodrigues.
      Cancer, a major world public health problem, is associated with chemotherapy treatments whose administration leads to secondary concerns, such as oral mucositis (OM). The OM disorder is characterized by the presence of ulcers in the oral mucosa that cause pain, bleeding, and difficulty in ingesting fluids and solids, or speaking. Bioactive compounds from natural sources have arisen as an effective approach for OM. This review aims to summarize the new potential application of different natural products in the prevention and treatment of OM in comparison to conventional ones, also providing a deep insight into the most recent clinical studies. Natural products, such as Aloe vera, Glycyrrhiza glabra, Camellia sinensis, Calendula officinalis, or honeybee crops, constitute examples of sources of bioactive compounds with pharmacological interest due to their well-reported activities (e.g., antimicrobial, antiviral, anti-inflammatory, analgesic, or wound healing). These activities are associated with the bioactive compounds present in their matrix (such as flavonoids), which are associated with in vivo biological activities and minimal or absent toxicity. Finally, encapsulation has arisen as a future opportunity to preserve the chemical stability and the drug bioa vailability of bioactive compounds and, most importantly, to improve the buccal retention period and the therapeutic effects.
    Keywords:  cancer; drug delivery; natural products; oral mucositis; treatment
    DOI:  https://doi.org/10.3390/ijms23084385
  15. Antioxidants (Basel). 2022 Mar 24. pii: 625. [Epub ahead of print]11(4):
    Hyperthermia Treatment as a Promising Anti-Cancer Strategy: Therapeutic Targets, Perspective Mechanisms and Synergistic Combinations in Experimental Approaches.
    Ga Yeong Yi, Min Ju Kim, Hyo In Kim, Jinbong Park, Seung Ho Baek.
      Despite recent developments in diagnosis and treatment options, cancer remains one of the most critical threats to health. Several anti-cancer therapies have been identified, but further research is needed to provide more treatment options that are safe and effective for cancer. Hyperthermia (HT) is a promising treatment strategy for cancer because of its safety and cost-effectiveness. This review summarizes studies on the anti-cancer effects of HT and the detailed mechanisms. In addition, combination therapies with anti-cancer drugs or natural products that can effectively overcome the limitations of HT are reviewed because HT may trigger protective events, such as an increase of heat shock proteins (HSPs). In the 115 reports included, the mechanisms related to apoptosis, cell cycle, reactive oxygen species, mitochondrial membrane potential, DNA damage, transcription factors and HSPs were considered important. This review shows that HT is an effective inducer of apoptosis. Moreover, the limitations of HT may be overcome using combined therapy with anti-cancer drugs or natural products. Therefore, appropriate combinations of such agents with HT will exert maximal effects to treat cancer.
    Keywords:  cancer; chemotherapy; combination therapy; heat shock protein; hyperthermia; natural product; reactive oxygen species; synergistic effect
    DOI:  https://doi.org/10.3390/antiox11040625
  16. Curr Drug Deliv. 2022 Apr 14.
    Synthesis and Characterization of Curcumin Incorporated Multi component Nano-Scaffold with Enhanced Anti-bacterial and Wound Healing Properties.
    Yi-Ying Wu, Ramya Kumar, Chi-Cheng Wong, Desu Naveen Kumar Reddy, Fu-Yung Huang.
      BACKGROUND: Wound healing is one of the major challenges in chronic diseases, the current treatment options are less effective with undesirable side effects, and are expensive. Extensive research is carried out to develop cost-effective, natural, biodegradable wound dressings that can reduce oxidative stress, inflammation and prevent bacterial infections. Curcumin has a plethora of therapeutic applications; however, its low solubility limits its clinical use.OBJECTIVE: In this study, curcumin nanoparticles (Cur NP) and curcumin-chitosan nanoparticles (CCNP) were incorporated into the chitosan collagen vanillin scaffold, characterized and investigated their potential wound healing properties.
    METHOD: The nano-scaffolds were prepared by freeze-drying method and were characterized using Fourier transform infrared spectroscopy, X-ray diffraction, nanoparticle tracking analysis, and scanning electron microscopy. The drug release, antioxidant, antibacterial, and wound healing properties were assessed by in vitro assays.
    RESULTS: Cur nano-scaffolds showed particle size of 195.9 nm and 110.6 nm for Cur NP+VC and CCNP+VC respectively. The curcumin encapsulated in the Cur NP+VC and CC+VC nano-scaffolds showed a release profile of > 60% and an improved antioxidant activity of greater than 80%. The nano-scaffolds were antagonistic against Escherichia coli and Staphylococcus aureus, and likewise enhanced wound healing capacity of 85.62 % and 77.05% was observed in murine cell line.
    CONCLUSION: The curcumin nano-scaffold is a biodegradable and effective drug delivery system for topical use that can act as an antioxidant, facilitate wound healing, as well as prevent bacterial infections.
    Keywords:  Curcumin; E. coli.; NIH/3T3; S. aureus; collagen; nanoparticle; vanillin
    DOI:  https://doi.org/10.2174/1567201819666220414092342
  17. Eur J Cell Biol. 2022 Apr 13. pii: S0171-9335(22)00028-0. [Epub ahead of print]101(3): 151225
    Mitochondrial and metabolic alterations in cancer cells.
    Jacopo Di Gregorio, Sabrina Petricca, Roberto Iorio, Elena Toniato, Vincenzo Flati.
      Metabolic alterations have been observed in many cancer types. The deregulated metabolism has thus become an emerging hallmark of the disease, where the metabolism is frequently rewired to aerobic glycolysis. This has led to the concept of "metabolic reprogramming", which has therefore been extensively studied. Over the years, it has been characterized the enhancement of aerobic glycolysis, where key mutations in some of the enzymes of the TCA cycle, and the increased glucose uptake, are used by cancer cells to achieve a "metabolic phenotype" useful to gain a proliferation advantage. Many studies have highlighted in detail the signaling pathways and the molecular mechanisms responsible for the glycolytic switch. However, glycolysis is not the only metabolic process that cancer cells rely on. Oxidative Phosphorylation (OXPHOS), gluconeogenesis or the beta-oxidation of fatty acids (FAO) may be involved in the development and progression of several tumors. In some cases, these metabolisms are even more crucial than aerobic glycolysis for the tumor survival. This review will focus on the contribution of these alterations of metabolism to the development and survival of cancers. We will also analyze the molecular mechanisms by which the balance between these metabolic processes may be regulated, as well as some of the therapeutical approaches that can derive from their study.
    Keywords:  Amino acids; Cancer; Fatty acids; Metabolism; Mitochondria; OXPHOS
    DOI:  https://doi.org/10.1016/j.ejcb.2022.151225
  18. Small. 2022 Apr 22. e2200330
    Cyclodextrin-Derived ROS-Generating Nanomedicine with pH-Modulated Degradability to Enhance Tumor Ferroptosis Therapy and Chemotherapy.
    Meng Xu, Haidong Zha, Run Han, Yaxin Cheng, Jiamao Chen, Ludan Yue, Ruibing Wang, Ying Zheng.
      Nowadays, destruction of redox homeostasis to induce cancer cell death is an emerging anti-cancer strategy. Here, the authors utilized pH-sensitive acetalated β-cyclodextrin (Ac-β-CD) to efficiently deliver dihydroartemisinin (DHA) for tumor ferroptosis therapy and chemodynamic therapy in a synergistic manner. The Ac-β-CD-DHA based nanoparticles are coated by an iron-containing polyphenol network. In response to the tumor microenvironment, Fe2+ /Fe3+ can consume glutathione (GSH) and trigger the Fenton reaction in the presence of hydrogen peroxide (H2 O2 ), leading to the generation of lethal reactive oxygen species (ROS). Meanwhile, the OO bridge bonds of DHA are also disintegrated to enable ferroptosis of cancer cells. Their results demonstrate that these nanoparticles acted as a ROS generator to break the redox balance of cancer cells, showing an effective anticancer efficacy, which is different from traditional approaches.
    Keywords:  chemotherapy; dihydroartemisinin; ferroptosis therapy; metal-polyphenol network; β-cyclodextrin
    DOI:  https://doi.org/10.1002/smll.202200330
  19. ACS Appl Bio Mater. 2022 Apr 22.
    Folic Acid-Functionalized Carbon Dot-Enabled Starvation Therapy in Synergism with Paclitaxel against Breast Cancer.
    Aparajita Ghosh, Anup Kumar Ghosh, Monalisa Chowdhury, Prasanta Kumar Das.
      Glucose oxidase (GOx)-induced cancer starvation has recently emerged for halting the abnormal proliferation of triple-negative breast cancer (TNBC). However, monotherapy with GOx or a conventional chemotherapeutic displays suboptimal efficacy in eliminating tumors and poses impending risks to healthy tissues. To augment therapeutic efficacy and tumor selectivity, folic acid (FA)-functionalized carbon dots (CDs) embedded with GOx and paclitaxel (PTX) [FA-CD-(PTX-GOx)] was developed that showed the efficient killing of TNBC, MDA-MB-468 cells over noncancerous HEK 293 cells through synergistic effects of cancer starvation-induced oxidative stress and chemotherapy. The cargo-laden FA-CD complex resulted in a 4-8 fold increase in cancer cell death at 60 μg/mL when compared to standalone therapy with the native compounds and individually loaded cargo on FA-CD. This improved cancer cell killing efficacy of the FA-CD-(PTX-GOx) complex could be endorsed by folate receptor (FR)-mediated target-specific cellular internalization of the FA-CD complex. The antitumorigenic efficacy of the FA-CD-(PTX-GOx) complex was further validated in a three-dimensional (3D) breast tumor spheroid model. A significant 4.5-fold reduction in spheroid dimension along with antiproliferation was observed with time up to 72 h following exposure to the FA-CD-(PTX-GOx) complex. This antitumorigenic potential of FA-CD-(PTX-GOx) could be attributed to the enhanced intratumoral reactive oxygen species generation following glucose depletion by GOx that has been facilitated by the chemotherapeutic efficacy of PTX resulting in the efficient killing of cancer cells. The present study provides a novel strategy of FR-mediated fluorescent CD-enabled combined formulation of GOx and PTX for the target-specific superior killing of TNBC cells in the synergism of glucose starvation with chemotherapy.
    Keywords:  ROS; cancer starvation; carbon dot; folic acid; glucose oxidase; paclitaxel; tumor spheroid
    DOI:  https://doi.org/10.1021/acsabm.2c00235
  20. Int J Mol Sci. 2022 Apr 09. pii: 4153. [Epub ahead of print]23(8):
    Crossing the Blood-Brain Barrier: Advances in Nanoparticle Technology for Drug Delivery in Neuro-Oncology.
    Andrew M Hersh, Safwan Alomari, Betty M Tyler.
      The blood-brain barrier (BBB) constitutes a microvascular network responsible for excluding most drugs from the brain. Treatment of brain tumors is limited by the impermeability of the BBB and, consequently, survival outcomes for malignant brain tumors remain poor. Nanoparticles (NPs) represent a potential solution to improve drug transport to brain tumors, given their small size and capacity to target tumor cells. Here, we review the unique physical and chemical properties of NPs that aid in BBB transport and discuss mechanisms of NP transport across the BBB, including paracellular transport, carrier-mediated transport, and adsorptive- and receptor-mediated transcytosis. The major types of NPs investigated for treatment of brain tumors are detailed, including polymeric NPs, liposomes, solid lipid NPs, dendrimers, metals, quantum dots, and nanogels. In addition to their role in drug delivery, NPs can be used as imaging contrast agents and can be conjugated with imaging probes to assist in visualizing tumors, demarcating lesion boundaries and margins, and monitoring drug delivery and treatment response. Multifunctional NPs can be designed that are capable of targeting tumors for both imaging and therapeutic purposes. Finally, limitations of NPs for brain tumor treatment are discussed.
    Keywords:  blood-brain barrier; drug delivery; nanoparticle; tumor
    DOI:  https://doi.org/10.3390/ijms23084153
  21. Semin Cancer Biol. 2022 Apr 19. pii: S1044-579X(22)00099-2. [Epub ahead of print]
    Exosome-based nanomedicine for cancer treatment by targeting inflammatory pathways: Current status and future perspectives.
    Mohammad Azam Ansari, Muthu Thiruvengadam, Baskar Venkidasamy, Mohammad N Alomary, Abdulmohsin J Alamoudi, Ill-Min Chung, Mohammad Ali Shariati, Maksim Rebezov.
      Cancer is one of the dreadful diseases worldwide. Surgery, radiation and chemotherapy, are the three basic standard modes of cancer treatment. However, difficulties in cancer treatment are increasing due to immune escape, spreading of cancer to other places, and resistance of cancer cells to therapies. Various signaling mechanisms, including PI3K/Akt/mTOR, RAS, WNT/β-catenin, TGF-beta, and notch pathways, are involved in cancer resistance. The adaptive inflammatory response is the initial line of defence against infection. However, chronic inflammation can lead to tumorigenesis, malignant transformation, tumor growth, invasion, and metastasis. The most commonly dysregulated inflammatory pathways linked to cancer include NF-κB, MAPK, JAK-STAT, and PI3K/AKT. To overcome major hurdles in cancer therapy, nanomedicine is receiving much attention due to its role as a vehicle for delivering chemotherapeutic agents that specifically target tumor sites. Several biocompatible nanocarriers including polymer and inorganic nanoparticles, liposomes, micellar nanoparticles, nanotubes, and exosomes have been extensively studied. Exosome has been reported as an important potential sytem that could be effectively used as a bioinspired, bioengineered, and biomimetic drug delivery solution considering its toxicity, immunogenicity, and rapid clearance by the mononuclear phagocyte system. Exosome-mimetic vesicles are receiving much interest for developing nano-sized delivery systems. In this review, exosomes in detail as well as certain other nanocarriers, and their potential therapeutic roles in cancer therapy has been thoroughly discussed. Additionally, we also reviewed on oncogenic and tumor suppressor proteins, inflammation, and their associated signaling pathways and their interference by exosomes based nanomedicine.
    Keywords:  Cancer resistance; cell signaling; exosome; inflammation; nanoparticle
    DOI:  https://doi.org/10.1016/j.semcancer.2022.04.005
  22. Ann Transl Med. 2022 Mar;10(6): 297
    The development of a redox-sensitive curcumin conjugated chitosan oligosaccharide nanocarrier for the efficient delivery of docetaxel to glioma cells.
    Chunxi Liu, Yuan Gao, Lixia Zhao, Rui Wang, Fei Xie, Guangxi Zhai, Anchang Liu.
      Background: A redox-sensitive nanoscale delivery system was developed, based on the hydrophilic chitosan oligosaccharide-ss-hydrophobic curcumin conjugate (CSO-ss-CUR) loaded with docetaxel (DTX), for the targeting and synergistic treatment of gliomas.Methods: Redox-sensitive nanoparticles were loaded with DTX (DTX/CSO-ss-CUR) using the improved ultrasonic-dialysis approach. The morphology and particle size of the loaded nanoparticles were examined by transmission electron microscopy (TEM) and dynamic light scattering (DLS), respectively. The cytotoxicity and cellular uptake of the nanoparticles were assessed in vitro using the C6 glial cell line. The in vivo antitumor efficacy and in vivo biodistribution studies were evaluated using the C6 tumor-bearing Balb/c female mouse model.
    Results: The DTX/CSO-ss-CUR nanoparticles were generally spherical in shape and exhibited desirable particle size (under 250 nm) with high drug loading efficiency (DL) (8.96%±0.56%) and encapsulation efficiency (EE) (35.23%±3.26%). In vitro, the drug was released from the nanoparticles in a redox-sensitive manner. The DTX/CSO-ss-CUR nanoparticles exhibited superior hemocompatibility in the hemolytic test and in vitro cytotoxicity and live/dead cell staining experiments revealed a higher cytotoxicity to glioma cells compared to the free drug. Furthermore, in vitro uptake experiments using C6 glioma cells demonstrated that the CSO-ss-CUR nanoparticles had good cell penetration ability. The in vivo antitumor efficacy and in vivo biodistribution studies suggested that the CSO-ss-CUR nanoparticles could effectively inhibit C6 tumor growth. More importantly, after intravenous injection, more CSO-ss-CUR nanoparticles were concentrated in the brain of the mice than free 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR) group.
    Conclusions: A unique drug delivery system formed by the self-assembly of CSO-ss-CUR was developed and shown to effectively cross the blood-brain barrier (BBB), enriching the abundance of the drug in the brain tissues. This may represent a potential therapeutic strategy for the treatment of gliomas.
    Keywords: Chitosan oligosaccharide (CSO); curcumin (CUR); docetaxel (DTX); glioma.
    DOI:  https://doi.org/10.21037/atm-22-288
  23. Pharmaceutics. 2022 Apr 03. pii: 783. [Epub ahead of print]14(4):
    Formulation and Evaluation of Apigenin-Loaded Hybrid Nanoparticles.
    Imran Kazmi, Fahad A Al-Abbasi, Syed Sarim Imam, Muhammad Afzal, Muhammad Shahid Nadeem, Hisham N Altayb, Sultan Alshehri.
      Apigenin (AGN) is a potent phytochemical with strong antioxidant and anticancer potential. But its therapeutic efficacy is limited due to its high lipophilic characteristics. Therefore, the present investigation aimed to develop AGN-loaded polymer-lipid hybrid nanoparticles (AGN-PLHNPs). Herein, we successfully developed AGN-PLHNPs and optimized them by a 33-Box-Behnken de-sign. The poly (lactic-co-glycolic acid) (PLGA; coded as F1), phospholipon 90 G (PL-90G; coded as F2), and poloxamer 188 (P-188; coded as F3) were considered as the independent factors while particle size (PS; coded as R1), entrapment efficiency (%EE; R2), and cumulative drug release (%CDR; R3) were selected as dependent responses. The average PS, %EE, and %CDR of the AGN-PLHNPs were observed in the range of 101.93 nm to 175.26 nm, 58.35% to 81.14%, and 71.21% to 93.31%, respectively. The optimized AGN-PLHNPs revealed better homogeneity (poly-dispersity index < 0.2) and colloidal stability with high zeta potential (>25 mV). It also exhibited fast release in the initial 4 h after that sustained release up to 48 h of study. Moreover, the results of both DPPH as well as ABTS assays revealed significant improvement in the antioxidant activity. Furthermore, the optimized AGN-PLHNPs exhibited enhanced cytotoxicity efficacy against MCF-7 as well as MDA-MB-231 breast cancer cell lines.
    Keywords:  Apigenin; antioxidant activity; breast cancer; cytotoxicity study; optimization
    DOI:  https://doi.org/10.3390/pharmaceutics14040783
  24. Eur J Pharm Sci. 2022 Apr 14. pii: S0928-0987(22)00072-0. [Epub ahead of print] 106187
    Estrone-targeted PEGylated Liposomal Nanoparticles for Cisplatin (DDP) Delivery in Cervical Cancer.
    Qianwen Li, Ming Zhu, Yao Li, Huan Tang, Zeng Wang, Yan Zhang, Yizhuo Xie, Zhe Lv, Han Bao, Yan Li, Rui Liu, Yujia Shen, Yucui Zheng, Dongfanghui Miao, Xin Guo, Jin Pei.
      Cisplatin (DDP), a first-line chemo-drug for cervical cancer therapy, has limited the clinical use due to its high-dose administration and strong side effects. In this study, estrone-targeted PEGylated Liposomal DDP (ES-SSL-DDP) was prepared by thin-film hydration method and characterized. ES-SSL-DDP presented a spherical structure, with a particle size of about 97.3 nm, a surface charge of -19 mV and a high encapsulation efficiency of 47.7%. ES-SSL-DDP showed higher stability with a lower leakage rate less than 10% at 4°C. In vitro cellular uptake and internalization mechanisms in HeLa cells showed that ES-SSL-DDP had a stronger cellular uptake which was mainly via caveolin-mediated endocytosis. In vivo targeting evaluation demonstrated ES-SSL-DDP could specifically accumulated into the tumor site of HeLa-bearing mice. Cytotoxicity test on HeLa cells demonstrated the stronger cytotoxic activity of ES-SSL-DDP by MTT assay. In vivo anti-tumor efficacy of ES-SSL-DDP in HeLa tumor-bearing mice exhibited the most effective tumor inhibition. Pharmacokinetics and biodistribution of ES-SSL-DDP presented an improved metabolic behavior of the DDP. The acute toxicity demonstrated that ES-SSL-DDP could increase the LD50 and reduce the myelosuppression in healthy ICR mice. ES-SSL-DDP could be a novel promising chemo-formulation for cervical cancer in the future clinic.
    Keywords:  Antitumor activity; Cervical cancer; Chemotherapy; Estrogen receptors; Pharmacokinetics; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.ejps.2022.106187
  25. Cell Death Dis. 2022 Apr 19. 13(4): 370
    Leukemia inhibitory factor drives glucose metabolic reprogramming to promote breast tumorigenesis.
    Xuetian Yue, Jianming Wang, Chun-Yuan Chang, Juan Liu, Xue Yang, Fan Zhou, Xia Qiu, Vrushank Bhatt, Jessie Yanxiang Guo, Xiaoyang Su, Lanjing Zhang, Zhaohui Feng, Wenwei Hu.
      LIF, a multifunctional cytokine, is frequently overexpressed in many types of solid tumors, including breast cancer, and plays an important role in promoting tumorigenesis. Currently, how LIF promotes tumorigenesis is not well-understood. Metabolic reprogramming is a hallmark of cancer cells and a key contributor to cancer progression. However, the role of LIF in cancer metabolic reprogramming is unclear. In this study, we found that LIF increases glucose uptake and drives glycolysis, contributing to breast tumorigenesis. Blocking glucose uptake largely abolishes the promoting effect of LIF on breast tumorigenesis. Mechanistically, LIF overexpression enhances glucose uptake via activating the AKT/GLUT1 axis to promote glycolysis. Blocking the AKT signaling by shRNA or its inhibitors greatly inhibits glycolysis driven by LIF and largely abolishes the promoting effect of LIF on breast tumorigenesis. These results demonstrate an important role of LIF overexpression in glucose metabolism reprogramming in breast cancers, which contributes to breast tumorigenesis. This study also reveals an important mechanism underlying metabolic reprogramming of breast cancers, and identifies LIF and its downstream signaling as potential therapeutic targets for breast cancers, especially those with LIF overexpression.
    DOI:  https://doi.org/10.1038/s41419-022-04820-x
  26. Pharmaceutics. 2022 Apr 18. pii: 884. [Epub ahead of print]14(4):
    β-Lactoglobulin-Modified Mesoporous Silica Nanoparticles: A Promising Carrier for the Targeted Delivery of Fenbendazole into Prostate Cancer Cells.
    Maedeh Koohi Moftakhari Esfahani, Seyed Ebrahim Alavi, Peter J Cabot, Nazrul Islam, Emad L Izake.
      The clinical utilization of fenbendazole (FBZ) as a potential anticancer drug has been limited due to its low water solubility, which causes its low bioavailability. The development of a drug nanoformulation that includes the solubilizing agent as a drug carrier can improve solubility and bioavailability. In this study, Mobil Composition of Matter Number 48 (MCM-48) nanoparticles were synthesized and functionalized with succinylated β-lactoglobulin (BLG) to prevent early-burst drug release. The BLG-modified amine-functionalized MCM-48 (MCM-BLG) nanoparticles were loaded with FBZ to produce the drug nanoformulation (FBZ-MCM-BLG) and improved the water solubility and, consequently, its anticancer effects against human prostate cancer PC-3 cells. The prepared FBZ-MCM-BLG was characterized in terms of size, zeta potential, drug loading capacity, morphology, thermal and chemical analyses, drug release, cellular uptake, cell viability, cell proliferation, production of reactive oxygen species (ROS), and cell migration. The results demonstrated that the FBZ-MCM-BLG nanoparticles have a spherical morphology with a size and zeta potential of 369 ± 28 nm and 28 ± 0.4 mV, respectively. The drug loading efficiency of the new nanoformulation was 19%. The release of FBZ was pH-dependent; a maximum cumulative release of about 76 and 62% in 12 h and a burst release of 53 and 38% in the first 0.5 h was observed at pH 1.2 and 6.8, respectively. The prepared FBZ-MCM-BLG formulation demonstrated higher cytotoxicity effects against PC-3 cells by 5.6- and 1.8-fold, respectively, when compared to FBZ and FBZ-MCM nanoparticles. The new formulation also increased the production of ROS by 1.6- and 1.2-fold and inhibited the migration of PC-3 cells when compared to the FBZ and FBZ-MCM nanoparticles, respectively. Overall, FBZ-MCM-BLG nanoparticles improved FBZ delivery to PC-3 cells and have the potential to be evaluated for the treatment of prostate cancer following a comprehensive in vivo study.
    Keywords:  anthelmintic; fenbendazole; mesoporous silica nanoparticle; prostate cancer
    DOI:  https://doi.org/10.3390/pharmaceutics14040884
  27. Exp Cell Res. 2022 Apr 18. pii: S0014-4827(22)00153-7. [Epub ahead of print] 113160
    Combinatorial epigenetic mechanisms of sulforaphane, genistein and sodium butyrate in breast cancer inhibition.
    Manvi Sharma, Trygve O Tollefsbol.
      Dietary phytochemicals are currently being studied with great interest due to their ability to regulate the epigenome resulting in prevention of cancer. Some natural botanicals have been reported to have enhanced and synergistic impact on cancer suppression when administered at optimum concentrations and in-conjunction. Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables and sodium butyrate (NaB) is a short-chain fatty acid produced by gut microbiota. They have been intensively explored due to numerous anti-cancerous properties and ability to modulate epigenetic machinery by inhibition of histone deacetylase (HDAC). Genistein (GE), present in soy, is a known DNA methyltransferase (DNMT) inhibitor. While combined chemoprotective epigenetic effects induced by SFN and GE have been investigated, the key impact of combinatorial SFN-NaB, GE-NaB, and SFN-GE-NaB bioactive components in regulation of various mechanisms are poorly defined. In the present study, we found that combinations of dietary compounds had synergistic effects in decreasing cellular viability at lower dosages than their single dosages in breast cancer cell lines. The respective combinations limited growth and increased apoptosis and necrosis in cancerous cells among which the tri-combination displayed the most significant impact. Additionally, the respective combinations of compounds arrested MDA-MB-231 and MCF-7 breast cancer cells at G2/M phase. Our further mechanistic evaluation revealed that respective di-combinations and tri-combination had higher impact in down-regulation of DNMTs (DNMT3A and DNMT3B), HDACs (HDAC1, HDAC6 and HDAC11), histone methyltransferases (EZH2 and SUV39H1) and histone acetyltransferases (GCN5, PCAF, P300 and CBP) levels as compared to singly administered compounds. We also found that these combinations exhibited global epigenetic changes by inhibition of DNMT and HDAC activity, H3K27me and H3K9me levels, and by induction of histone acetyltransferases activity. Collectively, our investigation indicates that combined SFN, GE and NaB is highly effective in inhibiting breast cancer genesis by, at least in part, regulating epigenetic modifications, which may have implications in breast cancer therapy.
    Keywords:  Breast cancer; Combinatorial; Epigenetics; Genistein; Sodium butyrate; Sulforaphane; Therapy
    DOI:  https://doi.org/10.1016/j.yexcr.2022.113160
  28. Nanomaterials (Basel). 2022 Apr 13. pii: 1333. [Epub ahead of print]12(8):
    Unique Properties of Surface-Functionalized Nanoparticles for Bio-Application: Functionalization Mechanisms and Importance in Application.
    Faheem Ahmad, Mounir M Salem-Bekhit, Faryad Khan, Sultan Alshehri, Amir Khan, Mohammed M Ghoneim, Hui-Fen Wu, Ehab I Taha, Ibrahim Elbagory.
      This review tries to summarize the purpose of steadily developing surface-functionalized nanoparticles for various bio-applications and represents a fascinating and rapidly growing field of research. Due to their unique properties-such as novel optical, biodegradable, low-toxicity, biocompatibility, size, and highly catalytic features-these materials are considered superior, and it is thus vital to study these systems in a realistic and meaningful way. However, rapid aggregation, oxidation, and other problems are encountered with functionalized nanoparticles, inhibiting their subsequent utilization. Adequate surface modification of nanoparticles with organic and inorganic compounds results in improved physicochemical properties which can overcome these barriers. This review investigates and discusses the iron oxide nanoparticles, gold nanoparticles, platinum nanoparticles, silver nanoparticles, and silica-coated nanoparticles and how their unique properties after fabrication allow for their potential use in a wide range of bio-applications such as nano-based imaging, gene delivery, drug loading, and immunoassays. The different groups of nanoparticles and the advantages of surface functionalization and their applications are highlighted here. In recent years, surface-functionalized nanoparticles have become important materials for a broad range of bio-applications.
    Keywords:  bio-fabrication; magnetic nanoparticles; nanocarrier; nanomaterial; nanomedicine
    DOI:  https://doi.org/10.3390/nano12081333
  29. Pharmaceutics. 2022 Apr 12. pii: 844. [Epub ahead of print]14(4):
    Iron Oxide Nanoparticles-Plant Insignia Synthesis with Favorable Biomedical Activities and Less Toxicity, in the "Era of the-Green": A Systematic Review.
    Nadia M Hamdy, Amira A Boseila, Ahmed Ramadan, Emad B Basalious.
      In the era of favoring environment-friendly approaches for pharmaceutical synthesis, "green synthesis" is expanding. Green-based nanomedicine (NM), being less toxic and if having biomedical acceptable activities, thence, the chemical methods of synthesis are to be replaced by plants for reductive synthesis. Iron oxide nanoparticles (IONPs) exhibited remarkable anti-microbial and anti-cancer properties, besides being a drug delivery tool. However, owing to limitations related to the chemical synthetic method, plant-mediated green synthesis has been recognized as a promising alternative synthetic method. This systematic review (SR) is addressing plant-based IONPs green synthesis, characteristics, and toxicity studies as well as their potential biomedical applications. Furthermore, the plant-based green-synthesized IONPs in comparison to nanoparticles (NPs) synthesized via other conventional methods, characteristics, and efficacy or toxicity profiles would be mentioned (if available). Search strategy design utilized electronic databases including Science Direct, PubMed, and Google Scholar search. Selection criteria included recent clinical studies, available in the English language, published till PROSPERO registration. After screening articles obtained by first electronic database search, by title, abstract and applying the PICO criteria, the search results yielded a total of 453 articles. After further full text filtrations only 48 articles were included. In conclusion, the current SR emphasizes the perspective of the IONPs plant-mediated green synthesis advantage(s) when utilized in the biomedical pharmaceutical field, with less toxicity.
    Keywords:  antimicrobial; bioactivities; cancer hallmarks; iron oxide nanoparticles; nanotechnology; plant-based green synthesis; toxicity
    DOI:  https://doi.org/10.3390/pharmaceutics14040844
  30. AAPS PharmSciTech. 2022 Apr 19. 23(5): 115
    Curcumin and Derivatives in Nanoformulations with Therapeutic Potential on Colorectal Cancer.
    Sourour Idoudi, Takwa Bedhiafi, Yousef Mohammad Hijji, Nashiru Billa.
      There is growing concern in the rise of colorectal cancer (CRC) cases globally, and with this rise is the presentation of drug resistance. Like other cancers, current treatment options are either invasive or manifest severe side effects. Thus, there is a move towards implementing safer treatment options. Curcumin (CUR), extracted from Curcuma longa, has received significant attention by scientists as possible alternative to chemotherapeutic agents. It is safe and effective against CRC and nontoxic in moderate concentrations. Crucially, it specifically modulates apoptotic effects on CRC. However, the use of CUR is limited by its low solubility and poor bioavailability in aqueous media. These limitations are surmountable through novel approaches, such as nanoencapsulation of CUR, which masks the physicochemical properties of CUR, thus potentiating its anti-CRC effects. Furthermore, chemical derivatization of CUR is another approach that can be used to address the above constraints. This review spans published work in the last two decades, with key findings employing either of the two approaches, in addition to a combined approach in managing CRC. The combined approach affords the possibility of better treatment outcomes but not widely investigated nor yet clinically implemented.
    Keywords:  colorectal cancer; curcumin; derivatives; nanoformulations
    DOI:  https://doi.org/10.1208/s12249-022-02268-y
  31. Nanomaterials (Basel). 2022 Apr 11. pii: 1299. [Epub ahead of print]12(8):
    Development of a Novel Methotrexate-Loaded Nanoemulsion for Rheumatoid Arthritis Treatment with Site-Specific Targeting Subcutaneous Delivery.
    Parvathy Suresh, Mounir M Salem-Bekhit, Hafsa Palathum Veedu, Sultan Alshehri, Sreeja Chandrasekhar Nair, Sarah I Bukhari, Vidya Viswanad, Ehab I Taha, Ram Kumar Sahu, Mohammed M Ghoneim, Ibrahim Elbagory.
      Rheumatoid arthritis (RA) is a systemic, chronic autoimmune disease that causes disability due to progressive inflammation and destruction of the tissues around the joints. Methotrexate is mainly used to prevent the progression of joint destruction and reduce the deformity. The major challenge in treating RA with methotrexate is the systemic side effects that limit dose escalation. Hence, a novel formulation of a methotrexate-loaded nanoemulsion for subcutaneous administration was developed that aims to deliver methotrexate into the system via the lymph. The methotrexate-loaded nanoemulsion was prepared by using the aqueous-titration method. The prepared nanoemulsion was investigated for particle size, surface charge, surface morphology, entrapment efficiency, DSC (differential scanning colorimetry), drug release, hemocompatibility assay, and cytotoxicity, as well as anti-arthritic and stability studies. The vesicle size, zeta potential, PDI (polydispersity index), and entrapment efficiency of the optimized nanoemulsion were 87.89 ± 2.86 nm, 35.9 ± 0.73 mV, 0.27, and 87 ± 0.25%, respectively. The DSC study showed that the crystalline methotrexate was converted to an amorphous form and the drug was fully incorporated into the vesicles. After 72 h, the optimized nanoemulsion showed a drug release of 96.77 ± 0.63%, indicating a sustained-release dosage form. Cytocompatibility testing by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay on macrophage cell lines showed that the nanoemulsion was non-toxic. The formulation showed significant anti-arthritic activity compared to the marketed drug solution. In addition, the nanoemulsion containing methotrexate remained stable for three months when stored at a low temperature. Since the nanoemulsion containing methotrexate has excellent physicochemical properties and lowers systemic side effects by targeted delivery, it is a desirable technology for subcutaneous drug delivery.
    Keywords:  MTT assay; anti-arthritic activity; hemocompatibility; methotrexate; nanoemulsion; rheumatoid arthritis; stability studies
    DOI:  https://doi.org/10.3390/nano12081299
  32. Curr Drug Metab. 2022 Apr 16.
    Receptor-Mediated Targeting in Breast Cancer through Solid Lipid Nanoparticles and Its Mechanism.
    Zoya Malik, Rabea Parveen, Sageer Abass, Mohammad Irfan, Syed Akhtar Husain, Sayeed Ahmad.
      Nanoparticles have gained prominence in many areas and domains world-wide such as metallic NP, carbon-dots, quantum dots, polymeric NP, nano-suspension, nanocrystals, solid lipid nanoparticles (SLN), etc. and have been applied in the field of medicine as nanomedicine with promising results. Rise in global cancer mortality rate has been an issue since long with female breast cancer as one of the most detected cancers. No permanent treatment has been developed till date that could combat breast cancer with minimum side effects that are not long-lasting as there is not any proper technique through which the anticancer drugs can recognize benign or malignant or normal cells that causes systematic toxicity. Advancement in technology has led to the discovery of many biological pathways and mechanisms. Tumor cells or cancer cells overexpress some high-affinity receptors that can be targeted to deliver the anticancer drugs at specific site using these pathways and mechanisms. Solid lipid nanoparticles (SLN) are among some of the excellent drug delivery systems, especially stealth SLN (sSLN). SLN when conjugated with a ligand (called as sSLN) has affinity and specificity towards a specific receptor, and can deliver the drug in breast cancer cells overexpressing the receptors. Using this technique, various investigations have reported better anti-breast cancer activity than simple SLN (non-conjugated to ligand or no receptor targeting). This review includes the investigations and data on receptor-mediated targeting in breast cancer from 2010 to 2021 by searching different databases. Overall, information on SLN in different cancers are reviewed. Effectiveness of sSLN is discussed with in vivo studies, pharmacokinetics, biodistribution, and stability. Investigations included in this review demonstrate that sSLN delivers the drug by overcoming the biological barriers and shows enhanced and better activity than non-conjugated SLN that also verifies that lesser concentration of drug can show anti-breast cancer activity. The efficacy of medicines could be increased with lower cancer deaths through stealth-SLN. Due to the low cost of synthesis, biocompatibility and easy to formulate, more study is needed in vitro and in vivo so that this novel technique could be utilized in the treatment of human breast cancer.
    Keywords:  Breast cancer; Caveolin-mediated endocytosis; Clathrin-mediated endocytosis; Receptor-mediated targeting; olid lipid nanoparticles; stealth-Solid lipid nanoparticles
    DOI:  https://doi.org/10.2174/1389200223666220416213639
  33. Pharmaceutics. 2022 Apr 05. pii: 795. [Epub ahead of print]14(4):
    Mucoadhesive Nanocarriers as a Promising Strategy to Enhance Intracellular Delivery against Oral Cavity Carcinoma.
    Manisha Pandey, Hira Choudhury, Jenifer Ngu Shao Ying, Jessica Foo Sze Ling, Jong Ting, Jocelyn Su Szhiou Ting, Ivory Kuek Zhia Hwen, Ho Wan Suen, Hazimah Syazwani Samsul Kamar, Bapi Gorain, Neha Jain, Mohd Cairul Iqbal Mohd Amin.
      Oral cancer, particularly squamous cell carcinoma (SCC), has posed a grave challenge to global health due to its high incidence, metastasis, and mortality rates. Despite numerous studies and favorable improvements in the therapeutic strategies over the past few decades, the prognosis of this disease remains dismal. Moreover, several drawbacks are associated with the conventional treatment; including permanent disfigurement and physical impairment that are attributed to surgical intervention, and systemic toxicity that results from aggressive radio- or chemotherapies, which impacts patients' prognosis and post-treatment quality of life. The highly vascularized, non-keratinized oral mucosa appears as a potential route for cytotoxic drug administration in treating oral cancer. It acts as a non-invasive portal for drug entry targeting the local oral lesions of the early stages of cancer and the systemic metastasis sites of advanced cancer. The absorption of the poorly aqueous-soluble anti-cancer drugs can be enhanced due to the increased permeability of the ulcerous mucosa lining in the disease state and by bypassing the hepatic first-pass metabolism. However, some challenges in oral transmucosal drug delivery include the drugs' taste, the limited surface area of the membrane lining the oral cavity, and flushing and enzymatic degradation by saliva. Therefore, mucoadhesive nanocarriers have emerged as promising platforms for controlled, targeted drug delivery in the oral cavity. The surface functionalization of nanocarriers with various moieties allows for drug targeting, bioavailability enhancement, and biodistribution at the site of action, while the mucoadhesive feature prolongs the drug's residence time for preferential accumulation to optimize the therapeutic effect and reduce systemic toxicity. This review has been focused to highlight the potential of various nanocarriers (e.g., nanoparticles, nanoemulsions, nanocapsules, and liposomes) in conferring targeting, solubility and bioavailability enhancement of actives and mucoadhesive properties as novel tumor-targeted drug delivery approaches in oral cancer treatment.
    Keywords:  cytoplasmic delivery; improved efficacy; mucoadhesion; nanocarriers; oral cancer; targeted drug delivery approach
    DOI:  https://doi.org/10.3390/pharmaceutics14040795
  34. Small. 2022 Apr 21. e2200993
    Deep Tumor Penetrating Gold Nano-Adjuvant for NIR-II-Triggered In Situ Tumor Vaccination.
    Anhong Chen, Lei Wu, Yao Luo, Shaojin Lu, Yupeng Wang, Zhengzheng Zhou, Dongfang Zhou, Zhigang Xie, Jun Yue.
      Local tumor photothermal treatment with the near-infrared light at the second window (NIR-II) is a promising strategy in triggering the in situ tumor vaccination (ISTV) for cancer therapy. However, limited penetration of photothermal agents within tumors seriously limits their spatial effect in generating sufficient tumor-associated antigens, a key factor to the success of ISTV. In this study, a nano-adjuvant system is fabricated based on the NIR-II-absorbable gold nanostars decorated with hyaluronidases and immunostimulatory oligodeoxynucleotides CpG for ISTV. The nano-adjuvant displays a deep tumor penetration capacity via loosening the dense extracellular matrix of tumors. Upon NIR-II light irradiation, the nano-adjuvant significantly inhibits the tumor growth, induces a cascade of immune responses, generates an obvious adaptive immunity against the re-challenged cancers, boosts the abscopal effect, and completely inhibits the pulmonary metastases. The study highlights an advanced nano-adjuvant formulation featuring deep tumor penetration for NIR-II-triggered ISTV.
    Keywords:  NIR-II light; deep tumor penetration; gold nano-adjuvant; immune responses; in situ tumor vaccination
    DOI:  https://doi.org/10.1002/smll.202200993
  35. Gels. 2022 Apr 02. pii: 219. [Epub ahead of print]8(4):
    Phytosterol-Loaded Surface-Tailored Bioactive-Polymer Nanoparticles for Cancer Treatment: Optimization, In Vitro Cell Viability, Antioxidant Activity, and Stability Studies.
    Shahid Karim, Md Habban Akhter, Abdulhadi S Burzangi, Huda Alkreathy, Basma Alharthy, Sabna Kotta, Shadab Md, Md Abdur Rashid, Obaid Afzal, Abdulmalik S A Altamimi, Habibullah Khalilullah.
      This study aimsto optimize, characterize, and assess the phytosterol-loaded surface-tailored bioactive Alginate/Chitosan NPs for antitumor efficacy against breast cancer. β-Sitosterol-loaded Alginate/Chitosan nanoparticles (β-SIT-Alg/Ch-NPs) were fabricated using an ion-gelation technique, and then the NPs' surfaces were activated using an EDC/sulfo-NHS conjugation reaction. The activated chitosan NPs werefunctionalized with folic acid (FA), leveled as β-SIT-Alg/Ch-NPs-FA. Moreover, the functionalized NPs were characterized for size distribution, polydispersity index (PDI), and surface charge, FT-IR and DSC. β-SIT released from β-SIT-Alg/Ch-NPs was estimated in various biorelevant media of pH 7.4, 6.5, and 5.5, and data werefitted into various kinetic models. The cytotoxic study of β-SIT-Alg/Ch-NPs-FA against the cancer cell line was established. The antioxidant study of developed β-SIT-Alg/Ch-NPs was performed using DPPH assay. The stability of developed optimized formulation was assessed in phosphate buffer saline (PBS, pH 7.4), as per ICH guidelines. The drug-entrapped Alg/Ch-NPs-FA appeared uniform and nonaggregated, and the nanoscale particle measured a mean size of 126 ± 8.70 nm. The %drug encapsulation efficiency and %drug loading in β-SIT-Alg/Ch-NPs-FA were 91.06 ± 2.6% and 6.0 ± 0.52%, respectively. The surface charge on β-SIT-Alg/Ch-NPs-FA was measured as +25 mV. The maximum β-SIT release from β-SIT-Alg/Ch-NPs-FA was 71.50 ± 6.5% in pH 5.5. The cytotoxic assay expressed an extremely significant antitumor effect by β-SIT-Alg/Ch-NPs-FA when compared to β-SIT-suspension (p < 0.001). The antioxidant capacity of β-SIT-Alg/Ch-NPs-FA was 91 ± 5.99% compared to 29 ± 8.02% for β-SIT-suspension. The stability of NPs noticed an unworthy alteration (p > 0.05) in particle sizes and other parameters under study in the specific period.
    Keywords:  breast cancer; chitosan; drug delivery; folic acid; nanoparticles; β-sitosterol
    DOI:  https://doi.org/10.3390/gels8040219
  36. Pharmaceutics. 2022 Mar 30. pii: 743. [Epub ahead of print]14(4):
    Current Advances of Nanomedicines Delivering Arsenic Trioxide for Enhanced Tumor Therapy.
    Mengzhen Yu, Yanwen Zhang, Meirong Fang, Shah Jehan, Wenhu Zhou.
      Arsenic trioxide (ATO) is one of the first-line chemotherapeutic drugs for acute promyelocytic leukemia. Its anti-cancer activities against various human neoplastic diseases have been extensively studied. However, the clinical use of ATO for solid tumors is limited, and these limitations are because of severe systemic toxicity, low bioavailability, and quick renal elimination before it reaches the target site. Although without much success, several efforts have been made to boost ATO bioavailability toward solid tumors without raising its dose. It has been found that nanomedicines have various advantages for drug delivery, including increased bioavailability, effectiveness, dose-response, targeting capabilities, and safety as compared to traditional drugs. Therefore, nanotechnology to deliver ATO to solid tumors is the main topic of this review, which outlines the previous and present medical applications of ATO. We also summarised ATO anti-cancer mechanisms, limitations, and outcomes of combinatorial treatment with chemo agents. As a result, we strongly recommend conducting pre-clinical and clinical studies of ATO, especially nano-system-based ones that might lead to a novel combination therapy for cancer treatment with high efficacy, bioavailability, and low toxicity for cancer patients.
    Keywords:  Arsenic trioxide; bioavailability; combinatorial treatment; cytotoxicity; nanomedicines; synergistic effect
    DOI:  https://doi.org/10.3390/pharmaceutics14040743
  37. Biomed Pharmacother. 2022 Apr 18. pii: S0753-3322(22)00340-7. [Epub ahead of print]150 112951
    Biomedical applications of metallic nanoparticles in cancer: Current status and future perspectives.
    Rubiya Khursheed, Kamal Dua, Sukriti Vishwas, Monica Gulati, Niraj Kumar Jha, Ghalib Mohammed Aldhafeeri, Fayez Ghadeer Alanazi, Bey Hing Goh, Gaurav Gupta, Keshav Raj Paudel, Philip M Hansbro, Dinesh Kumar Chellappan, Sachin Kumar Singh.
      The current advancements in nanotechnology are as an outcome of the development of engineered nanoparticles. Various metallic nanoparticles have been extensively explored for various biomedical applications. They attract lot of attention in biomedical field due to their significant inert nature, and nanoscale structures, with size similar to many biological molecules. Their intrinsic characteristics which include electronic, optical, physicochemical and, surface plasmon resonance, that can be changed by altering certain particle characteristics such as size, shape, environment, aspect ratio, ease of synthesis and functionalization properties have led to numerous applications in various fields of biomedicine. These include targeted drug delivery, sensing, photothermal and photodynamic therapy, imaging, as well as the modulation of two or three applications. The current article also discusses about the various properties of metallic nanoparticles and their applications in cancer imaging and therapeutics. The associated bottlenecks related to their clinical translation are also discussed.
    Keywords:  Cancer; Drug delivery; Metallic nanoparticles; Nanotechnology
    DOI:  https://doi.org/10.1016/j.biopha.2022.112951
  38. Colloids Surf B Biointerfaces. 2022 Apr 11. pii: S0927-7765(22)00186-2. [Epub ahead of print]215 112503
    Cell membrane-based biomimetic nanosystems for advanced drug delivery in cancer therapy: A comprehensive review.
    Jianing Zhao, Jian Ruan, Guangyao Lv, Qi Shan, Zhiping Fan, Hongbo Wang, Yuan Du, Longbing Ling.
      Natural types of cells display distinct characteristics with homotypic targeting and extended circulation in the blood, which are worthy of being explored as promising drug delivery systems (DDSs) for cancer therapy. To enhance their delivery efficiency, these cells can be combined with therapeutic agents and artificial nanocarriers to construct the next generation of DDSs in the form of biomimetic nanomedicines. In this review, we present the recent advances in cell membrane-based DDSs (CDDSs) and their applications for efficient cancer therapy. Different sources of cell membranes are discussed, mainly including red blood cells (RBC), leukocytes, cancer cells, stem cells and hybrid cells. Moreover, the extraction methods used for obtaining such cells and the mechanism contributing to the functional action of these biomimetic CDDSs are explained. Finally, a future perspective is proposed to highlight the limitations of CDDSs and the possible resolutions toward clinical transformation of currently developed biomimetic chemotherapies.
    Keywords:  Biomimetic; Cancer therapy; Cell membrane; Drug delivery systems; Nanoparticles
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112503
  39. Front Pharmacol. 2022 ;13 872810
    Water-Extracted Prunella vulgaris Alleviates Endometriosis by Reducing Aerobic Glycolysis.
    Min Kyoung Cho, Ling Jin, Jung Ho Han, Jung-Suk Jin, Se-Yun Cheon, Su Shin, Sung-Jin Bae, Jang-Kyung Park, Ki-Tae Ha.
      Endometriosis is a chronic inflammatory disorder caused by abnormal adhesion of endometrial tissue to the outside of the uterus. The combination of surgery, non-steroidal anti-inflammatory drugs, and hormone treatment is well established therapy for endometriosis, however, case reports have showed that high rates of relapse and unpleasant side effect. For these reasons, recently, the studies have been focused on the Warburg-like metabolic shift of endometriosis. Prunella vulgaris is one of traditionally used herbal medicine for inflammatory disease and the anti-estrogenic effects of P. vulgaris is well-established. Therefore, in this work, we evaluated water-extracted P. vulgaris (PV) as a potential treatment for endometriosis. To this, we artificially induced endometriosis in ovarectomized mice by intra-peritoneal inoculation of uterus extracts. PV was orally administered, and PV significantly alleviated endometriosis, particularly the growth of ectopic endometrial lesions in artificially endometriosis-induced mice. For the mechanism study of anti-endometriosis by PV, we designed an in vitro study using human normal endometrial stromal cells (T-HESCs) and human endometrial cell (12Z) obtained from patients with endometriosis. PV strongly induced the apoptosis of 12Z cells rather than T-HESCs by control the activity or expression of aerobic glycolysis enzymes, such as lactate dehydrogenase A (LDHA), pyruvate dehydrogenase A, and pyruvate dehydrogenase kinase 1/3. In addition, lactate production was enhanced, and oxygen consumption rate was suppressed in 12Z cells upon PV treatment. These changes in aerobic glycolysis eventually caused mitochondrial damage following decreased mitochondrial membrane potential and excessive mitochondrial ROS production. Especially, ulsolic acid (UA), one of the compounds in PV considerably led 12Z cell apoptosis with inhibition of LDHA activity. Therefore, UA could be a major active substance of PV in terms of endometriosis inhibitors. In conclusion, this study provides the evidence that the beneficial efficacy of PV for the prevention/treatment of endometriosis.
    Keywords:  Aerobic glycolysis; Prunella vulgaris; Warburg-like metabolism; endometriosis; lactate dehydrogenase; pyruvate dehydrogenase kinase; ulsoric acid
    DOI:  https://doi.org/10.3389/fphar.2022.872810
  40. Molecules. 2022 Apr 14. pii: 2529. [Epub ahead of print]27(8):
    Light-Activated Monomethyl Auristatin E Prodrug Nanoparticles for Combinational Photo-Chemotherapy of Pancreatic Cancer.
    In Kyung Cho, Man Kyu Shim, Wooram Um, Jong-Ho Kim, Kwangmeyung Kim.
      Pancreatic cancer is a highly fatal disease that is becoming an increasingly leading cause of cancer-related deaths. In clinic, the most effective approach to treat pancreatic cancers is the combination treatment of several chemotherapeutic drugs, including fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), but this approach is not adequate to manage patients due to their severe toxic side effects. Herein, we proposed light-activated monomethyl auristatin E (MMAE) prodrug nanoparticles for combinational photo-chemotherapy and optimized its applications for pancreatic cancer treatment. The photosensitizer (Ce6) and chemotherapeutic drug (MMAE) were conjugated through caspase-3-specific cleavable peptide (KGDEVD). The resulting CDM efficiently promoted the reactive oxygen species (ROS) under visible light irradiation and thereby induced caspase-3 overexpression in pacreatic cancers, which subsequently released the MMAE from the system. Importantly, MMAE released from CDM further amplified the activation of CDM into MMAE by inducing extensive apoptotic cell death in tumor microenvironment for treatment of tumor cells in deep in the tumor tissues as far visible light cannot reach. In addition, CDM formed prodrug nanoparticles via intermolecular π-π stacking and hydrophobic interactions, allowing durable and reliable treatment by preventing fast leakage from the pancreatic cancers via the lymphatic vessels. The CDM directly (intratumoral) injected into pancreatic cancers in orthotopic models through an invasive approach significantly delayed the tumor progression by combinational photo-chemotherapy with less toxic side effects. This study offers a promising and alternative approach for safe and more effective pancreatic cancer treatment via prodrug nanoparticles that combine photodynamic therapy and chemotherapy.
    Keywords:  combination treatment; pancreatic cancer; prodrug nanoparticles; synergistic effect
    DOI:  https://doi.org/10.3390/molecules27082529
  41. Biomolecules. 2022 Apr 14. pii: 580. [Epub ahead of print]12(4):
    Effects of Glucose Metabolism, Lipid Metabolism, and Glutamine Metabolism on Tumor Microenvironment and Clinical Implications.
    Longfei Zhu, Xuanyu Zhu, Yan Wu.
      In recent years, an increasingly more in depth understanding of tumor metabolism in tumorigenesis, tumor growth, metastasis, and prognosis has been achieved. The broad heterogeneity in tumor tissue is the critical factor affecting the outcome of tumor treatment. Metabolic heterogeneity is not only found in tumor cells but also in their surrounding immune and stromal cells; for example, many suppressor cells, such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and tumor-associated T-lymphocytes. Abnormalities in metabolism often lead to short survival or resistance to antitumor therapy, e.g., chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Using the metabolic characteristics of the tumor microenvironment to identify and treat cancer has become a great research hotspot. This review systematically addresses the impacts of metabolism on tumor cells and effector cells and represents recent research advances of metabolic effects on other cells in the tumor microenvironment. Finally, we introduce some applications of metabolic features in clinical oncology.
    Keywords:  fatty acid metabolism; glutaminolysis; glycolysis; immunotherapy; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom12040580
  42. Int J Mol Sci. 2022 Apr 08. pii: 4120. [Epub ahead of print]23(8):
    KRAS: A Druggable Target in Colon Cancer Patients.
    Francesca Negri, Lorena Bottarelli, Gian Luigi de'Angelis, Letizia Gnetti.
      Mutations in KRAS are among the most frequent aberrations in cancer, including colon cancer. KRAS direct targeting is daunting due to KRAS protein resistance to small molecule inhibition. Moreover, its elevated affinity to cellular guanosine triphosphate (GTP) has made the design of specific drugs challenging. Indeed, KRAS was considered 'undruggable'. KRASG12C is the most commonly mutated variant of KRAS in non-small cell lung cancer. Currently, the achievements obtained with covalent inhibitors of this variant have given the possibility to assess the best therapeutic approach to KRAS-driven tumors. Mutation-related biochemical assets and the tissue of origin are expected to influence responses to treatment. Further attempts to obtain mutant-specific KRAS (KRASG12C) switch-II covalent inhibitors are ongoing and the results are promising. Drugs targeted to block KRAS effector pathways could be combined with direct KRAS inhibitors, immunotherapy or T cell-targeting approaches in KRAS-mutant tumors. The development of valuable combination regimens will be essential against potential mechanisms of resistance that may arise during treatment.
    Keywords:  KRAS oncogene; RAS pathway; adagrasib; colon cancer; sotorasib; targeted therapy
    DOI:  https://doi.org/10.3390/ijms23084120
  43. Carbohydr Polym. 2022 Jul 15. pii: S0144-8617(22)00305-8. [Epub ahead of print]288 119401
    Chitosan-coated nanostructured lipid carriers for transdermal delivery of tetrahydrocurcumin for breast cancer therapy.
    Thien Hoang Truong, Khent Primo Alcantara, Bryan Paul I Bulatao, Feuangthit Niyamissara Sorasitthiyanukarn, Chawanphat Muangnoi, Nonthaneth Nalinratana, Opa Vajragupta, Pornchai Rojsitthisak, Pranee Rojsitthisak.
      Chitosan (Ch)-coated nanostructured lipid carriers (NLCs) have great potential for transdermal delivery with high localization of chemotherapeutics in breast cancer. This study used tetrahydrocurcumin (THC), a primary metabolite of curcumin with enhanced antioxidant and anticancer properties, as a model compound to prepare NLCs. Response surface methodology was employed to optimize THC-loaded Ch-coated NLCs (THC-Ch-NLCs) fabricated by high-shear homogenization. The optimized THC-Ch-NLCs had particle size of 244 ± 18 nm, zeta potential of -17.5 ± 0.5 mV, entrapment efficiency of 76.6 ± 0.2% and drug loading of 0.28 ± 0.01%. In vitro release study of THC-Ch-NLCs showed sustained release following the Korsmeyer-Peppas model with Fickian and non-Fickian diffusion at pH 7.4 and 5.5, respectively. THC-Ch-NLCs demonstrated significantly enhanced in vitro skin permeation, cell uptake, and remarkable cytotoxicity toward MD-MBA-231 breast cancer cells compared to the unencapsulated THC, suggesting Ch-NLCs as potential transdermal nanocarriers of THC for triple-negative breast cancer treatment.
    Keywords:  Breast cancer; Chitosan; Cytotoxicity; Nanostructured lipid carriers; Tetrahydrocurcumin; Transdermal delivery
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119401
  44. Nanomaterials (Basel). 2022 Apr 17. pii: 1376. [Epub ahead of print]12(8):
    Nanocarriers for Drug Delivery: An Overview with Emphasis on Vitamin D and K Transportation.
    Andreea Crintea, Alina Gabriela Dutu, Alina Sovrea, Anne-Marie Constantin, Gabriel Samasca, Aurelian Lucian Masalar, Brigitta Ifju, Eugen Linga, Lidia Neamti, Rares Andrei Tranca, Zsolt Fekete, Ciprian Nicolae Silaghi, Alexandra Marioara Craciun.
      Mounting evidence shows that supplementation with vitamin D and K or their analogs induces beneficial effects in various diseases, e.g., osteoarticular, cardiovascular, or carcinogenesis. The use of drugs delivery systems via organic and inorganic nanocarriers increases the bioavailability of vitamins and analogs, enhancing their cellular delivery and effects. The nanotechnology-based dietary supplements and drugs produced by the food and pharmaceutical industries overcome the issues associated with vitamin administration, such as stability, absorption or low bioavailability. Consequently, there is a continuous interest in optimizing the carriers' systems in order to make them more efficient and specific for the targeted tissue. In this pioneer review, we try to circumscribe the most relevant aspects related to nanocarriers for drug delivery, compare different types of nanoparticles for vitamin D and K transportation, and critically address their benefits and disadvantages.
    Keywords:  drug delivery; nanocarriers; vitamin D; vitamin K
    DOI:  https://doi.org/10.3390/nano12081376
  45. Int J Pharm. 2022 Apr 15. pii: S0378-5173(22)00306-4. [Epub ahead of print]620 121751
    Recent development of aptamer conjugated chitosan nanoparticles as cancer therapeutics.
    Afsana Sheikh, Shadab Md, Nabil A Alhakamy, Prashant Kesharwani.
      There is a surge in demand for safe and targeted therapy against cancer as the conventional treatment approach fails to reach the specific site. Chemotherapeutic agents are generally associated with low tumoral accumulation, off-site effect, and drug resistance. Targeted delivery with the use of nanocarrier could elevate the drug accumulation at the target site, reduce toxicity to non-cancerous cells, overcome drug resistance, and reduce dosing. Aptamers are single-stranded oligonucleotide that folds in a way to get into the pocket of target cells with high affinity and specificity due to the ability to recognize and interact with the biomarkers such as nucleolin, Mucin, EGFR, etc. overexpressed by cancer cells. Aptamer also plays a key role in cancer immunotherapy and the delivery of anti-cancer agents. The review brings the light upon the use of aptamer-chitosan nanoparticles against cancer therapy and their role in the reduction of toxic effects.
    Keywords:  Aptamer; Cancer; Chitosan; Gene delivery; Nanomedicine; Nanoparticles; Targeted therapy; Toxicity
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121751
  46. Pharmaceutics. 2022 Apr 06. pii: 797. [Epub ahead of print]14(4):
    Drug Nanocrystals for Active Tumor-Targeted Drug Delivery.
    Linwei Lu, Qianzhu Xu, Jun Wang, Sunyi Wu, Zimiao Luo, Weiyue Lu.
      Drug nanocrystals, which are comprised of active pharmaceutical ingredients and only a small amount of essential stabilizers, have the ability to improve the solubility, dissolution and bioavailability of poorly water-soluble drugs; in turn, drug nanocrystal technology can be utilized to develop novel formulations of chemotherapeutic drugs. Compared with passive targeting strategy, active tumor-targeted drug delivery, typically enabled by specific targeting ligands or molecules modified onto the surface of nanomedicines, circumvents the weak and heterogeneous enhanced permeability and retention (EPR) effect in human tumors and overcomes the disadvantages of nonspecific drug distribution, high administration dosage and undesired side effects, thereby contributing to improving the efficacy and safety of conventional nanomedicines for chemotherapy. Continuous efforts have been made in the development of active tumor-targeted drug nanocrystals delivery systems in recent years, most of which are encouraging and also enlightening for further investigation and clinical translation.
    Keywords:  active targeting; cancer; drug delivery; drug nanocrystals
    DOI:  https://doi.org/10.3390/pharmaceutics14040797
  47. Molecules. 2022 Apr 15. pii: 2568. [Epub ahead of print]27(8):
    Natural Bioactive Compounds Targeting Histone Deacetylases in Human Cancers: Recent Updates.
    Abdelhakim Bouyahya, Naoufal El Hachlafi, Tarik Aanniz, Ilhame Bourais, Hamza Mechchate, Taoufiq Benali, Mohammad Ali Shariati, Pavel Burkov, José M Lorenzo, Polrat Wilairatana, Mohammad S Mubarak, Nasreddine El Omari.
      Cancer is a complex pathology that causes a large number of deaths worldwide. Several risk factors are involved in tumor transformation, including epigenetic factors. These factors are a set of changes that do not affect the DNA sequence, while modifying the gene's expression. Histone modification is an essential mark in maintaining cellular memory and, therefore, loss of this mark can lead to tumor transformation. As these epigenetic changes are reversible, the use of molecules that can restore the functions of the enzymes responsible for the changes is therapeutically necessary. Natural molecules, mainly those isolated from medicinal plants, have demonstrated significant inhibitory properties against enzymes related to histone modifications, particularly histone deacetylases (HDACs). Flavonoids, terpenoids, phenolic acids, and alkaloids exert significant inhibitory effects against HDAC and exhibit promising epi-drug properties. This suggests that epi-drugs against HDAC could prevent and treat various human cancers. Accordingly, the present study aimed to evaluate the pharmacodynamic action of different natural compounds extracted from medicinal plants against the enzymatic activity of HDAC.
    Keywords:  cancer; epidrugs; epigenetic; histone deacetylases; natural compounds
    DOI:  https://doi.org/10.3390/molecules27082568
  48. Int J Mol Sci. 2022 Apr 07. pii: 4102. [Epub ahead of print]23(8):
    Nutraceutical Concepts and Dextrin-Based Delivery Systems.
    Gjylije Hoti, Adrián Matencio, Alberto Rubin Pedrazzo, Claudio Cecone, Silvia Lucia Appleton, Yousef Khazaei Monfared, Fabrizio Caldera, Francesco Trotta.
      Nutraceuticals are bioactive or chemical compounds acclaimed for their valuable biological activities and health-promoting effects. The global community is faced with many health concerns such as cancers, cardiovascular and neurodegenerative diseases, diabetes, arthritis, osteoporosis, etc. The effect of nutraceuticals is similar to pharmaceuticals, even though the term nutraceutical has no regulatory definition. The usage of nutraceuticals, to prevent and treat the aforementioned diseases, is limited by several features such as poor water solubility, low bioavailability, low stability, low permeability, low efficacy, etc. These downsides can be overcome by the application of the field of nanotechnology manipulating the properties and structures of materials at the nanometer scale. In this review, the linear and cyclic dextrin, formed during the enzymatic degradation of starch, are highlighted as highly promising nanomaterials- based drug delivery systems. The modified cyclic dextrin, cyclodextrin (CD)-based nanosponges (NSs), are well-known delivery systems of several nutraceuticals such as quercetin, curcumin, resveratrol, thyme essential oil, melatonin, and appear as a more advanced drug delivery system than modified linear dextrin. CD-based NSs prolong and control the nutraceuticals release, and display higher biocompatibility, stability, and solubility of poorly water-soluble nutraceuticals than the CD-inclusion complexes, or uncomplexed nutraceuticals. In addition, the well-explored CD-based NSs pathways, as drug delivery systems, are described. Although important progress is made in drug delivery, all the findings will serve as a source for the use of CD-based nanosystems for nutraceutical delivery. To sum up, our review introduces the extensive literature about the nutraceutical concepts, synthesis, characterization, and applications of the CD-based nano delivery systems that will further contribute to the nutraceutical delivery with more potent nanosystems based on linear dextrins.
    Keywords:  cyclic dextrin; disease; drug delivery; linear dextrin; nano-carrier; nanosponges; nutraceutical delivery; nutraceuticals; starch
    DOI:  https://doi.org/10.3390/ijms23084102
  49. Int J Mol Sci. 2022 Apr 15. pii: 4393. [Epub ahead of print]23(8):
    Application of Ultrasound Combined with Microbubbles for Cancer Therapy.
    Deepa Sharma, Kai Xuan Leong, Gregory J Czarnota.
      At present, cancer is one of the leading causes of death worldwide. Treatment failure remains one of the prime hurdles in cancer treatment due to the metastatic nature of cancer. Techniques have been developed to hinder the growth of tumours or at least to stop the metastasis process. In recent years, ultrasound therapy combined with microbubbles has gained immense success in cancer treatment. Ultrasound-stimulated microbubbles (USMB) combined with other cancer treatments including radiation therapy, chemotherapy or immunotherapy has demonstrated potential improved outcomes in various in vitro and in vivo studies. Studies have shown that low dose radiation administered with USMB can have similar effects as high dose radiation therapy. In addition, the use of USMB in conjunction with radiotherapy or chemotherapy can minimize the toxicity of high dose radiation or chemotherapeutic drugs, respectively. In this review, we discuss the biophysical properties of USMB treatment and its applicability in cancer therapy. In particular, we highlight important preclinical and early clinical findings that demonstrate the antitumour effect combining USMB and other cancer treatment modalities (radiotherapy and chemotherapy). Our review mainly focuses on the tumour vascular effects mediated by USMB and these cancer therapies. We also discuss several current limitations, in addition to ongoing and future efforts for applying USMB in cancer treatment.
    Keywords:  cancer; cell death; ultrasound-stimulated microbubbles; vascular damage
    DOI:  https://doi.org/10.3390/ijms23084393
  50. Antioxidants (Basel). 2022 Mar 29. pii: 660. [Epub ahead of print]11(4):
    Cannabis sativa L. Bioactive Compounds and Their Protective Role in Oxidative Stress and Inflammation.
    Dalia M Kopustinskiene, Ruta Masteikova, Robertas Lazauskas, Jurga Bernatoniene.
      Cannabis (Cannabis sativa L.) plants from the family Cannabidaceae have been used since ancient times, to produce fibers, oil, and for medicinal purposes. Psychoactive delta-9-tetrahydrocannabinol (THC) and nonpsychoactive cannabidiol (CBD) are the main pharmacologically active compounds of Cannabis sativa. These compounds have, for a long time, been under extensive investigation, and their potent antioxidant and inflammatory properties have been reported, although the detailed mechanisms of their actions have not been fully clarified. CB1 receptors are suggested to be responsible for the analgesic effect of THC, while CB2 receptors may account for its immunomodulatory properties. Unlike THC, CBD has a very low affinity for both CB1 and CB2 receptors, and behaves as their negative allosteric modulator. CBD activity, as a CB2 receptor inverse agonist, could be important for CBD anti-inflammatory properties. In this review, we discuss the chemical properties and bioavailability of THC and CBD, their main mechanisms of action, and their role in oxidative stress and inflammation.
    Keywords:  Cannabis sativa; cannabidiol; delta-9-tetrahydrocannabinol; inflammation; oxidative stress
    DOI:  https://doi.org/10.3390/antiox11040660
  51. Oxid Med Cell Longev. 2022 ;2022 5100904
    Bioactive Compounds and Their Derivatives: An Insight into Prospective Phytotherapeutic Approach against Alzheimer's Disease.
    Fahadul Islam, Jannatul Fardous Khadija, Md Harun-Or-Rashid, Md Saidur Rahaman, Mohamed H Nafady, Md Rezaul Islam, Aklima Akter, Talha Bin Emran, Polrat Wilairatana, Mohammad S Mubarak.
      Alzheimer's disease (AD) is a common neurodegenerative brain disorder that causes cellular response alterations, such as impaired cholinergic mechanism, amyloid-beta (Aβ) AD aggregation, neuroinflammation, and several other pathways. AD is still the most prevalent form of dementia and affects many individuals across the globe. The exact cause of the disorder is obscure. There are yet no effective medications for halting, preventing, or curing AD's progress. Plenty of natural products are isolated from several sources and analyzed in preclinical and clinical settings for neuroprotective effects in preventing and treating AD. In addition, natural products and their derivatives have been promising in treating and preventing AD. Natural bioactive compounds play an active modulatory role in the pathological molecular mechanisms of AD development. This review focuses on natural products from plant sources and their derivatives that have demonstrated neuroprotective activities and maybe promising to treat and prevent AD. In addition, this article summarizes the literature pertaining to natural products as agents in the treatment of AD. Rapid metabolism, nonspecific targeting, low solubility, lack of BBB permeability, and limited bioavailability are shortcomings of most bioactive molecules in treating AD. We can use nanotechnology and nanocarriers based on different types of approaches.
    DOI:  https://doi.org/10.1155/2022/5100904
  52. Front Oncol. 2022 ;12 874554
    Vascular Co-Option and Other Alternative Modalities of Growth of Tumor Vasculature in Glioblastoma.
    Domenico Ribatti, Francesco Pezzella.
      Non-angiogenic tumors grow in the absence of angiogenesis by two main mechanisms: cancer cells infiltrating and occupying the normal tissues to exploit pre-existing vessels (vascular co-option); the cancer cells themselves forms channels able to provide blood flow (the so called vasculogenic mimicry). In the original work on vascular co-option initiated by Francesco Pezzella, the non-angiogenic cancer cells were described as "exploiting" pre-existing vessels. Vascular co-option has been described in primary and secondary (metastatic) sites. Vascular co-option is defined as a process in which tumor cells interact with and exploit the pre-existing vasculature of the normal tissue in which they grow. As part of this process, cancer cells first migrate toward vessels of the primary tumor, or extravasate at a metastatic site and rest along the ab-luminal vascular surface. The second hallmark of vascular co-option is the interaction of cancer cells with the ab-luminal vascular surface. The first evidence for this was provided in a rat C6 glioblastoma model, showing that the initial tumor growth phase was not always avascular as these initial tumors can be vascularized by pre-existing vessels. The aim of this review article is to analyze together with vascular co-option, other alternative mode of vascularization occurring in glioblastoma multiforme (GBM), including vasculogenic mimicry, angiotropism and trans-differentiation of glioblastoma stem cells.
    Keywords:  angiotropism; glioblastoma; glioblastoma stem cells; vascular co-option; vasculogenic mimicry
    DOI:  https://doi.org/10.3389/fonc.2022.874554
  53. Int J Mol Sci. 2022 Apr 16. pii: 4411. [Epub ahead of print]23(8):
    Molecular Pathways Involved in the Anti-Cancer Activity of Flavonols: A Focus on Myricetin and Kaempferol.
    Maria Rosa Felice, Alessandro Maugeri, Giovambattista De Sarro, Michele Navarra, Davide Barreca.
      Natural compounds have always represented valuable allies in the battle against several illnesses, particularly cancer. In this field, flavonoids are known to modulate a wide panel of mechanisms involved in tumorigenesis, thus rendering them worthy candidates for both cancer prevention and treatment. In particular, it was reported that flavonoids regulate apoptosis, as well as hamper migration and proliferation, crucial events for the progression of cancer. In this review, we collect recent evidence concerning the anti-cancer properties of the flavonols myricetin and kaempferol, discussing their mechanisms of action to give a thorough overview of their noteworthy capabilities, which are comparable to those of their most famous analogue, namely quercetin. On the whole, these flavonols possess great potential, and hence further study is highly advised to allow a proper definition of their pharmaco-toxicological profile and assess their potential use in protocols of chemoprevention and adjuvant therapies.
    Keywords:  cancer; flavonols; in vitro; in vivo; kaempferol; myricetin; polyphenols
    DOI:  https://doi.org/10.3390/ijms23084411
  54. Acta Biomater. 2022 Apr 18. pii: S1742-7061(22)00226-4. [Epub ahead of print]
    A neutrophil-mediated carrier regulates tumor stemness by inhibiting autophagy to prevent postoperative triple-negative breast cancer recurrence and metastasis.
    Kebai Ren, Jiao He, Yue Qiu, Zhuping Xu, Xuhui Wang, Jiaxin Li, Shuya Zang, Yiliang Yang, Jiaxin Li, Yang Long, Zhirong Zhang, Man Li, Qin He.
      Recurrence and metastasis after resection are still the main challenges in clinical treatment of breast cancer. Residual tumor and cancer stem-like cells are the primary culprits of recurrence and metastasis. Recent research studies indicate that autophagy is a cytoprotective mechanism of tumors, which maintains the stemness of cancer cells and promotes tumor proliferation and metastasis. Here, we constructed a "Trojan horse" using neutrophils as the carrier (PH-RL@NEs) to prevent the recurrence and metastasis of postoperative breast cancer. Neutrophils, as a "Trojan horse," can quickly respond to postoperative inflammation and accurately deliver drugs to the residual tumor site. The inflammation-triggered "Trojan horse" was then opened to release the liposomes containing the chemotherapeutic drug paclitaxel (PTX) and the autophagy inhibitor hydroxychloroquine (HCQ). We found that HCQ could effectively inhibit tumor cell autophagy, interfere with tumor epithelial-mesenchymal transition, and reduce the tumor stem cell-like population. In the orthotopic 4T1 postoperative recurrence models, PTX and HCQ synergistically killed tumors and regulated the stemness of tumor cells, thereby significantly inhibiting tumor recurrence and metastasis. Our work proved that the inhibition of autophagy to reduce tumor stemness is feasible and effective, which opens up a new prospect for postoperative tumor treatment. STATEMENT OF SIGNIFICANCE: The present study aimed to solve the issues of postoperative recurrence and metastasis of breast cancer and low efficiency of drug administration after surgery. For this purpose, we constructed neutrophils containing hydroxychloroquine (HCQ) and paclitaxel (PTX) co-loaded liposomes (PH-RL@NEs), which for the first time regulated the stemness of tumor cells by inhibiting autophagy, thereby inhibiting postoperative recurrence and metastasis of breast cancer cells. The results showed that PH-RL@NEs enhanced the targeted drug delivery efficiency, with the help of postoperative inflammation chemotaxis of neutrophils. HCQ effectively inhibited autophagy of tumor cells and reduced tumor stem cell-like cells, thus improving the therapeutic effect in the 4T1 in situ postoperative recurrence model.
    Keywords:  Autophagy; Bioinspired drug delivery; Neutrophils; Postoperative recurrence and metastasis; Tumor stemness
    DOI:  https://doi.org/10.1016/j.actbio.2022.04.017
  55. Int J Mol Sci. 2022 Apr 12. pii: 4249. [Epub ahead of print]23(8):
    Nanoliposomes in Cancer Therapy: Marketed Products and Current Clinical Trials.
    Raquel Taléns-Visconti, Octavio Díez-Sales, Jesus Vicente de Julián-Ortiz, Amparo Nácher.
      The drugs used for cancer treatment have many drawbacks, as they damage both tumor and healthy cells and, in addition, they tend to be poorly soluble drugs. Their transport in nanoparticles can solve these problems as these can release the drug into tumor tissues, as well as improve their solubility, bioavailability, and efficacy, reducing their adverse effects. This article focuses on the advantages that nanotechnology can bring to medicine, with special emphasis on nanoliposomes. For this, a review has been made of the nanoliposomal systems marketed for the treatment of cancer, as well as those that are in the research phase, highlighting the clinical trials being carried out. All marketed liposomes studied are intravenously administered, showing a reduced intensity of side-effects compared with the nonliposomal form. Doxorubicin is the active ingredient most frequently employed. Ongoing clinical trials expand the availability of liposomal medicines with new clinical indications. In conclusion, the introduction of drugs in nanoliposomes means an improvement in their efficacy and the quality of life of patients. The future focus of research could be directed to develop multifunctional targeted nanoliposomes using new anticancer drugs, different types of existing drugs, or new standardized methodologies easily translated into industrial scale.
    Keywords:  cancer; clinical trials; nanoliposomes; translational medicine
    DOI:  https://doi.org/10.3390/ijms23084249
  56. Curr Neuropharmacol. 2022 Apr 20.
    Insight into the cellular interactions and molecular mechanisms of ketogenic diet for comprehensive management of epilepsy.
    Amit Kumar, Savita Kumari, Damanpreet Singh.
      A high-fat diet with appropriate protein and low carbohydrate content, widely known as the ketogenic diet (KD), is considered as an effective non-pharmacotherapeutic treatment option for certain types of epilepsies. Several preclinical and clinical studies have been carried out to elucidate its mechanism of antiepileptic action. Ketone bodies produced after KD's breakdown interacts with cellular excito-inhibitory processes and inhibits abnormal neuronal firing. The generated ketone bodies decrease glutamate release by inhibiting the Vesicular glutamate transporter 1 and alters the transmembrane potential by hyperpolarization. Apart from their effect on the well-known pathogenic mechanisms of epilepsy, some recent studies have shown the interaction of KD metabolites with novel neuronal targets, particularly adenosine receptors, adenosine triphosphate sensitive potassium channel, mammalian target of rapamycin, histone deacetylase, hydroxycarboxylic acid receptors, and the NLR family pyrin domain containing 3 inflammasome to suppress seizures. The role of KD in augmenting gut microbiota as a potential mechanism in epileptic seizures suppression has been established. Furthermore, some recent findings also support the beneficial effect of KD against epilepsy-associated comorbidities. Despite several advantages of the KD in epilepsy management, its use is also associated with a wide range of side effects. Hypoglycemia, excessive ketosis, acidosis, renal stones, cardiomyopathies, and other metabolic disturbances are the primary adverse effects observed with the use of KD. However, in some recent studies, modified KD has been tested with lesser side effects and better tolerability. The present review discusses the molecular mechanism of KD and its role in managing epilepsy and its associated comorbidities.
    Keywords:  Epilepsy-associated comorbidities; Gut microbiota; Mammalian target for rapamycin; Medium-chain triglyceride; Neuronal activity; Vesicular glutamate transporters
    DOI:  https://doi.org/10.2174/1570159X20666220420130109
  57. Pharmaceutics. 2022 Apr 11. pii: 835. [Epub ahead of print]14(4):
    Recent Advances in the Treatment of Alzheimer's Disease Using Nanoparticle-Based Drug Delivery Systems.
    Prashant Poudel, Soyeun Park.
      Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. Most existing treatments only provide symptomatic solutions. Here, we introduce currently available commercial drugs and new therapeutics, including repositioned drugs, to treat AD. Despite tremendous efforts, treatments targeting the hallmarks of AD show limited efficacy. Challenges in treating AD are partly caused by difficulties in penetrating the blood-brain barrier (BBB). Recently, nanoparticle (NP)-based systems have shown promising potential as precision medicines that can effectively penetrate the BBB and enhance the targeting ability of numerous drugs. Here, we describe how NPs enter the brain by crossing, avoiding, or disrupting the BBB. In addition, we provide an overview of the action of NPs in the microenvironment of the brain for the treatment of AD. Diverse systems, including liposomes, micelles, polymeric NPs, solid-lipid NPs, and inorganic NPs, have been investigated for NP drug loading to relieve AD symptoms, target AD hallmarks, and target moieties to diagnose AD. We also highlight NP-based immunotherapy, which has recently gained special attention as a potential treatment option to disrupt AD progression. Overall, this review focuses on recently investigated NP systems that represent innovative strategies to understand AD pathogenesis and suggests treatment and diagnostic modalities to cure AD.
    Keywords:  Alzheimer’s disease; blood–brain barrier; dendrimers; liposomes; nanoparticles; polymeric nanoparticles; solid–lipid nanoparticles
    DOI:  https://doi.org/10.3390/pharmaceutics14040835
  58. Cells. 2022 Apr 13. pii: 1326. [Epub ahead of print]11(8):
    Role of Plant-Derived Active Constituents in Cancer Treatment and Their Mechanisms of Action.
    Abdul Waheed Khan, Mariya Farooq, Muhammad Haseeb, Sangdun Choi.
      Despite significant technological advancements in conventional therapies, cancer remains one of the main causes of death worldwide. Although substantial progress has been made in the control and treatment of cancer, several limitations still exist, and there is scope for further advancements. Several adverse effects are associated with modern chemotherapy that hinder cancer treatment and lead to other critical disorders. Since ancient times, plant-based medicines have been employed in clinical practice and have yielded good results with few side effects. The modern research system and advanced screening techniques for plants' bioactive constituents have enabled phytochemical discovery for the prevention and treatment of challenging diseases such as cancer. Phytochemicals such as vincristine, vinblastine, paclitaxel, curcumin, colchicine, and lycopene have shown promising anticancer effects. Discovery of more plant-derived bioactive compounds should be encouraged via the exploitation of advanced and innovative research techniques, to prevent and treat advanced-stage cancers without causing significant adverse effects. This review highlights numerous plant-derived bioactive molecules that have shown potential as anticancer agents and their probable mechanisms of action and provides an overview of in vitro, in vivo and clinical trial studies on anticancer phytochemicals.
    Keywords:  cancer; clinical trials; epidemiology; incidence; mechanism; phytochemicals
    DOI:  https://doi.org/10.3390/cells11081326
  59. J Control Release. 2022 Apr 16. pii: S0168-3659(22)00213-9. [Epub ahead of print]
    Advancements in cell membrane camouflaged nanoparticles: A bioinspired platform for cancer therapy.
    Namdev Dhas, Mónica C García, Ritu Kudarha, Abhijeet Pandey, Ajinkya Nitin Nikam, Divya Gopalan, Gasper Fernandes, Soji Soman, Sanjay Kulkarni, Raviraja N Seetharam, Ruchi Tiwari, Sarika Wairkar, Chandrakantsing Pardeshi, Srinivas Mutalik.
      The idea of employing natural cell membranes as a coating medium for nanoparticles (NPs) endows man-made vectors with natural capabilities and benefits. In addition to retaining the physicochemical characteristics of the NPs, the biomimetic NPs also have the functionality of source cell membranes. It has emerged as a promising approach to enhancing the properties of NPs for drug delivery, immune evasion, imaging, cancer-targeting, and phototherapy sensitivity. Several studies have been reported with a multitude of approaches to reengineering the surface of NPs using biological membranes. Owing to their low immunogenicity and intriguing biomimetic properties, cell-membrane-based biohybrid delivery systems have recently gained a lot of interest as therapeutic delivery systems. This review summarises different kinds of biomimetic NPs reported so far, their fabrication aspects, and their application in the biomedical field. Finally, it briefs on the latest advances available in this biohybrid concept.
    Keywords:  Biomimetic nanoparticles; Camouflage; Cancer and biomedical applications; Therapeutic modifications
    DOI:  https://doi.org/10.1016/j.jconrel.2022.04.019
  60. Curr Mol Pharmacol. 2022 Apr 15.
    Resveratrol Augments Doxorubicin and Cisplatin Chemotherapy: A Novel Therapeutic Strategy.
    Sepideh Mirzaei, Mohammad Hossein Gholami, Amirhossein Zabolian, Hossein Saleki, Morteza Bagherian, Seyed Mohammadreza Torabi, Seyed Omid Sharifzadeh, Kiavash Hushmandi, Kaila R Fives, Haroon Khan, Milad Ashrafizadeh, Ali Zarrabi, Anupam Bishayee.
      BACKGROUND: The treatment of cancer is a current challenge for public health, causing high rates of morbidity and mortality around the world. Doxorubicin (DOX) and cisplatin (CP) are two well-known chemotherapeutic agents approved by the Food and Drug Administration for the treatment of cancer patients. However, there are two problems associated with DOX and CP, namely, drug resistance and adverse impact. Resveratrol (Res) belongs to the stilbene class and possesses a variety of health-promoting effects, such as antioxidant, an-ti-inflammatory, anticancer, hepatoprotective, and neuroprotective effects.OBJECTIVE: The aim of the present review is to give special attention towards the therapeutic impacts of Res in potentiating DOX and CP's antitumor activities as well as reducing their side effects.
    METHODS: PubMed, Science Direct, and Google Scholar were used to search articles for the current manuscripts.
    RESULTS: Co-administration of Res can prevent chemoresistance and potentiate the induction of apoptosis as well as cell cycle arrest in cancer cells. Res can enhance the sensitivity of can-cer cells to DOX and CP chemotherapy, via inhibiting the migration and metastasis of cancer cells. Simultaneously, Res, owing to its therapeutic actions, ameliorates the adverse impacts of DOX and CP on normal cells and organs, including the liver, kidney, brain, and testes. As Res suffers from poor bioavailability, to improve its antitumor activity and protective effects, nanoformulations have been developed with promising results.
    CONCLUSION: Based on preclinical studies, it is obvious that Res is a promising adjuvant for CP and DOX chemotherapy and its benefits can be utilized in the clinical course.
    Keywords:  Resveratrol; antitumor activity; cancer chemotherapy; chemoprotection; chemoresistance; cisplatin; doxorubicin
    DOI:  https://doi.org/10.2174/1874467215666220415131344
  61. Evid Based Complement Alternat Med. 2022 ;2022 1534083
    Cruciferous Vegetables and Their Bioactive Metabolites: from Prevention to Novel Therapies of Colorectal Cancer.
    Duygu Ağagündüz, Teslime Özge Şahin, Birsen Yılmaz, Kübra Damla Ekenci, Şehriban Duyar Özer, Raffaele Capasso.
      The Brassicaceae family, known as cruciferous vegetables, includes many economically important species, mainly edible oil plants, vegetable species, spice plants, and feed plants. Cruciferous vegetables are foods rich in nutritive composition and are also a good source of dietary fiber. Besides, cruciferous vegetables contain various bioactive chemicals known as glucosinolates and S-methyl cysteine sulfoxide, including sulphur-containing cancer-protective chemicals. Numerous studies have reported that daily intake of sulphurous vegetables helps prevent cancer formation and reduces cancer incidence, especially in colorectal cancer, through various mechanisms. The potential mechanisms of these compounds in preventing cancer in experimental studies are as follows: protecting cells against DNA damage, inactivating carcinogenic substances, showing antiviral and antibacterial effects, triggering apoptosis in cells with disrupted structure, inhibiting tumour cell migration causing metastasis and the development of tumour-feeding vessels (angiogenesis). These beneficial anticancer effects of cruciferous vegetables are generally associated with glucosinolates in their composition and some secondary metabolites, as well as other phenolic compounds, seed oils, and dietary fiber in the literature. This review aims to examine to the roles of cruciferous vegetables and their important bioactive metabolites in the prevention and treatment of colorectal cancer.
    DOI:  https://doi.org/10.1155/2022/1534083
  62. Biomed Res Int. 2022 ;2022 9165443
    Using Chitosan-Coated Polymeric Nanoparticles-Thermosensitive Hydrogels in association with Limonene as Skin Drug Delivery Strategy.
    Estefânia V R Campos, Patrícia L F Proença, Tais G da Costa, Renata de Lima, Leonardo F Fraceto, Daniele R de Araujo.
      Topical delivery of local anesthetics (LAs) is commonly used to decrease painful sensations, block pain throughout procedures, and alleviate pain after surgery. Dermal and/or transdermal delivery of LAs has other advantages, such as sustained drug delivery and decreased systemic adverse effects. This study reports the development of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles coated with chitosan for the sustained release and topicality of benzocaine (BZC) and topical delivery. BZC PLGA nanoparticles or nonencapsulated drugs were further incorporated into Poloxamer hydrogels (Pluronic™ F-127). The nanoparticles showed a mean diameter of 380 ± 4 nm, positive zeta potential after coating with chitosan (23.3 ± 1.7 mV), and high encapsulation efficiency (96.7 ± 0.02%). Cellular viability greater than 70% for both fibroblasts and keratinocytes was observed after treatment with nanoparticles, which is in accordance with the preconized guidelines for biomedical devices and delivery systems. Both the nanoparticles and hydrogels were able to modulate BZC delivery and increase drug permeation when compared to the nonencapsulated drug. Furthermore, the incorporation of limonene into hydrogels containing BZC-loaded nanoparticles increased the BZC permeation rates. Non-Newtonian and pseudoplastic behaviors were observed for all hydrogel nanoformulations with or without nanoparticles. These results demonstrate that the hydrogel-nanoparticle hybrids could be a promising delivery system for prolonged local anesthetic therapy.
    DOI:  https://doi.org/10.1155/2022/9165443
  63. Nanomedicine (Lond). 2022 Apr 22.
    Drug delivery through nanoparticles in solid tumors: a mechanistic understanding.
    Farshad Moradi Kashkooli, Mohsen Rezaeian, M Soltani.
      Aim: In this study, the main goal was to apply a multi-scale computational model in evaluating nano-sized drug-delivery systems, following extracellular drug release, into solid tumors in order to predict treatment efficacy. Methods: The impact of several parameters related to tumor (size, shape, vessel-wall pore size, and necrotic core size) and therapeutic agents (size of nanoparticles, binding affinity of drug, drug release rate from nanoparticles) are examined in detail. Results: This study illustrates that achieving a higher treatment efficacy requires smaller nanoparticles (NPs) or a low binding affinity and drug release rate. Long-term analysis finds that a slow release rate in extracellular space does not always improve treatment efficacy compared with a rapid release rate; NP size as well as binding affinity of drug are also highly influential. Conclusions: The presented methodology can be used as a step forward towards optimization of patient-specific nanomedicine plans.
    Keywords:  binding affinity of drug; drug release rate; drug-loaded nanocarrieres; mathematical modeling of cancer nanomedicine; solid tumor; targeted drug delivery
    DOI:  https://doi.org/10.2217/nnm-2021-0126
  64. Pharmaceuticals (Basel). 2022 Mar 24. pii: 397. [Epub ahead of print]15(4):
    Antiosteoporosis Effects, Pharmacokinetics, and Drug Delivery Systems of Icaritin: Advances and Prospects.
    Lifang Gao, Shuang-Qing Zhang.
      Osteoporosis is a systemic skeletal disorder affecting over 200 million people worldwide and contributes dramatically to global healthcare costs. Available anti-osteoporotic drug treatments including hormone replacement therapy, anabolic agents, and bisphosphonates often cause adverse events which limit their long-term use. Therefore, the application of natural products has been proposed as an alternative therapy strategy. Icaritin (ICT) is not only an enzyme-hydrolyzed product of icariin but also an intestinal metabolite of eight major flavonoids of the traditional Chinese medicinal plant Epimedium with extensive pharmacological activities, such as strengthening the kidney and reinforcing the bone. ICT displays several therapeutic effects, including osteoporosis prevention, neuroprotection, antitumor, cardiovascular protection, anti-inflammation, and immune-protective effect. ICT inhibits bone resorption activity of osteoclasts and stimulates osteogenic differentiation and maturation of bone marrow stromal progenitor cells and osteoblasts. As for the mechanisms of effect, ICT regulates relative activities of two transcription factors Runx2 and PPARγ, determines the differentiation of MSCs into osteoblasts, increases mRNA expression of OPG, and inhibits mRNA expression of RANKL. Poor water solubility, high lipophilicity, and unfavorable pharmacokinetic properties of ICT restrict its anti-osteoporotic effects, and novel drug delivery systems are explored to overcome intrinsic limitations of ICT. The paper focuses on osteogenic effects and mechanisms, pharmacokinetics and delivery systems of ICT, and highlights bone-targeting strategies to concentrate ICT on the ideal specific site of bone. ICT is a promising potential novel therapeutic agent for osteoporosis.
    Keywords:  antiosteoporosis; drug delivery systems; icaritin; pharmacokineticcs
    DOI:  https://doi.org/10.3390/ph15040397
  65. Metabolites. 2022 Apr 14. pii: 350. [Epub ahead of print]12(4):
    Reprogramming of Fatty Acid Metabolism in Gynaecological Cancers: Is There a Role for Oestradiol?
    Azilleo Kristo Mozihim, Ivy Chung, Nur Akmarina B M Said, Amira Hajirah Abd Jamil.
      Gynaecological cancers are among the leading causes of cancer-related death among women worldwide. Cancer cells undergo metabolic reprogramming to sustain the production of energy and macromolecules required for cell growth, division and survival. Emerging evidence has provided significant insights into the integral role of fatty acids on tumourigenesis, but the metabolic role of high endogenous oestrogen levels and increased gynaecological cancer risks, notably in obesity, is less understood. This is becoming a renewed research interest, given the recently established association between obesity and incidence of many gynaecological cancers, including breast, ovarian, cervical and endometrial cancers. This review article, hence, comprehensively discusses how FA metabolism is altered in these gynaecological cancers, highlighting the emerging role of oestradiol on the actions of key regulatory enzymes of lipid metabolism, either directly through its classical ER pathways, or indirectly via the IGIFR pathway. Given the dramatic rise in obesity and parallel increase in the prevalence of gynaecological cancers among premenopausal women, further clarifications of the complex mechanisms underpinning gynaecological cancers are needed to inform future prevention efforts. Hence, in our review, we also highlight opportunities where metabolic dependencies can be exploited as viable therapeutic targets for these hormone-responsive cancers.
    Keywords:  cancer metabolism; fatty acid; gynaecological cancer; obesity; oestradiol
    DOI:  https://doi.org/10.3390/metabo12040350
  66. Pharmaceuticals (Basel). 2022 Apr 12. pii: 466. [Epub ahead of print]15(4):
    Evening Primrose Oil Improves Chemotherapeutic Effects in Human Pancreatic Ductal Adenocarcinoma Cell Lines-A Preclinical Study.
    Laura Zeppa, Cristina Aguzzi, Giorgia Versari, Margherita Luongo, Maria Beatrice Morelli, Federica Maggi, Consuelo Amantini, Giorgio Santoni, Oliviero Marinelli, Massimo Nabissi.
      Evening Primrose oil (EPO), obtained from the seeds of Evening Primrose (Oenothera L.), is largely used as a dietary supplement, especially after cancer diagnosis. Human pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease correlated with poor clinical prognosis and a very low response rate to common chemotherapy. The aim of this work was to study the potential ability of EPO to improve the effects of chemotherapeutic drugs in PANC-1 and MIAPaCa-2 cell lines. Cytotoxicity, cell death, reactive oxygen species (ROS) production and EPO anticancer activity associated with the main chemotherapeutic drugs commonly used in therapy were investigated. Results showed that EPO reduced PDAC cell viability and increased paclitaxel efficacy. This evidence suggests that EPO may be used as a potential supplement to increase chemotherapeutic efficacy in PDAC therapy.
    Keywords:  Oenothera biennis; chemoresistance; cytotoxicity; evening primrose oil; human pancreatic ductal adenocarcinoma; paclitaxel chemoresistance; pancreatic cancer
    DOI:  https://doi.org/10.3390/ph15040466
  67. Biomolecules. 2022 Mar 24. pii: 491. [Epub ahead of print]12(4):
    Cannabis Biomolecule Effects on Cancer Cells and Cancer Stem Cells: Cytotoxic, Anti-Proliferative, and Anti-Migratory Activities.
    Hadar Peeri, Hinanit Koltai.
      Cancer is a complex family of diseases affecting millions of people worldwide. Gliomas are primary brain tumors that account for ~80% of all malignant brain tumors. Glioblastoma multiforme (GBM) is the most common, invasive, and lethal subtype of glioma. Therapy resistance and intra-GBM tumoral heterogeneity are promoted by subpopulations of glioma stem cells (GSCs). Cannabis sativa produces hundreds of secondary metabolites, such as flavonoids, terpenes, and phytocannabinoids. Around 160 phytocannabinoids have been identified in C. sativa. Cannabis is commonly used to treat various medical conditions, and it is used in the palliative care of cancer patients. The anti-cancer properties of cannabis compounds include cytotoxic, anti-proliferative, and anti-migratory activities on cancer cells and cancer stem cells. The endocannabinoids system is widely distributed in the body, and its dysregulation is associated with different diseases, including various types of cancer. Anti-cancer activities of phytocannabinoids are mediated in glioma cells, at least partially, by the endocannabinoid receptors, triggering various cellular signaling pathways, including the endoplasmic reticulum (ER) stress pathway. Specific combinations of multiple phytocannabinoids act synergistically against cancer cells and may trigger different anti-cancer signaling pathways. Yet, due to scarcity of clinical trials, there remains no solid basis for the anti-cancer therapeutic potential of cannabis compounds.
    Keywords:  cancer; cancer stem cells; cannabinoid receptors; cannabis; cytotoxicity; glioblastoma; glioma; phytocannabinoids; synergy
    DOI:  https://doi.org/10.3390/biom12040491
  68. Front Oncol. 2022 ;12 850401
    Tumor Glucose and Fatty Acid Metabolism in the Context of Anthracycline and Taxane-Based (Neo)Adjuvant Chemotherapy in Breast Carcinomas.
    Anna Mária Tőkés, Stefan Vári-Kakas, Janina Kulka, Beáta Törőcsik.
      Breast cancer is characterized by considerable metabolic diversity. A relatively high percentage of patients diagnosed with breast carcinoma do not respond to standard-of-care treatment, and alteration in metabolic pathways nowadays is considered one of the major mechanisms responsible for therapeutic resistance. Consequently, there is an emerging need to understand how metabolism shapes therapy response, therapy resistance and not ultimately to analyze the metabolic changes occurring after different treatment regimens. The most commonly applied neoadjuvant chemotherapy regimens in breast cancer contain an anthracycline (doxorubicin or epirubicin) in combination or sequentially administered with taxanes (paclitaxel or docetaxel). Despite several efforts, drug resistance is still frequent in many types of breast cancer, decreasing patients' survival. Understanding how tumor cells rapidly rewire their signaling pathways to persist after neoadjuvant cancer treatment have to be analyzed in detail and in a more complex system to enable scientists to design novel treatment strategies that target different aspects of tumor cells and tumor resistance. Tumor heterogeneity, the rapidly changing environmental context, differences in nutrient use among different cell types, the cooperative or competitive relationships between cells pose additional challenges in profound analyzes of metabolic changes in different breast carcinoma subtypes and treatment protocols. Delineating the contribution of metabolic pathways to tumor differentiation, progression, and resistance to different drugs is also the focus of research. The present review discusses the changes in glucose and fatty acid pathways associated with the most frequently applied chemotherapeutic drugs in breast cancer, as well the underlying molecular mechanisms and corresponding novel therapeutic strategies.
    Keywords:  anthracycline; breast carcinoma; glucose and lipid metabolism; neoadjuvant and adjuvant chemotherapy; taxane
    DOI:  https://doi.org/10.3389/fonc.2022.850401
  69. Life (Basel). 2022 Mar 27. pii: 485. [Epub ahead of print]12(4):
    Self-Assembled Nanomicellar Formulation of Docetaxel as a Potential Breast Cancer Chemotherapeutic System.
    Meshal Alshamrani, Navid J Ayon, Abdullah Alsalhi, Omowumi Akinjole.
      Docetaxel (DTX) is classified as a class IV drug that exhibits poor aqueous solubility (6-7 µg/mL in water) and permeability (P-glycoprotein substrate). The main objective of this study was to construct, characterize, and evaluate docetaxel loaded nanomicellar formulation in vitro for oral delivery to enhance the absorption and bioavailability of DTX, as well as to circumvent P-gp efflux inhibition. Formulations were prepared with two polymeric surfactants, hydrogenated castor oil-40 (HCO-40) and D-α-Tocopherol polyethylene glycol 1000 succinate (VIT E TPGS) with solvent evaporation technique, and the resulting DTX nanomicellar formulations were characterized by proton nuclear magnetic resonance spectroscopy (1H NMR), Fourier Transform Infrared Spectroscopy (FT-IR), X-ray powder diffraction (XRD), and transmission electron microscopy (TEM). Proton NMR, FT-IR, and XRD data indicated that DTX was completely encapsulated within the hydrophobic core of the nanomicelles in its amorphous state. TEM data revealed a smooth spherical shape of the nanomicellar formulation. The optimized formulation (F-2) possessed a mean diameter of 13.42 nm, a zeta potential of -0.19 mV, with a 99.3% entrapment efficiency. Dilution stability study indicated that nanomicelles were stable up to 100-fold dilution with minimal change in size, poly dispersity index (PDI), and zeta potential. In vitro cytotoxicity study revealed higher anticancer activity of DTX nanomicelles at 5 µM compared to the native drug against breast cancer cell line (MCF-7) cells. The LC-MS data confirmed the chemical stability of DTX within the nanomicelles. In vitro drug release study demonstrated faster dissolution of DTX from the nanomicelles compared to the naked drug. Our experimental results exhibit that nanomicelles could be a drug delivery system of choice to encapsulate drugs with low aqueous solubility and permeability that can preserve the stability of the active constituents to provide anticancer activity.
    Keywords:  anticancer activity; breast cancer; docetaxel; enhanced solubility; nanomicelles; vitamin E TPGS delivery
    DOI:  https://doi.org/10.3390/life12040485
  70. Anticancer Agents Med Chem. 2022 Apr 18.
    Liposomal Drug Delivery And Its Potential Impact On Cancer Research.
    Sankha Bhattacharya, Dnyanesh Saindane, Bhupendra G Prajapati.
      Liposomes are one of the most versatile drug carriers due to their functional properties, such as higher biocompatibility, the ability to encapsulate hydrophilic and hydrophobic products, and higher biodegradability. Liposomes are a better and more significant nanocarrier for cancer therapy. The key to developing a better cancer-targeted nanocarrier is the development of targeted liposomes using various approaches. Several traditional and novel liposome preparation methods are briefly discussed in this mini-review. The current state of liposome targeting, active and passive liposome targeting in cancer therapy, ligand directed targeting (antibody, aptamer, and protein/peptide-mediated targeting), and other miscellaneous approaches such as stimuli-responsive liposome-based targeting, autophagy inhibition mediated targeting, and curcumin loaded liposomal targeting are all discussed within. All of this gathered and compiled information will shed new light on liposome targeting strategies in cancer treatment and will pique the interest of aspiring researchers and academicians.
    Keywords:  Aptamer drug delivery; Cancer therapy.; Ligand-based targeting; Liposomes; Marketed liposomal formulations; lipoplexes
    DOI:  https://doi.org/10.2174/1871520622666220418141640
  71. Life (Basel). 2022 Apr 15. pii: 591. [Epub ahead of print]12(4):
    A Flavonoid on the Brain: Quercetin as a Potential Therapeutic Agent in Central Nervous System Disorders.
    Dagmara Wróbel-Biedrawa, Karolina Grabowska, Agnieszka Galanty, Danuta Sobolewska, Irma Podolak.
      Quercetin is one of the most common, naturally occurring flavonoids, structurally classified to the flavonol subfamily. This compound, found in many edible and medicinal plants either as a free or glycosidated form, has been scientifically exploited for many years, and one could hardly expect it could be a hero of some additional story. Commonly recognized as an anti-inflammatory agent, quercetin not only limits capillary vessel permeability by inhibiting hyaluronidase but also blocks cyclooxygenases and lipoxygenases. As a typical flavonoid, it is also known for its antioxidant effect, which was confirmed by many in vitro and in vivo studies. Throughout the years, numerous other activities were reported for quercetin, including antidiabetic, anti-proliferative, or anti-viral. Of note, recent data have revealed its potential role as a therapeutic agent for several central nervous system disorders. This review provides an overview of available experimental data on quercetin and its complexes with respect to central nervous system diseases, with a main focus on some aspects that were not discussed previously, such as anti-anxiolytic effects, anti-Huntington's disease activity, or therapeutic potential in brain cancer. Moreover, quercetin's protective role in some of these diseases is discussed, especially as an anti-neuroinflammatory agent. Bearing in mind the poor bioavailability of this compound, possible options that would enhance its delivery to the site of action are also presented.
    Keywords:  CNS; antioxidant; cognition; nanoformulations; neurodegeneration; neuroinflammation; quercetin
    DOI:  https://doi.org/10.3390/life12040591
  72. Nanomaterials (Basel). 2022 Apr 11. pii: 1304. [Epub ahead of print]12(8):
    3D-Printable Oxygen- and Drug-Carrying Nanocomposite Hydrogels for Enhanced Cell Viability.
    Ravi Kumar, Nermin Seda Kehr.
      Nanocomposite (NC) hydrogels have been widely studied due to their tunable biochemical/ physical properties for tissue engineering and biomedical applications. Nanoparticles (NPs) that can carry bioactive hydrophilic/hydrophobic molecules and provide sustained release within hydrogels are an ideal all-in-one-platform for local drug delivery applications. Dual delivery of different bioactive molecules is desired to achieve synergetic therapeutic effect in biomedical applications. For example, the co-administration of drug molecules and oxygen (O2) is an ideal choice to improve cell viability, while reducing the harmful effects of hypoxia. Therefore, we prepared drug-loaded O2-carrying periodic mesoporous organosilica (PMO-PFC) NPs and their 3D-printable hydrogel precursors based on gelatin methacryloyl (GelMa) to fabricate 3D-scaffolds to improve cell-viability under both normoxia (21% O2) and hypoxia (1% O2) conditions. We used rutin as the hydrophobic drug molecule to demonstrate that our O2-carrying PMO-PFC NPs can improve hydrophobic drug loading and their sustained delivery over 7 days, while supporting sustained O2-delivery for 14 days under hypoxia conditions. Furthermore, the fibroblast cells were interacted with NC hydrogel scaffolds to test their impact on cell-viability under both normoxia and hypoxia conditions. The improved rheological properties suggest the prepared NC hydrogels can be further tested or used as an injectable hydrogel. The improved mechanical properties and 3D printability of NC hydrogels indicate their potential use as artificial tissue constructs.
    Keywords:  3D-printing; NC hydrogel; drug-delivery; oxygen-carrying hydrogels
    DOI:  https://doi.org/10.3390/nano12081304
  73. J Control Release. 2022 Apr 19. pii: S0168-3659(22)00218-8. [Epub ahead of print]
    Tailored protein-conjugated DNA nanoplatform for synergistic cancer therapy.
    Dingkang Liu, Ye Chen, Qun Wang, Yue Ji, Lichen Bao, Wenbing Yao, Xiangdong Gao, Jun Yin.
      Multidrug resistance (MDR) to chemotherapeutic drugs and targeted drug delivery are recurring issues in clinical cancer treatment. Here, a multifunctional fusion protein-DNA conjugate was designed as a co-delivery vehicle for anticancer peptides and chemotherapeutic drugs to combat both drug-resistant and drug-sensitive tumor cells. The fusion protein was constructed by fusing a PsTag polypeptide, a matrix metalloproteinase 2 (MMP2)-degradable domain, and the mitochondria-targeted pro-apoptotic peptide KLAKLAKKLAKLAK. Doxorubicin was efficiently loaded into the fusion protein pre-conjugated dendrimer-like DNA nanostructure. With the incorporation of enhanced stability, tumor targeting, and controlled-release elements, the tailored nanostructure can selectively enter tumor cells and synergistically exert antitumor activity with no significant adverse effects. Thus, these protein-conjugated DNA nanocarriers could be a potential co-delivery system for protein/peptide and chemotherapeutic drugs delivery in synergistic cancer therapy.
    Keywords:  Cancer; DNA nanotechnology; Drug delivery; Multidrug resistance; Peptide therapeutics
    DOI:  https://doi.org/10.1016/j.jconrel.2022.04.022
  74. Front Pharmacol. 2021 ;12 800481
    CD44-Targeted Nanocarrier for Cancer Therapy.
    Prashant Kesharwani, Rahul Chadar, Afsana Sheikh, Waleed Y Rizg, Awaji Y Safhi.
      Cluster of differentiation 44 (CD44) is a cell surface glycoprotein overexpressed in varieties of solid tumors including pancreatic, breast, ovary, brain, and lung cancers. It is a multi-structural glycoprotein of the cell surface which is majorly involved in cell proliferation, cell-to-cell interaction, cellular migration, inflammation, and generation of immune responses. Numerous studies focus on the development of nanocarriers for active targeting of the CD44 receptor to improve efficacy of targeting chemotherapy and achieve precise chemotherapy by defining the release, uptake, and accumulation of therapeutic agents. The CD44 receptor has a selective binding affinity towards hyaluronic and chondroitin sulfate (CS). Taking this into consideration, this review focused on the role of CD44 in cancer and its therapy using several nanocarriers such as polymeric/non-polymeric nanoparticles, dendrimer, micelles, carbon nanotubes, nanogels, nanoemulsions etc., for targeted delivery of several chemotherapeutic molecules and nucleic acid. This review also illuminates the role of hyaluronic acid (HA) in cancer therapy, interaction of HA with CD44, and various approaches to target CD44-overexpressed neoplastic cells.
    Keywords:  CD44; anticancer therapy; gene delivery; hyaluronic acid; nanocarrier; targeted drug delivery
    DOI:  https://doi.org/10.3389/fphar.2021.800481
  75. Molecules. 2022 Apr 13. pii: 2498. [Epub ahead of print]27(8):
    Health Benefits of Quercetin in Age-Related Diseases.
    Deepika, Pawan Kumar Maurya.
      Polyphenols are the known group of phytochemicals that essentially consists of phenolic rings. These are the plant product present in varied fruits and vegetables. These secondary metabolites perform a protective function in plants from environmental and biological stress. When consumed as a human diet these are also known to prevent various age-associated diseases. Polyphenols are known to possess antioxidant properties and protect against oxidative stress. The literature survey was carried out using databases such as PubMed, Science direct and Springer. The research articles from last 10-12 years were selected for this review based on its relevancy with the topic. The articles selected was mainly focused on quercetin and its health benefits. The present review highlights the main functions of a flavonoid, quercetin. Quercetin is among the widely occurring polyphenol, found abundantly in nature. It is commonly present in different plant products. Onion is known to have the highest quantity of quercetin. This plant compound is possessed antioxidant properties and is considered to have a protective function against aging. It is known to be present in both free and conjugated forms. Quercetin has anti-oxidative, anti-inflammatory, anti-proliferative, anti-carcinogenic, anti-diabetic, and anti-viral properties. The molecule is lipophilic and can easily cross the BBB (Blood-Brain Barrier) and hence protects from neurodegenerative diseases. Various in vivo and in vitro studies have demonstrated the role of quercetin and here a detailed review of quercetin as a curative agent in neurodegeneration, diabetes, cancer, and inflammation has been carried out. Studies have proved that quercetin plays a crucial role in the prevention of age-related disorders. Quercetin is a potent antioxidant which is currently being used in various pharmaceuticals. Properties of quercetin can be further explored in various other disorders. Nanoformulations and liposomal formulations of quercetin can be made to treat other age associated diseases.
    Keywords:  antioxidant; cancer; diabetes; neurodegeneration; polyphenols; quercetin
    DOI:  https://doi.org/10.3390/molecules27082498
  76. J Control Release. 2022 Apr 18. pii: S0168-3659(22)00208-5. [Epub ahead of print]
    Caspase-3 mediated switch therapy of self-triggered and long-acting prodrugs for metastatic TNBC.
    Ha Rin Kim, Young Seok Cho, Seung Woo Chung, Jeong Uk Choi, Yoon Gun Ko, Seong Jin Park, Sang Yoon Kim, Youngro Byun.
      Triple-negative breast cancer (TNBC) is characterized by its highly heterogeneous microenvironment and propensity for aggressive behavior, both of which represent, along with poor prognosis and high incidence of relapse, the main challenges of curing the disease. Although recent progress in targeted chemotherapy combinations has shown promising outcomes, conventional targeted chemotherapeutic approaches have relied on exploiting the expression of certain molecules or proteins overexpressed on cancer cells as drug targets, which have demonstrated limited clinical benefit against metastatic cancers. Here, we describe a tumoral caspase-3 mediated peptide-doxorubicin conjugates (PDC) switch therapy that adopts two different caspase-3 cleavable PDCs, RGDEVD-DOX (TPD1) and EMC-KGDEVD-DOX (MPD1), for targeting metastatic triple-negative breast cancer (mTNBC). First, using TPD1, an integrin αVβ3 based targeted strategy was utilized to target tumor cells or tumor vasculature associated with the highly malignant progression of mTNBC. TPD1 triggered the tumor cell-specific initial apoptosis and the induction of caspase-3 expression in the target tumor site. Then MPD1 was administered sequentially, which is an albumin-binding prodrug, and activated by induced caspase-3 in order to maintain the tumoral caspase-3 level and release the cytotoxic payload. The PDC switch therapy markedly accumulated doxorubicin in the tumor site and augmented tumor-specific in situ amplification of apoptosis. Importantly, the PDC switch therapy exerted a bystander killing effect on the neighboring cancer cells thus demonstrating potent therapeutic efficacy against both local and metastatic cancers. Given the limited therapeutic outcomes with conventional targeted therapies, our strategy of regulating the expression of caspase-3 level as a drug target could provide as a more durable and effective alternative in the treatment of highly heterogeneous mTNBC.
    Keywords:  Caspase-3; Heterogeneity; Metastasis; Peptide-drug conjugate; Switch therapy; TNBC
    DOI:  https://doi.org/10.1016/j.jconrel.2022.04.014
  77. Pharmaceutics. 2022 Apr 03. pii: 781. [Epub ahead of print]14(4):
    Carbon Nanotubes-Based Assays for Cancer Detection and Screening.
    Cristina Bura, Teodora Mocan, Cristiana Grapa, Lucian Mocan.
      Carbon nanotubes (CNTs) were considered a potential cargo for cancer therapy and diagnosis following researchers' shared goal of finding a new delivery system to enhance the pharmacological performance of the administered drugs. To date, several excellent reviews have focused on the role of CNTs as drug delivery systems, although there is currently no existing study that gathers all the advances in research-connected carbon nanotubes-based assay development for the early detection of cancer. In this review article, we will focus on the emerging role of CNTs as anticancer detection agents.
    Keywords:  cancer; carbon nanotubes; diagnosis; markers
    DOI:  https://doi.org/10.3390/pharmaceutics14040781
  78. Carbohydr Polym. 2022 Jul 15. pii: S0144-8617(22)00306-X. [Epub ahead of print]288 119402
    pH/reduction dual-responsive hyaluronic acid-podophyllotoxin prodrug micelles for tumor targeted delivery.
    Min Li, Yinan Zhao, Jiao Sun, Huiying Chen, Zhanbiao Liu, Kexin Lin, Pengfei Ma, Wenjun Zhang, Yuhong Zhen, Shufen Zhang, Shubiao Zhang.
      Polymer-based prodrug nanocarriers with tumor-targeting and controlled-release properties are in great demand for enhanced cancer treatment. Hyaluronic acid (HA), which has excellent biocompatibility and targeting ability for cluster determinant 44 (CD44), has been proposed for delivering drugs that have poor solubility and high toxicity. Herein, podophyllotoxin (PPT) was conjugated to HA via ester and disulfide linkages to construct a pH- and reduction-responsive prodrug (HA-S-S-PPT). The micelles self-assembled from HA-S-S-PPT prodrug efficiently accumulated at tumor site due to HA receptor-mediated endocytosis. HA-S-S-PPT micelles exhibited 33.1% higher cumulative release than HA-NH-CO-PPT micelles (sensitive only to pH) owing to their dual responsiveness to pH and reduction. HA-S-S-PPT micelles achieved excellent antitumor activity in vivo, with the tumor inhibition rate reaching 92%, significantly higher than that of HA-NH-CO-PPT micelles (65%), and negligible systemic toxicity. This controllable-targeting nanoparticle system provides a potential platform for clinical application of PPT.
    Keywords:  Controlled release; Hyaluronic acid; Prodrug micelles; Targeted drug delivery; pH/reduction dual-responsive
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119402
  79. Int J Mol Sci. 2022 Apr 15. pii: 4380. [Epub ahead of print]23(8):
    The Result of Vitamin C Treatment of Patients with Cancer: Conditions Influencing the Effectiveness.
    János Hunyady.
      Vitamin C (ascorbic acid, AA) is a weak sugar acid structurally related to glucose. All known physiological and biochemical functions of AA are due to its action as an electron donor. Ascorbate readily undergoes pH-dependent autoxidation creating hydrogen peroxide (H2O2). In vitro evidence suggests that vitamin C functions at low concentrations as an antioxidant while high concentration is pro-oxidant. Thus, both characters of AA might be translated into clinical benefits. In vitro obtained results and murine experiments consequently prove the cytotoxic effect of AA on cancer cells, but current clinical evidence for high-dose intravenous (i.v.) vitamin C's therapeutic effect is ambiguous. The difference might be caused by the missing knowledge of AA's actions. In the literature, there are many publications regarding vitamin C and cancer. Review papers of systematic analysis of human interventional and observational studies assessing i.v. AA for cancer patients' use helps the overview of the extensive literature. Based on the results of four review articles and the Cancer Information Summary of the National Cancer Institute's results, we analyzed 20 publications related to high-dose intravenous vitamin C therapy (HAAT). The analyzed results indicate that HAAT might be a useful cancer-treating tool in certain circumstances. The AA's cytotoxic effect is hypoxia-induced factor dependent. It impacts only the anoxic cells, using the Warburg metabolism. It prevents tumor growth. Accordingly, discontinuation of treatment leads to repeated expansion of the tumor. We believe that the clinical use of HAAT in cancer treatment should be reassessed. The accumulation of more study results on HAAT is desperately needed.
    Keywords:  cancer; clinical trials; high-dose vitamin C therapy; intravenous vitamin C
    DOI:  https://doi.org/10.3390/ijms23084380
  80. Gels. 2022 Mar 24. pii: 205. [Epub ahead of print]8(4):
    Emerging Fabrication Strategies of Hydrogels and Its Applications.
    Fayaz Ali, Imran Khan, Jianmin Chen, Kalsoom Akhtar, Esraa M Bakhsh, Sher Bahadar Khan.
      Recently, hydrogels have been investigated for the controlled release of bioactive molecules, such as for living cell encapsulation and matrices. Due to their remote controllability and quick response, hydrogels are widely used for various applications, including drug delivery. The rate and extent to which the drugs reach their targets are highly dependent on the carriers used in drug delivery systems; therefore the demand for biodegradable and intelligent carriers is progressively increasing. The biodegradable nature of hydrogel has created much interest for its use in drug delivery systems. The first part of this review focuses on emerging fabrication strategies of hydrogel, including physical and chemical cross-linking, as well as radiation cross-linking. The second part describes the applications of hydrogels in various fields, including drug delivery systems. In the end, an overview of the application of hydrogels prepared from several natural polymers in drug delivery is presented.
    Keywords:  drug delivery; hydrogels; natural polymers
    DOI:  https://doi.org/10.3390/gels8040205
  81. J Ethnopharmacol. 2022 Apr 14. pii: S0378-8741(22)00310-5. [Epub ahead of print] 115271
    A review of the ethnomedicinal uses, chemistry, and pharmacological properties of the genus Acanthus (Acanthaceae).
    Patrícia Matos, Maria Teresa Batista, Artur Figueirinha.
      ETHNOPHARMACOLOGICAL RELEVANCE: The Acanthus genus belongs to the Acanthaceae family, and its species are distributed in all continents, mainly in tropical and subtropical regions. Several traditional applications are referred to, but few scientific studies validate them. Despite this, studies in animal models corroborate some of its uses in folk medicine, such as anticancer, antidiabetic, anti-inflammatory, and antinociceptive, which encourages the research on plants of this genus.AIM OF THE REVIEW: To our knowledge, this document is the first comprehensive review study that provides information on the geographic distribution, botanical characteristics, ethnomedicinal uses, phytochemicals, and pharmacological activities of some Acanthus species to understand the correlation between traditional uses, phytochemical, and pharmacological activities, providing perspectives for future studies.
    RESULTS: In traditional medicine, Acanthus species are mainly used for diseases of respiratory, nervous and reproductive system, gastrointestinal and urinary tract, and skin illness. The most used species are A. montanus, A. ilicifolius, and A. ebracteatus. Chemical compounds (125) from different chemical classes were isolated and identified in seven species, mainly from A. ilicifolius, about 80, followed by A. ebracteatus and A. montanus, appearing with a slightly lower number with fewer phytochemical profile studies. Isolated phytoconstituents have been mainly alkaloids, phenylpropanoid glycosides, and phenylethanoids. In addition, aliphatic glycosides, flavonoids, lignan glycosides, megastigmane derivatives, triterpenoids, steroids, fatty acids, alcohols, hydroxybenzoic acids, simple phenols were also cited. Scientific studies from Acanthus species extracts and their phytoconstituents support their ethnomedical uses. Antimicrobial activity that is the most studied, followed by the antioxidant, anti-inflammatory, and anticancer properties, underlie many Acanthus species activities. A. dioscoridis, A. ebracteatus, A. hirsutus, A. ilicifolius, A. mollis, A. montanus, and A. polystachyus have studies on these activities, A. ilicifolius being the one with the most publications. Most studies were essentially performed in vitro. However, the anticancer, antidiabetic, anti-inflammatory and antinociceptive properties have been studied in vivo.
    CONCLUSION: Acanthus species have remarkable phytoconstituents with different biological activities, such as antioxidant, antimicrobial, anti-inflammatory, antinociceptive, hepatoprotective, and leishmanicidal, supporting traditional uses of some species. However, many others remain unexplored. Future studies should focus on these species, especially pharmacological properties, toxicity, and action mechanisms. This review provides a comprehensive report on Acanthus genus plants, evidencing their therapeutic potential and prospects for discovering new safe and effective drugs from Acanthus species.
    Keywords:  Acanthus species; Alkaloids; Ethnomedicine; Pharmacology; Phenolic compounds; Triterpenes
    DOI:  https://doi.org/10.1016/j.jep.2022.115271
  82. Front Chem. 2022 ;10 859450
    Molecular Switches-Tools for Imparting Control in Drug Delivery Systems.
    Owen Fitzmaurice, Michał Bartkowski, Silvia Giordani.
      Cancer is a globally prevalent cause of premature mortality. Of growing interest is the development of novel anticancer therapies and the optimisation of associated risks. Major issues presently facing conventional anticancer therapies include systemic toxicity, poor solubility, membrane permeability, and multidrug resistance Nanocarriers have been employed to address these issues. Nanocarriers encapsulate anticancer drugs, enabling them to bypass biological barriers and minimise their adverse side effects. These drug delivery systems offer extensive benefits as they can be modified to gravitate towards specific environmental conditions. To further enhance the safety and efficacy of these drug carriers, modern developments have included incorporating a molecular switching mechanism into their structure. These molecular switches are responsive to endogenous and exogenous stimuli and may undergo reversible and repeatable conformational changes when activated. The incorporation of molecular switches can, therefore, impart stimuli-responsive drug-release control on a DDS. These stimuli can then be manipulated to offer precise dosage control over the drug release at a specific target site. This review discusses recent developments in the design of DDSs incorporating light and pH-responsive molecular switches as drug release controllers.
    Keywords:  drug delivery; endogenous and exogenous stimuli; molecular switches; optical control; pH triggered release; pH-switches; photo-switches; responsive systems
    DOI:  https://doi.org/10.3389/fchem.2022.859450
  83. Pharmaceuticals (Basel). 2022 Apr 12. pii: 464. [Epub ahead of print]15(4):
    Physiological Effects and Human Health Benefits of Hibiscus sabdariffa: A Review of Clinical Trials.
    Efigenia Montalvo-González, Zuamí Villagrán, Sughey González-Torres, Laura Elena Iñiguez-Muñoz, Mario Alberto Isiordia-Espinoza, José Martín Ruvalcaba-Gómez, Ramón Ignacio Arteaga-Garibay, José Luis Acosta, Napoleón González-Silva, Luis Miguel Anaya-Esparza.
      Hibiscus sabdariffa Linn. Malvaceae (HS) is characterized by its edible calyxes. The HS calyxes are widely used for cosmetic, food, and medicinal applications. According to ethnobotanical evidence, decoction, infusion, or maceration extracts from HS calyxes have been used in folk medicine to treat many ailments. Moreover, several in vitro and in vivo studies have demonstrated the pharmacological properties and potential human health benefits of HS consumption. On the other hand, the evaluation of the physiological effects and health benefits of HS in clinical studies is most challenging. Therefore, this narrative review summarizes and discusses the physiological effects and health benefits of HS calyxes reported in clinical trials. Preparations obtained from HS calyxes (extracts, infusions, decoction, teas, beverages, capsules, and pills) are used as non-pharmacological therapies to prevent/control diverse chronic non-communicable diseases. The most-reported HS health benefits are its antihypertensive, antidyslipidemic, hypoglycemic, body fat mass reduction, nephroprotective, antianemic, antioxidant, anti-inflammatory, and anti-xerostomic activities; these effects are associated with the phytochemicals found in HS. Moreover, no adverse effects were reported during the clinical trials. However, clinical studies exhibited some limitations; thus, further studies are required to validate the clinical efficacy of HS in large-scale studies with higher doses and a good experimental design.
    Keywords:  Hibiscus sabdariffa; bioactive compounds; calyx; clinical trials; health benefits
    DOI:  https://doi.org/10.3390/ph15040464
  84. Anticancer Agents Med Chem. 2022 Apr 15.
    Repurposing disulfiram as a chemo-therapeutic sensitizer: molecular targets and mechanisms.
    Feilong Sun, Hongzhi Wang, Jinfu Nie, Bo Hong.
      Currently, chemo-therapy is still the main strategy for cancer treatment. However, chemo-therapy resistance remains its main challenge. Disulfiram [DSF] is a drug approved by FDA for the treatment of alcohol addiction, but it is later discovered that it has the anticancer activity. Importantly, there have been many literatures reporting that DSF can be used as a chemo-therapeutic sensitizer to enhance the anticancer activity of chemo-drugs in a variety of cancers. Furthermore, the combinations of DSF and chemo-drugs have been tested in clinic trials. In the review, we summarized the possible molecular targets and mechanisms of DSF to reverse chemo-resistance. We also further discussed the opportunities and challenges of DSF as a chemo-therapeutic sensitizer. In conclusion, DSF could be a potential repurposed drug to sensitize cancer cells to chemo-therapy in clinic.
    Keywords:  Anticancer mechanisms; Chemo-therapy; Chemo-therapy sensitizer; Disulfiram; Drug resistance.; Molecular targets
    DOI:  https://doi.org/10.2174/1871520621666220415102553
  85. Pharmaceutics. 2022 Apr 13. pii: 851. [Epub ahead of print]14(4):
    Delivery of Molecules Using Nanoscale Systems for Cancer Treatment and/or Diagnosis.
    Marina Santiago Franco, Yu Seok Youn.
      Since clinical approval of the first liposomal formulation encapsulating a chemotherapeutic agent, nanoscale delivery systems have been a rapidly developing science [...].
    DOI:  https://doi.org/10.3390/pharmaceutics14040851
  86. Pharmaceutics. 2022 Apr 15. pii: 870. [Epub ahead of print]14(4):
    Effect of Solvents, Stabilizers and the Concentration of Stabilizers on the Physical Properties of Poly(d,l-lactide-co-glycolide) Nanoparticles: Encapsulation, In Vitro Release of Indomethacin and Cytotoxicity against HepG2-Cell.
    Musaed Alkholief, Mohd Abul Kalam, Md Khalid Anwer, Aws Alshamsan.
      A biocompatible, biodegradable and FDA-approved polymer [Poly lactic-co-glycolic acid (PLGA)] was used to prepare the nanoparticles (NPs) to observe the effect of solvents, stabilizers and their concentrations on the physical properties of the PLGA-NPs, following the encapsulation and in vitro release of Indomethacin (IND). PLGA-NPs were prepared by the single-emulsion solvent evaporation technique using dichloromethane (DCM)/chloroform as the organic phase with Polyvinyl-alcohol (PVA)/Polyvinylpyrrolidone (PVP) as stabilizers to encapsulate IND. The effects of different proportions of PVA/PVP with DCM/chloroform on the physiochemical properties (particle size, the polydispersity index, the zeta potential by Malvern Zetasizer and morphology by SEM) of the NPs were investigated. DSC was used to check the physical state, the possible complexation of PLGA with stabilizer(s) and the crystallinity of the encapsulated drug. Stabilizers at all concentrations produced spherical, regular-shaped, smooth-surfaced discrete NPs. Average size of 273.2-563.9 nm was obtained when PVA (stabilizer) with DCM, whereas it ranged from 317.6 to 588.1 nm with chloroform. The particle size was 273.2-563.9 nm when PVP was the stabilizer with DCM, while it was 381.4-466.6 nm with chloroform. The zeta potentials of PVA-stabilized NPs were low and negative (-0.62 mV) while they were comparatively higher and positive for PVP-stabilized NPs (+17.73 mV). Finally, drug-loaded optimal NPs were composed of PLGA (40 mg) and IND (4 mg) in 1 mL DCM/chloroform with PVA/PVP (1-3%), which resulted in sufficient encapsulation (54.94-74.86%) and drug loading (4.99-6.81%). No endothermic peak of PVA/PVP appeared in the optimized formulation, which indicated the amorphous state of IND in the core of the PLGA-NPs. The in vitro release study indicated a sustained release of IND (32.83-52.16%) from the PLGA-NPs till 72 h and primarily followed the Higuchi matrix release kinetics followed by Korsmeyer-Peppas models. The cell proliferation assay clearly established that the organic solvents used to prepare PLGA-NPs had evaporated. The PLGA-NPs did not show any particular toxicity in the HepG2 cells within the dose range of IND (250-500 µg/mL) and at an equivalent concentration of PLGA-NPs (3571.4-7142.7 µg/mL). The cytotoxicity of the hepatotoxic drug (IND) was reduced by its encapsulation into PLGA-NPs. The outcomes of this investigation could be implemented to prepare PLGA-NPs of acceptable properties for the encapsulation of low/high molecular weight drugs. It would be useful for further in vitro and in vivo applications to use this delivery system.
    Keywords:  Indomethacin; PLGA; cytotoxicity; drug release; encapsulation; morphology; nanoparticles; particle-size; solvents; stabilizers
    DOI:  https://doi.org/10.3390/pharmaceutics14040870
  87. Pharmaceutics. 2022 Mar 29. pii: 739. [Epub ahead of print]14(4):
    Carbohydrates Used in Polymeric Systems for Drug Delivery: From Structures to Applications.
    Xiangjie Di, Xiao Liang, Chao Shen, Yuwen Pei, Bin Wu, Zhiyao He.
      Carbohydrates, one of the most important compounds in living organisms, perform numerous roles, including those associated with the extracellular matrix, energy-related compounds, and information. Of these, polymeric carbohydrates are a class of substance with a long history in drug delivery that have attracted more attention in recent years. Because polymeric carbohydrates have the advantages of nontoxicity, biocompatibility, and biodegradability, they can be used in drug targeting, sustained drug release, immune antigens and adjuvants. In this review, various carbohydrate-based or carbohydrate-modified drug delivery systems and their applications in disease therapy have been surveyed. Specifically, this review focuses on the fundamental understanding of carbohydrate-based drug delivery systems, strategies for application, and the evaluation of biological activity. Future perspectives, including opportunities and challenges in this field, are also discussed.
    Keywords:  carbohydrate-based polymer; drug delivery; hydrogel; nanoparticle
    DOI:  https://doi.org/10.3390/pharmaceutics14040739
  88. Cancers (Basel). 2022 Apr 10. pii: 1905. [Epub ahead of print]14(8):
    Metabolic Vulnerabilities in Multiple Myeloma.
    Julia S L Lim, Phyllis S Y Chong, Wee-Joo Chng.
      Multiple myeloma (MM) remains an incurable malignancy with eventual emergence of refractory disease. Metabolic shifts, which ensure the availability of sufficient energy to support hyperproliferation of malignant cells, are a hallmark of cancer. Deregulated metabolic pathways have implications for the tumor microenvironment, immune cell function, prognostic significance in MM and anti-myeloma drug resistance. Herein, we summarize recent findings on metabolic abnormalities in MM and clinical implications driven by metabolism that may consequently inspire novel therapeutic interventions. We highlight some future perspectives on metabolism in MM and propose potential targets that might revolutionize the field.
    Keywords:  metabolic vulnerability; metabolism; multiple myeloma
    DOI:  https://doi.org/10.3390/cancers14081905
  89. Sports Med. 2022 Apr 23.
    Does a Hypertrophying Muscle Fibre Reprogramme its Metabolism Similar to a Cancer Cell?
    Henning Wackerhage, Ivan J Vechetti, Philipp Baumert, Sebastian Gehlert, Lore Becker, Richard T Jaspers, Martin Hrabě de Angelis.
      In 1924, Otto Warburg asked "How does the metabolism of a growing tissue differ from that of a non-growing tissue?" Currently, we know that proliferating healthy and cancer cells reprogramme their metabolism. This typically includes increased glucose uptake, glycolytic flux and lactate synthesis. A key function of this reprogramming is to channel glycolytic intermediates and other metabolites into anabolic reactions such as nucleotide-RNA/DNA synthesis, amino acid-protein synthesis and the synthesis of, for example, acetyl and methyl groups for epigenetic modification. In this review, we discuss evidence that a hypertrophying muscle similarly takes up more glucose and reprogrammes its metabolism to channel energy metabolites into anabolic pathways. We specifically discuss the functions of the cancer-associated enzymes phosphoglycerate dehydrogenase and pyruvate kinase muscle 2 in skeletal muscle. In addition, we ask whether increased glucose uptake by a hypertrophying muscle explains why muscularity is often negatively associated with type 2 diabetes mellitus and obesity.
    DOI:  https://doi.org/10.1007/s40279-022-01676-1
  90. Pharmaceutics. 2022 Apr 18. pii: 883. [Epub ahead of print]14(4):
    Nanocarrier Drug Delivery Systems: Characterization, Limitations, Future Perspectives and Implementation of Artificial Intelligence.
    Samar Zuhair Alshawwa, Abeer Ahmed Kassem, Ragwa Mohamed Farid, Shaimaa Khamis Mostafa, Gihan Salah Labib.
      There has been an increasing demand for the development of nanocarriers targeting multiple diseases with a broad range of properties. Due to their tiny size, giant surface area and feasible targetability, nanocarriers have optimized efficacy, decreased side effects and improved stability over conventional drug dosage forms. There are diverse types of nanocarriers that have been synthesized for drug delivery, including dendrimers, liposomes, solid lipid nanoparticles, polymersomes, polymer-drug conjugates, polymeric nanoparticles, peptide nanoparticles, micelles, nanoemulsions, nanospheres, nanocapsules, nanoshells, carbon nanotubes and gold nanoparticles, etc. Several characterization techniques have been proposed and used over the past few decades to control and predict the behavior of nanocarriers both in vitro and in vivo. In this review, we describe some fundamental in vitro, ex vivo, in situ and in vivo characterization methods for most nanocarriers, emphasizing their advantages and limitations, as well as the safety, regulatory and manufacturing aspects that hinder the transfer of nanocarriers from the laboratory to the clinic. Moreover, integration of artificial intelligence with nanotechnology, as well as the advantages and problems of artificial intelligence in the development and optimization of nanocarriers, are also discussed, along with future perspectives.
    Keywords:  artificial intelligence; challenges; future perspectives; nanocarriers characterization; regulatory aspects; safety considerations; stability
    DOI:  https://doi.org/10.3390/pharmaceutics14040883
  91. Eur J Pharm Biopharm. 2022 Apr 18. pii: S0939-6411(22)00077-7. [Epub ahead of print]
    Anchoring β-CD on simvastatin-loaded rHDL for selective cholesterol crystals dissolution and enhanced anti-inflammatory effects in macrophage/foam cells.
    Jianhua He, Xiaoju Zhou, Fengfei Xu, Hongliang He, Shuangyan Ma, Xinyue Liu, Mengyuan Zhang, Wenli Zhang, Jianping Liu.
      Macrophage/foam cells and cholesterol crystals (CCs) have been regarded as the central triggers of maladaptive inflammation in atherosclerotic plaque. Despite the tremendous progress of recombinant high-density lipoprotein (rHDL) serving for targeted drug delivery to alleviate inflammation in macrophage/foam cells, the active attempt to modulate/improve its CCs dissolution capacity remains poorly explored. The untreated CCs can seriously aggravate inflammation and threaten plaque stability. Based on the superb ability of β-cyclodextrin (β-CD) to bind CCs and promote cholesterol efflux, simvastatin-loaded discoidal-rHDL (ST-d-rHDL) anchored with β-CD (βCD-ST-d-rHDL) was constructed. We verified that βCD-ST-d-rHDL specifically bound and dissolved CCs extracellularly and intracellularly. Furthermore, anchoring β-CD onto the surface of ST-d-rHDL enhanced its cholesterol removal ability in RAW 264.7 cell-derived foam cells characterized by accelerated cholesterol efflux, reduced intracellular lipid deposition, and improved cell membrane fluidity/permeability. Finally, βCD-ST-d-rHDL exerted efficient drug delivery and effective anti-inflammatory effects in macrophage/foam cells. Collectively, anchoring β-CD onto the surface of ST-d-rHDL for selective CCs dissolution, accelerated cholesterol efflux, and improved drug delivery represents an effective strategy to enhance anti-inflammatory effects for the therapy of atherosclerosis.
    Keywords:  Anti-inflammation; Cholesterol crystals; Cholesterol efflux; Macrophage/foam cell; Recombinant high-density lipoprotein; β-cyclodextrin
    DOI:  https://doi.org/10.1016/j.ejpb.2022.04.005
  92. Molecules. 2022 Apr 07. pii: 2391. [Epub ahead of print]27(8):
    Evening Primrose Oil Enhances Tamoxifen's Anticancer Activity against Breast Cancer Cells by Inducing Apoptosis, Inhibiting Angiogenesis, and Arresting the Cell Cycle.
    Mohammad M Abd-Alhaseeb, Sarah M Massoud, Fatma Elsayed, Gamal A Omran, Ahmad Salahuddin.
      BACKGROUND: Despite advancements in cancer treatment, breast cancer (BC) is still one of the leading causes of death among women. The majority of anti-breast-cancer medications induce serious side effects and multidrug resistance. Although several natural compounds, such as evening primrose oil (EPO), have been shown to have anticancer properties when used alone, their combination with the anticancer medicine tamoxifen (TAM) has yet to be investigated. The present study aimed to investigate the anticancer efficacy of EPO, alone or in combination with TAM, in the BC cell lines MCF-7 and MDA-MB-231, as well as to elucidate the mechanism of action.METHODS: The MTT assay was used to investigate the cytotoxic effect of EPO on the two cell lines, and we discovered an acceptable IC50 that was comparable to TAM. The ELISA, qRT-PCR, flow cytometry and colorimetric techniques were used.
    RESULTS: The combination of EPO and TAM suppressed the VEGF level, VEGF gene expression and Cyclin D1 signaling pathways, arrested the cell cycle, and induced the apoptotic signaling pathways by increasing the Bax/Bcl-2 ratio and caspase 3 activity; this revealed significant anti-tumor activity.
    CONCLUSIONS: The most significant finding of this study was the confirmation of the anticancer activity of the natural product EPO, which potentiated the activity of the anticancer drug TAM against MCF-7 and MDA-MB-231 BC cell lines through the induction of apoptosis, inhibiting angiogenesis and halting cell proliferation.
    Keywords:  MCF-7; MDA-MB-231; breast cancer; evening primrose oil; tamoxifen
    DOI:  https://doi.org/10.3390/molecules27082391
  93. Int J Mol Sci. 2022 Apr 14. pii: 4339. [Epub ahead of print]23(8):
    Interactions between Nanoparticles and Intestine.
    Manuela Vitulo, Elisa Gnodi, Raffaella Meneveri, Donatella Barisani.
      The use of nanoparticles (NPs) has surely grown in recent years due to their versatility, with a spectrum of applications that range from nanomedicine to the food industry. Recent research focuses on the development of NPs for the oral administration route rather than the intravenous one, placing the interactions between NPs and the intestine at the centre of the attention. This allows the NPs functionalization to exploit the different characteristics of the digestive tract, such as the different pH, the intestinal mucus layer, or the intestinal absorption capacity. On the other hand, these same characteristics can represent a problem for their complexity, also considering the potential interactions with the food matrix or the microbiota. This review intends to give a comprehensive look into three main branches of NPs delivery through the oral route: the functionalization of NPs drug carriers for systemic targets, with the case of insulin carriers as an example; NPs for the delivery of drugs locally active in the intestine, for the treatment of inflammatory bowel diseases and colon cancer; finally, the potential concerns and side effects of the accidental and uncontrolled exposure to NPs employed as food additives, with focus on E171 (titanium dioxide) and E174 (silver NPs).
    Keywords:  colon cancer; food additives; inflammatory bowel diseases; insulin delivery; nanocarriers; nanoparticles
    DOI:  https://doi.org/10.3390/ijms23084339
  94. Anticancer Agents Med Chem. 2022 Apr 18.
    Recent literature review on Coumarin hybrids as potential anti-cancer agents.
    Baji Baba Shaik, Naresh Kumar Katari, Pule Seboletswe, Rambabu Gundla, Narva Deshwar Kushwaha, Vishal Kumar, Parvesh Singh, Rajshekhar Karpoormath, Muhammad D Bala.
      Cancer is considered as one of the leading causes of death in the world, especially patients with lung, pancreatic, or brain tumors are most likely to die of cancer and patients with prostate and breast cancer are at high risk of non-cancer death. As a result, there is on-going research regarding the development of new, safe and efficient anticancer agents. Coumarin-based naturally occurring compounds possess a broad spectrum of activity in medicinal chemistry such as anticancer, anti-inflammatory, antimicrobial, antioxidant agents, etc. Many researchers have synthesized coumarin-based novel therapeutic agents via molecular hybridization technique, which offers an excellent opportunity for development of novel compounds with improved biological activities by incorporating two or more pharmacophores. This review sheds light on the recent developments on coumarin based anticancer hybrid derivatives and their structure-activity relationships (SAR). This review serves as a medium that medicinal chemists could utilise for the design and synthesis of coumarin derivatives with significant pharmacological value as future anticancer agents.
    Keywords:  Coumarin; anticancer agent; molecular hybridization; therapeutic agent
    DOI:  https://doi.org/10.2174/1871520622666220418143438
  95. Biochem Pharmacol. 2022 Apr 15. pii: S0006-2952(22)00133-2. [Epub ahead of print] 115039
    Advances of podophyllotoxin and its derivatives: patterns and mechanisms.
    Rong-Jia Shi, Hua-Yang Fan, Xiang-Hua Yu, Ya-Ling Tang, Jian Jiang, Xin-Hua Liang.
      Podophyllotoxin (PPT) has attracted researchers' attention because of its ability to treat various ailments. A series of podophyllotoxin derivatives (PPTs) have been synthesized as candidate drugs to improve the pharmacological characteristics of PPT. Nowadays, an increasing number of reviews have summarized structure-optimization, anticancer application, and single nano delivery of PPT and PPTs. In this review, we focus on capturing the multidirectional pharmacological properties of PPT and PPTs, with an emphasis on the crosstalk with anticancer, anti-inflammatory, immunosuppression, and antivirals. Besides, the newly uncovered mechanisms governing PPT and PPTs in pharmacological properties including non-apoptotic regulated cell death are discussed. Moreover, their co-delivery nanocarriers with other antitumor drugs or biological agents that have the potential to achieve increased targeting efficacy are included, thus providing a reference for improving the druggability and expanding the clinical application of podophyllotoxin and its derivatives.
    Keywords:  anti-inflammatory; anticancer; antivirals; codelivery nano-drug systems; immunosuppression; podophyllotoxin
    DOI:  https://doi.org/10.1016/j.bcp.2022.115039
  96. Int J Mol Sci. 2022 Apr 14. pii: 4365. [Epub ahead of print]23(8):
    Oxygen and Drug-Carrying Periodic Mesoporous Organosilicas for Enhanced Cell Viability under Normoxic and Hypoxic Conditions.
    Ravi Kumar, Nermin Seda Kehr.
      Over the last decade, inorganic/organic hybrids have been exploited for oxygen-carrying materials and drug delivery. Its low-cost synthesis, controlled shape and size, and stability have made it a viable delivery strategy for therapeutic agents. Rutin (quercetin-3-O-rutinoside) is a bioflavonoid found in fruits and vegetables. Rutin has a variety of pharmaceutical applications, but its low water solubility reduces its stability and bioavailability. As a result, we introduce a new and stable nanosystem for loading a low-soluble drug (rutin) into oxygen-carrying periodic mesoporous organosilicas (PMO-PFCs). Over the course of 14 days, this nanosystem provided a sustained oxygen level to the cells in both normoxic and hypoxic conditions. At different pH values, the drug release (rutin) profile is also observed. Furthermore, the rutin-coated PMO-PFCs interacted with both healthy and malignant cells. The healthy cells have better cell viability on the rutin-coated oxygen-carrying PMO-PFCs, while the malignant cells have a lower cell viability.
    Keywords:  drug delivery; hybrid materials; nanostructured materials; oxygen-carrying materials
    DOI:  https://doi.org/10.3390/ijms23084365
  97. Mater Adv. 2022 Apr 04. 3(7): 3023-3040
    Making waves: how ultrasound-targeted drug delivery is changing pharmaceutical approaches.
    Lauren J Delaney, Selin Isguven, John R Eisenbrey, Noreen J Hickok, Flemming Forsberg.
      Administration of drugs through oral and intravenous routes is a mainstay of modern medicine, but this approach suffers from limitations associated with off-target side effects and narrow therapeutic windows. It is often apparent that a controlled delivery of drugs, either localized to a specific site or during a specific time, can increase efficacy and bypass problems with systemic toxicity and insufficient local availability. To overcome some of these issues, local delivery systems have been devised, but most are still restricted in terms of elution kinetics, duration, and temporal control. Ultrasound-targeted drug delivery offers a powerful approach to increase delivery, therapeutic efficacy, and temporal release of drugs ranging from chemotherapeutics to antibiotics. The use of ultrasound can focus on increasing tissue sensitivity to the drug or actually be a critical component of the drug delivery. The high spatial and temporal resolution of ultrasound enables precise location, targeting, and timing of drug delivery and tissue sensitization. Thus, this noninvasive, non-ionizing, and relatively inexpensive modality makes the implementation of ultrasound-mediated drug delivery a powerful method that can be readily translated into the clinical arena. This review covers key concepts and areas applied in the design of different ultrasound-mediated drug delivery systems across a variety of clinical applications.
    DOI:  https://doi.org/10.1039/d1ma01197a
  98. Pharmaceutics. 2022 Mar 28. pii: 726. [Epub ahead of print]14(4):
    Niosomal Nanocarriers for Enhanced Dermal Delivery of Epigallocatechin Gallate for Protection against Oxidative Stress of the Skin.
    Danhui Li, Nataly Martini, Zimei Wu, Shuo Chen, James Robert Falconer, Michelle Locke, Zhiwen Zhang, Jingyuan Wen.
      Among green tea catechins, epigallocatechin gallate (EGCG) is the most abundant and has the highest biological activities. This study aims to develop and statistically optimise an EGCG-loaded niosomal system to overcome the cutaneous barriers and provide an antioxidant effect. EGCG-niosomes were prepared by thin film hydration method and statistically optimised. The niosomes were characterised for size, zeta potential, morphology and entrapment efficiency. Ex vivo permeation and deposition studies were conducted using full-thickness human skin. Cell viability, lipid peroxidation, antioxidant enzyme activities after UVA-irradiation and cellular uptake were determined. The optimised niosomes were spherical and had a relatively uniform size of 235.4 ± 15.64 nm, with a zeta potential of -45.2 ± 0.03 mV and an EE of 53.05 ± 4.46%. The niosomes effectively prolonged drug release and demonstrated much greater skin penetration and deposition than free EGCG. They also increased cell survival after UVA-irradiation, reduced lipid peroxidation, and increased the antioxidant enzymes' activities in human dermal fibroblasts (Fbs) compared to free EGCG. Finally, the uptake of niosomes was via energy-dependent endocytosis. The optimised niosomes have the potential to be used as a dermal carrier for antioxidants and other therapeutic compounds in the pharmaceutical and cosmetic industries.
    Keywords:  antioxidant activity; catechin; cellular uptake; dermal delivery; niosomes; oxidative stress; penetration; skin barrier
    DOI:  https://doi.org/10.3390/pharmaceutics14040726
  99. Int J Mol Sci. 2022 Apr 18. pii: 4458. [Epub ahead of print]23(8):
    Applications of Metal-Organic Frameworks as Drug Delivery Systems.
    Bianca Maranescu, Aurelia Visa.
      In the last decade, metal organic frameworks (MOFs) have shown great prospective as new drug delivery systems (DDSs) due to their unique properties: these materials exhibit fascinating architectures, surfaces, composition, and a rich chemistry of these compounds. The DSSs allow the release of the active pharmaceutical ingredient to accomplish a desired therapeutic response. Over the past few decades, there has been exponential growth of many new classes of coordination polymers, and MOFs have gained popularity over other identified systems due to their higher biocompatibility and versatile loading capabilities. This review presents and assesses the most recent research, findings, and challenges associated with the use of MOFs as DDSs. Among the most commonly used MOFs for investigated-purpose MOFs, coordination polymers and metal complexes based on synthetic and natural polymers, are well known. Specific attention is given to the stimuli- and multistimuli-responsive MOFs-based DDSs. Of great interest in the COVID-19 pandemic is the use of MOFs for combination therapy and multimodal systems.
    Keywords:  drug delivery systems; encapsulation; metal organic frameworks; stimulus; surface modification
    DOI:  https://doi.org/10.3390/ijms23084458
  100. Pharm Res. 2022 Apr 21.
    Ionic Liquids: Promising Approach for Oral Drug Delivery.
    Linxia Jiang, Yi Sun, An Lu, Xiangyu Wang, Yujie Shi.
      Oral administration is the most preferred route for drug administration in clinic. However, due to unsatisfactory physicochemical properties of drugs and various physiological barriers, the oral bioavailability of most poorly water-soluble and macromolecules drugs is low and the therapeutic effect is unsatisfactory. Ionic liquids (ILs), molten salts with unique properties, show amazing potential for oral delivery. In addition to being able to form active pharmaceutical ingredients based ILs (API-ILs) to overcome drug solubility and polymorphism issues, ILs have also been used to enhance the solubility of poorly soluble drugs, enhance drug stability in the gastrointestinal environment, improve drug permeability in intestinal mucus, and facilitate drug penetration across the intestinal epithelial barrier. Furthermore, ILs were attempted as formulation components to develop novel oral drug delivery systems. This review focus on the application progress of ILs in oral drug delivery and the mechanisms. The challenges and perspectives of the development of ILs-based oral delivery systems are also discussed. This article reviews the latest advances of ionic liquids for oral drug delivery, focusing on the application and related mechanisms of ionic liquids in improving the drug physicochemical properties and enhancing drug delivery across physiological barriers.
    Keywords:  bioavailability; ionic liquids; oral delivery; protein peptide drugs; small molecule drugs
    DOI:  https://doi.org/10.1007/s11095-022-03260-8
  101. Crit Rev Biotechnol. 2022 Apr 17. 1-19
    Microbial torularhodin - a comprehensive review.
    Cassamo U Mussagy, Maria Gonzalez-Miquel, Valeria C Santos-Ebinuma, Jorge F B Pereira.
      The demand for food, feed, cosmeceutical, and nutraceutical supplements/additives from natural sources has been rapidly increasing, with expectations for a faster expansion than the growth of the global markets in the coming years. In this framework, a particular interest is given to carotenoids due to their outstanding antioxidant activities, particularly the xanthophylls class. Torularhodin is one of these carotenoids that stands out for its multifunctional role as: antioxidant, anticancer and antimicrobial, yet its commercial potential is still unexplored. Although most xanthophylls can be naturally found in: microbial, plant and animal sources, torularhodin is only produced by microbial species, especially red oleaginous yeast. The microbial production of xanthophylls has many advantages as compared to other natural sources, such as: the need for low production area, easier extraction, high yields (at optimum operating conditions), and low (or no) seasonal, climatic, and geographic variation dependency. Due to the importance of natural products and their relevance to the market, this review provides a comprehensive overview of the: properties, characteristics and potential health benefits of torularhodin. Moreover, the most promising developments in both upstream and downstream processing to obtain this colorant from microbial sources are considered. For this purpose, the main microorganisms used for torularhodin production are firstly reviewed, including biosynthesis pathway and torularhodin properties. Following, an overall analysis of the processing aspects related with its: extraction, separation and purification is provided. Lastly, current status and future trends of torularhodin-based processes and products such as therapeutic agents or biomaterials are discussed, indicating promising directions toward biorefinery and circular economy.
    Keywords:  Torularhodin; antioxidant; biorefinery; carotenoid; colorant; xanthophyll; yeast
    DOI:  https://doi.org/10.1080/07388551.2022.2041540
  102. J Mater Chem B. 2022 Apr 21.
    Bacterial cellulose as a potential biopolymer in biomedical applications: a state-of-the-art review.
    Prachi Shrivastav, Sheersha Pramanik, Gayatri Vaidya, Mohamed A Abdelgawad, Mohammed M Ghoneim, Ajeet Singh, Bassam M Abualsoud, Larissa Souza Amaral, Mohammed A S Abourehab.
      Throughout history, natural biomaterials have benefited society. Nevertheless, in recent years, tailoring natural materials for diverse biomedical applications accompanied with sustainability has become the focus. With the progress in the field of materials science, novel approaches for the production, processing, and functionalization of biomaterials to obtain specific architectures have become achievable. This review highlights an immensely adaptable natural biomaterial, bacterial cellulose (BC). BC is an emerging sustainable biopolymer with immense potential in the biomedical field due to its unique physical properties such as flexibility, high porosity, good water holding capacity, and small size; chemical properties such as high crystallinity, foldability, high purity, high polymerization degree, and easy modification; and biological characteristics such as biodegradability, biocompatibility, excellent biological affinity, and non-biotoxicity. The structure of BC consists of glucose monomer units polymerized via cellulose synthase in β-1-4 glucan chains, creating BC nano fibrillar bundles with a uniaxial orientation. BC-based composites have been extensively investigated for diverse biomedical applications due to their similarity to the extracellular matrix structure. The recent progress in nanotechnology allows the further modification of BC, producing novel BC-based biomaterials for various applications. In this review, we strengthen the existing knowledge on the production of BC and BC composites and their unique properties, and highlight the most recent advances, focusing mainly on the delivery of active pharmaceutical compounds, tissue engineering, and wound healing. Further, we endeavor to present the challenges and prospects for BC-associated composites for their application in the biomedical field.
    DOI:  https://doi.org/10.1039/d1tb02709c
  103. Biomater Sci. 2022 Apr 19.
    Photothermal-enhanced antibacterial and antioxidant hydrogel dressings based on catechol-modified chitosan-derived carbonized polymer dots for effective treatment of wound infections.
    Haojie Lu, Jing Liu, Meizhe Yu, Peili Li, Ruobing Huang, Wenzhen Wu, Zunhan Hu, Yuhong Xiao, Feng Jiang, Xiaodong Xing.
      Bacterial infection and excessive reactive oxygen species (ROS) remain challenging factors contributing to the delayed healing of chronic wounds. Although various antibacterial and antioxidant hydrogel dressings have been developed to accelerate wound healing, multifunctional hydrogels fabricated by rationally designing and introducing carbonized polymer dots (CPDs) have rarely been reported. Herein, inspired by the mussel biomimetic approach, we synthesized 3,4-dihydroxybenzaldehyde functionalized chitosan (DFC), and then the polymeric precursor was pyrolyzed into CPDs with abundant amino and catechol groups on the surface, which endowed it with a highly positively charged surface that could activate the photothermal effect under near-infrared (NIR) light irradiation. Finally, the nanocomposite hydrogel (PVA@CPDs) was simply constructed by directly mixing polyvinyl alcohol (PVA) with CPDs, utilizing the freeze-thaw cycle method to form a gel, in which, CPDs as a center of polyfunctional nanoparticles drove the formation of PVA microcrystalline crosslinking and endowed the PVA substrate with versatile functionalities. Remarkable and comprehensive improvements in the swelling behavior, mechanical properties and adhesive strength of the hydrogel could be conveniently achieved with the suitable loading of CPDs. The in vitro experiments demonstrated that the PVA@CPDs hydrogel presented broad-spectrum and rapid bactericidal activity, concurrently acting as an effective antioxidant being able to scavenge free radicals. In addition, no obvious cytotoxicity was observed for the multifunctional hydrogel after incubation with L02 cells. In vivo evaluation in an infected full-thickness skin wound model demonstrated that the PVA@CPDs hydrogel promoted wound closure without any side effects. As a consequence, the current work manifests a facile yet versatile strategy to develop effective and biocompatible multifunctional hydrogel dressings for bacteria-infected wound healing.
    DOI:  https://doi.org/10.1039/d2bm00221c
  104. Carbohydr Polym. 2022 Jul 15. pii: S0144-8617(22)00322-8. [Epub ahead of print]288 119418
    In situ injectable nano-complexed hydrogel based on chitosan/dextran for combining tumor therapy via hypoxia alleviation and TAMs polarity regulation.
    Wenxue Zhang, Yan Shi, Hu Li, Miao Yu, Jiaxuan Zhao, Hao Chen, Ming Kong.
      The tumor microenvironment (TME) is characterized by low pH, hypoxia, and infiltrated tumor-associated macrophages (TAMs). Therefore, regulation of TAMs polarization into anti-tumor M1 phenotype and meanwhile alleviation of the hypoxia in TME are expected to improve anti-tumor therapeutic efficacy. To this end, a novel in situ injectable nano-complexed hydrogel was developed in this study for combining tumor therapy. Thereunto, hyaluronic acid modified transfersomes loaded with chlorogenic acid functioned to reverse M2 type into M1 type via CD44 mediated internalization, the nanomedicine was entrapped in Schiff-based crosslinked injectable hydrogel (fabricated with carboxymethyl chitosan and oxidized dextran) whose linkage was labile to the acidic TME for controlled drug release. Moreover, catalase was integrated in the hydrogel enabling to convert hydrogen peroxide in TME into dissolved oxygen and alleviate tumor hypoxia. The multifunctional nano-complexed injectable hydrogel was verified to efficiently inhibit tumor growth through synergetic effects of hypoxia alleviation and TAMs polarity regulation.
    Keywords:  Hypoxia; Injectable hydrogel; Tumor microenvironment; Tumor therapy; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119418
  105. Daru. 2022 Apr 18.
    Solid dispersion technology as a formulation strategy for the fabrication of modified release dosage forms: A comprehensive review.
    Kaushika Patel, Shreeraj Shah, Jaymin Patel.
      Solubility limited bioavailability is one of the crucial parameters that affect the formulation development of the new chemical entities. Thus the major constraint in the pharmaceutical product development is the suitable solubility enhancement technique for Active Pharmaceutical Ingredient. Solid dispersion (SD) is an established and preferred method for improving the solubility which ultimately may be helpful to enhance bioavailability. For long period of time Amorphous solid dispersion (ASD) have been preferred for improving solubility, but since last two decades, ASD approach have been combined with different modified release approaches to improvise the stability and site specificity of SD to grasp a hold over the specific advantages associated with such dosage forms. It is an established fact now that the SD technique not only improves solubility limited bioavailability, but it may be combined with other approaches to modify the drug release profile from the formulation as per the requirement based on the apt selection of SD carriers and suitable technology. This review covers the comprehensive overview of all such formulations where SD technology is used to serve dual purpose rather than only the sole purpose of solubility enhancement. The SD approach has been successfully implemented for some of the poorly soluble herbal drugs and still there is a vast scope of advancement in that area. The current review will provide a broad outcome in the area of SD technology for modified release formulations along with the description of current status and future prospective of SD. The SD formed by dispersing drug within the conventional carrier to form ASD increases solubility, dissolution rate and bioavailability; whereas fourth generation hydrophobic carriers provide added advantage of controlled release (CR) or sustained release (SR) profile along with enhanced stability of SD. On the other frontier, pH dependant carriers enable the SD to achieve site specificity or delayed release (DR) profile.
    Keywords:  Bioavailability; Dissolution rate; Low aqueous soluble drug; Modified release; Solid dispersion; Sustained release
    DOI:  https://doi.org/10.1007/s40199-022-00440-0
  106. Mol Cell Biochem. 2022 Apr 22.
    Energetic metabolic reprogramming in Jurkat DFF40-deficient cancer cells.
    Merve Kulbay, Bruno Johnson, Guillaume Ricaud, Marie-Noëlle Séguin-Grignon, Jacques Bernier.
      DNA fragmentation factor 40 (DFF40), or the caspase-activated DNase (CAD), is an endonuclease specific for double-stranded DNA. Alterations in its function and expression have been linked to apoptosis resistance, a mechanism likely used by cancer cells. However, how the DFF40-related apoptosis resistance pathway occurs remains unclear. Here, we sought to determine if DFF40 expression could be linked to cell metabolism through the regulation of mitochondrial integrity and function. We demonstrated that DFF40-deficient cells are more resistant to staurosporine and tributyltin (TBT)-induced apoptosis, and express higher levels of Mcl-1 at basal state. Treatment with TBT induces higher Bcl-2 and caspase-9 mRNA transcripts in DFF40 KO Jurkat cells, as well as enhanced Bcl-2 phosphorylation. A loss of DFF40 expression induces a higher mitochondrial mass, mtDNA copy number, mitochondrial membrane potential, and glycolysis rates in resting T cells. DFF40-deficient cells exhibit the Warburg effect phenotype, where they rely significantly more on glycolysis than oxidative phosphorylation and have a higher proliferative state, demonstrated by a higher Ki-67 transcription factor expression and AKT phosphorylation. Finally, we demonstrated with cell fractioning that DFF40 can translocate to the mitochondria following apoptosis induction. Our study reveals that DFF40 may act as a regulator of mitochondria during cell death and its loss could compromise mitochondrial integrity and cause an energetic reprogramming in pathologies such as cancer.
    Keywords:  Apoptosis; Cancer; Cell proliferation; DFF40; DNA; Energetic metabolism; Mitochondria; Reprogramming; Warburg effect
    DOI:  https://doi.org/10.1007/s11010-022-04433-0
  107. Nutrients. 2022 Apr 07. pii: 1540. [Epub ahead of print]14(8):
    Egg Allergy in Children and Weaning Diet.
    Carlo Caffarelli, Arianna Giannetti, Arianna Rossi, Giampaolo Ricci.
      Eggs are a fundamental food in the human diet, and together with cow's milk, they are the most common food allergen. This work highlights the main nutritional characteristics of eggs to show how their absence from a child's diet can constitute a serious deficiency. We then analyze the risk factors that facilitate the onset of egg allergy. The third part of the paper reports possible interventions to lower the appearance of food allergy that have been occurred in trials. The last part of the paper is a synthesis of this research study that has been taken from several of the latest guidelines or from position papers.
    Keywords:  dietetic interventions; egg; egg allergy; food allergy; infant; prevention; weaning
    DOI:  https://doi.org/10.3390/nu14081540
  108. Biomed Pharmacother. 2022 Apr 19. pii: S0753-3322(22)00381-X. [Epub ahead of print]150 112992
    Hyaluronic acid functionalization improves dermal targeting of polymeric nanoparticles for management of burn wounds: In vitro, ex vivo and in vivo evaluations.
    Zahid Hussain, Manisha Pandey, Hnin Ei Thu, Taasjir Kaur, Gan Wei Jia, Pang Cheau Ying, Tan Mei Xian, Mohammad A S Abourehab.
      Owing to its intricate pathophysiology, impaired wound healing is one of the substantial challenges in the treatment of burn wounds (BWs). Despite the variety of conventional therapies available, morbidities associated with BWs have not subsided. Therefore, aim of the present study was to design an advanced nanotechnology-composited therapy for effectual management of BWs. Hyaluronic acid (HA)-functionalized curcumin (CUR) and quercetin (QUE) co-loaded nanoparticle (HA-CUR-QUE-CSNPs) were fabricated, optimized, characterized and evaluated for successful co-encapsulation of drugs, morphology, stability, drug release, cell proliferation, penetration across the skin, localization in the epidermis and dermis, and in vivo wound healing efficacy. Fabricated HA-functionalized CSNPs exhibited ultra-small size (177 ± 11 nm), good zeta potential (+37.0 ± 3.2 mV), high encapsulation efficiency (EE) (QUE ∼84% and CUR ∼64%) and loading capacity (LC) (QUE ∼38% and CUR ∼43%), and spherical shape with uniformly rough surface. HA-functionalized CSNPs showed a triphasic release pattern with Fickian diffusion kinetics, a time-mannered progression in MC3T3-E1 cells proliferation, improved penetration of CUR (2414 µg/cm2) and QUE (1984 µg/cm2) through stratum corneum, and good localization of drugs in the epidermis and dermis. A superior wound healing efficacy (98% wound closure rate at day 28) with marked histological signs of minimal infiltration of inflammatory cells, re-epithelization, ECM formation, fibroblast infiltration at wound site, granulation tissue formation, angiogenesis, and collagen deposition were also evidenced. This study concludes that HA-functionalization of polymeric NPs could be a promising approach to maximize skin penetration efficiency, localization of drugs in skin tissues, tissue regeneration and BWs healing.
    Keywords:  Burn wounds; Curcumin; Functionalization; Hyaluronic acid; Polymeric nanoparticles; Quercetin
    DOI:  https://doi.org/10.1016/j.biopha.2022.112992
  109. Pharmaceutics. 2022 Apr 16. pii: 875. [Epub ahead of print]14(4):
    Tailoring of Selenium-Plated Novasomes for Fine-Tuning Pharmacokinetic and Tumor Uptake of Quercetin: In Vitro Optimization and In Vivo Radiobiodistribution Assessment in Ehrlich Tumor-Bearing Mice.
    Heba M Aboud, Amal K Hussein, Abdallah Z Zayan, Tarek Saad Makram, Mona O Sarhan, Dina M El-Sharawy.
      Quercetin (QRC) is a bioflavonoid with anti-inflammatory, antioxidant, and anticancer activities, yet QRC poor bioavailability has hampered its clinical implementation. The aim of the current work was to harness novasomes (NOVs), free fatty acid enriched vesicles, as a novel nano-cargo for felicitous QRC delivery with subsequent functionalization with selenium (SeNOVs), to extend the systemic bio-fate of NOVs and potentiate QRC anticancer efficacy through the synergy with selenium. QRC-NOVs were primed embedding oleic acid, Brij 35, and cholesterol adopting thin-film hydration technique according to Box-Behnken design. Employing Design-Expert® software, the impact of formulation variables on NOVs physicochemical characteristics besides the optimum formulation election were explored. Based on the optimal NOVs formulation, QRC-SeNOVs were assembled via electrostatic complexation/in situ reduction method. The MTT cytotoxicity assay of the uncoated, and coated nanovectors versus crude QRC was investigated in human rhabdomyosarcoma (RD) cells. The in vivo pharmacokinetic and biodistribution studies after intravenous administrations of technetium-99m (99mTc)-labeled QRC-NOVs, QRC-SeNOVs, and QRC-solution were scrutinized in Ehrlich tumor-bearing mice. QRC-NOVs and QRC-SeNOVs disclosed entrapment efficiency of 67.21 and 70.85%, vesicle size of 107.29 and 129.16 nm, ζ potential of -34.71 and -43.25 mV, and accumulatively released 43.26 and 31.30% QRC within 24 h, respectively. Additionally, QRC-SeNOVs manifested a far lower IC50 of 5.56 μg/mL on RD cells than that of QRC-NOVs (17.63 μg/mL) and crude QRC (38.71 μg/mL). Moreover, the biodistribution study elicited higher preferential uptake of 99mTc-QRC-SeNOVs within the tumorous tissues by 1.73- and 5.67-fold as compared to 99mTc-QRC-NOVs and 99mTc-QRC-solution, respectively. Furthermore, the relative uptake efficiency of 99mTc-QRC-SeNOVs was 5.78, the concentration efficiency was 4.74 and the drug-targeting efficiency was 3.21. Hence, the engineered QRC-SeNOVs could confer an auspicious hybrid nanoparadigm for QRC delivery with fine-tuned pharmacokinetics, and synergized antitumor traits.
    Keywords:  in vivo biodistribution; novasomes; quercetin; radiolabeling; selenium; tumor targeting
    DOI:  https://doi.org/10.3390/pharmaceutics14040875
  110. Molecules. 2022 Apr 17. pii: 2585. [Epub ahead of print]27(8):
    Recent Advances in the Antiproliferative and Proapoptotic Activity of Various Plant Extracts and Constituents against Murine Malignant Melanoma.
    Daria-Antonia Dumitraș, Sanda Andrei.
      Although conventional medicine, chemical drug synthesis and pharmaceutical research are advancing at a rapid pace, nature remains a major supplier of biological molecules. Natural bioactive compounds are studied closely especially as an alternative to the limitations of conventional therapy in many diseases, melanoma being one of them. Malignant melanoma is a highly aggressive type of cancer, and the current methods of treatment used are cryotherapy, external surgery, radiation therapy, chemotherapy, photodynamic therapy, biological therapy, and targeted drug therapy. Unfortunately, these treatment methods are often inefficient, extremely expensive and cause many side effects, which is why focusing on melanoma chemoprevention and adjuvant therapy with natural herbal phytoconstituents is an emerging strategy to prevent, cure or treat melanoma. This review aims to examine the latest discoveries in terms of potential natural bioactive compounds that possess important activity against the development and spread of murine melanoma cancer. In particular, the use of different phytochemicals such as phenolic acids, flavonoids, anthocyanins, terpenoids, essential oils and carotenoids in vitro and in vivo models will be discussed. These data are helpful in guiding researchers in the direction of studying phytonutrients with important effects in the prevention and treatment of melanoma.
    Keywords:  bioactive compounds; in vitro; in vivo; malignant melanoma; phytotherapy
    DOI:  https://doi.org/10.3390/molecules27082585
  111. PLoS One. 2022 ;17(4): e0266601
    Targeting pancreatic cancer with combinatorial treatment of CPI-613 and inhibitors of lactate metabolism.
    Simone Kumstel, Tim Schreiber, Lea Goldstein, Jan Stenzel, Tobias Lindner, Markus Joksch, Xianbin Zhang, Edgar Heinz Uwe Wendt, Maria Schönrogge, Bernd Krause, Brigitte Vollmar, Dietmar Zechner.
      Pancreatic cancer is the fourth leading cause of cancer death, with a 5-year survival rate of 10%. A stagnant high mortality rate over the last decades highlights the need for innovative therapeutic approaches. Pancreatic tumors pursue an altered metabolism in order to maintain energy generation under low nutrient influx and hypoxic conditions. Targeting these metabolic strategies might therefore be a reasonable therapeutic approach for pancreatic cancer. One promising agent is CPI- 613, a potent inhibitor of two enzymes of the tricarboxylic acid cycle. The present study evaluated the anti-cancerous efficacy of CPI-613 in combination with galloflavin, a lactate dehydrogenase inhibitor or with alpha-cyano-4-hydroxycinnamic acid, an inhibitor of monocarboxylate transporters. The efficacy of both combination therapies was tested in vitro on one human and two murine pancreatic cancer cell lines and in vivo in an orthotopic pancreatic cancer model. Tumor progression was evaluated by MRI and 18F-FDG PET-CT. Both combinatorial treatments demonstrated in vitro a significant inhibition of pancreatic cancer cell proliferation and induction of cell death. In contrast to the in vitro results, both combination therapies did not significantly reduce tumor growth in vivo. The in vitro results suggest that a combined inhibition of different metabolic pathways might be a promising approach for cancer therapy. However, the in vivo experiments indicate that applying a higher dosage or using other drugs targeting these metabolic pathways might be more promising.
    DOI:  https://doi.org/10.1371/journal.pone.0266601
  112. Mar Drugs. 2022 Apr 18. pii: 271. [Epub ahead of print]20(4):
    Phytoplankton Toxins and Their Potential Therapeutic Applications: A Journey toward the Quest for Potent Pharmaceuticals.
    Biswajita Pradhan, Jang-Seu Ki.
      Phytoplankton are prominent organisms that contain numerous bioactive substances and secondary metabolites, including toxins, which can be valuable to pharmaceutical, nutraceutical, and biotechnological industries. Studies on toxins produced by phytoplankton such as cyanobacteria, diatoms, and dinoflagellates have become more prevalent in recent years and have sparked much interest in this field of research. Because of their richness and complexity, they have great potential as medicinal remedies and biological exploratory probes. Unfortunately, such toxins are still at the preclinical and clinical stages of development. Phytoplankton toxins are harmful to other organisms and are hazardous to animals and human health. However, they may be effective as therapeutic pharmacological agents for numerous disorders, including dyslipidemia, obesity, cancer, diabetes, and hypertension. In this review, we have focused on the properties of different toxins produced by phytoplankton, as well as their beneficial effects and potential biomedical applications. The anticancer properties exhibited by phytoplankton toxins are mainly attributed to their apoptotic effects. As a result, phytoplankton toxins are a promising strategy for avoiding postponement or cancer treatment. Moreover, they also displayed promising applications in other ailments and diseases such as Alzheimer's disease, diabetes, AIDS, fungal, bacterial, schizophrenia, inflammation, allergy, osteoporosis, asthma, and pain. Preclinical and clinical applications of phytoplankton toxins, as well as future directions of their enhanced nano-formulations for improved clinical efficacy, have also been reviewed.
    Keywords:  pharmaceuticals; phytoplankton; therapeutic; toxins
    DOI:  https://doi.org/10.3390/md20040271
  113. Cancer Causes Control. 2022 Apr 19.
    Dietary behavior and urinary gallic acid concentration differences among underserved elder racial and ethnic minorities in New York City.
    Cristina N Zambrano, Wenyue Lu, Cicely Johnson, Maayan Beeber, April Panitz, Safa Ibrahim, Marilyn Fraser, Grace X Ma, Khursheed Navder, Ming-Chin Yeh, Olorunseun O Ogunwobi.
      PURPOSE: Diet and nutrition are important for cancer prevention. To investigate associations between dietary behavior, demographics, and risk of cancer, we assessed dietary behavior and urinary concentration of gallic acid, a polyphenol with anticancer properties found in various fruits and vegetables, in racial and ethnic minorities.METHODS: Ninety-one (91) participants were recruited from senior centers in East Harlem, New York City, a racially diverse and underserved community. A National Institute of Health (NIH)-validated dietary survey questionnaire-was used to collect dietary fruits and vegetables consumption data. Demographic and cancer information were also collected. All 91 participants completed the survey and forty-five (45) participants provided urine samples for gallic acid analysis.
    RESULTS: Gender differences were significantly associated with dietary behavior and urinary gallic acid concentration (UGAC). Female participants had a higher total daily intake of fruits and a significantly higher UGAC compared to male participants (p < 0.05). Age was negatively associated with the serving quantity of French fries/fried potatoes and white potatoes (p < 0.05), while positively associated with the daily intake frequency and daily intake of fruits (p < 0.05). Furthermore, Asian race was associated with higher daily intake frequencies of fruits and vegetable soup (p < 0.05), compared to other races. In a multivariate analysis, a significant association was observed between the serving quantities of fruits and other vegetables and UGAC (p < 0.05) after controlling for demographic characteristics.
    CONCLUSION: The observed differences in dietary behavior and UGAC in this study provide limited information on the association between demographic differences and cancer prevalence in elder racial and ethnic minorities. Future research should investigate this association further for potential implications in cancer prevention.
    Keywords:  Antioxidants; Cancer prevention; Fruits and vegetables; Minority; Nutrition
    DOI:  https://doi.org/10.1007/s10552-022-01581-y
  114. Cancers (Basel). 2022 Apr 07. pii: 1865. [Epub ahead of print]14(8):
    Extracellular Vesicle-Mediated Mitochondrial Reprogramming in Cancer.
    Roger Carles-Fontana, Nigel Heaton, Elena Palma, Shirin E Khorsandi.
      Altered metabolism is a defining hallmark of cancer. Metabolic adaptations are often linked to a reprogramming of the mitochondria due to the importance of these organelles in energy production and biosynthesis. Cancer cells present heterogeneous metabolic phenotypes that can be modulated by signals originating from the tumor microenvironment. Extracellular vesicles (EVs) are recognized as key players in intercellular communications and mediate many of the hallmarks of cancer via the delivery of their diverse biological cargo molecules. Firstly, this review introduces the most characteristic changes that the EV-biogenesis machinery and mitochondria undergo in the context of cancer. Then, it focuses on the EV-driven processes which alter mitochondrial structure, composition, and function to provide a survival advantage to cancer cells in the context of the hallmarks of cancers, such as altered metabolic strategies, migration and invasiveness, immune surveillance escape, and evasion of apoptosis. Finally, it explores the as yet untapped potential of targeting mitochondria using EVs as delivery vectors as a promising cancer therapeutic strategy.
    Keywords:  metabolism; miRNA; mitochondrial dynamics; tumor microenvironment (TME); tumor-derived EVs (TEVs)
    DOI:  https://doi.org/10.3390/cancers14081865
  115. J Sci Food Agric. 2022 Apr 19.
    Application of γ-Cyclodextrin-lysozyme as host materials for encapsulation of curcumin: characterization, stability and controlled release properties.
    Hedi Wen, Deju Zhang, Jingbo Liu, Xiaomin Shang, Xuanting Liu, Zhiyang Du, Ting Zhang.
      BACKGROUND: In the present study, a safe and relatively stable γ-cyclodextrin-lysozyme (γ-CD-Lys) was synthesized using epichlorohydrin as the cross-linking agent, and curcumin was successfully encapsulated in γ-CD-Lys.RESULTS: The successful Lys grafting onto γ-CD can be demonstrated by a high grafting ratio (79.02%) and was further confirmed by FT-IR bands shifts and the new signal obtained at δ 2.75 in 1 H NMR. The encapsulation efficiency value of γ-CD-Lys was 76.74%, and the successful encapsulation of curcumin into γ-CD-Lys was confirmed by crystal structure change, increased melting point, and bands shifts of FT-IR. The intermolecular bonds results suggested that associative forces between curcumin and γ-CD-Lys were electrostatic interaction, hydrogen bonds interaction, and hydrophobic interaction. The designed nanoparticles had excellent stability at low pH and low salt concentration. The release rate of these nanoparticles was inhibited in simulated gastric conditions, while it increased significantly in intestinal media. Simulated gastrointestinal digestion experiments further confirmed that nanoparticles showed higher bioaccessibility (86.05%) compared to curcumin (58.82%).
    CONCLUSION: Overall, our study showed that the nanoparticles were highly promising for delivering curcumin because of their enhanced functional attributes and stabilization in acid or low salt environments. Also, it was an excellent wall material for targeting hydrophobic bioactive compounds in the intestinal tract via oral administration. This article is protected by copyright. All rights reserved.
    Keywords:  Curcumin; Cyclodextrin; Microencapsulation; Nanoparticles; Stability
    DOI:  https://doi.org/10.1002/jsfa.11943
  116. Cancers (Basel). 2022 Apr 18. pii: 2044. [Epub ahead of print]14(8):
    How Did Conventional Nanoparticle-Mediated Photothermal Therapy Become "Hot" in Combination with Cancer Immunotherapy?
    Wan Su Yun, Ji-Ho Park, Dong-Kwon Lim, Cheol-Hee Ahn, In-Cheol Sun, Kwangmeyung Kim.
      One of the promising cancer treatment methods is photothermal therapy (PTT), which has achieved good therapeutic efficiency through nanoparticle-based photoabsorbers. Because of the various functions of nanoparticles, such as targeting properties, high light-to-heat conversion, and photostability, nanoparticle-mediated PTT successfully induces photothermal damage in tumor tissues with minimal side effects on surrounding healthy tissues. The therapeutic efficacy of PTT originates from cell membrane disruption, protein denaturation, and DNA damage by light-induced heat, but these biological impacts only influence localized tumor areas. This conventional nanoparticle-mediated PTT still attracts attention as a novel cancer immunotherapy, because PTT causes immune responses against cancer. PTT-induced immunogenic cell death activates immune cells for systemic anti-cancer effect. Additionally, the excellent compatibility of PTT with other treatment methods (e.g., chemotherapy and immune checkpoint blockade therapy) reinforces the therapeutic efficacy of PTT as combined immunotherapy. In this review, we investigate various PTT agents of nanoparticles and compare their applications to reveal how nanoparticle-mediated PTT undergoes a transition from thermotherapy to immunotherapy.
    Keywords:  cancer; immunotherapy; photothermal therapy
    DOI:  https://doi.org/10.3390/cancers14082044
  117. Pharmaceuticals (Basel). 2022 Apr 18. pii: 490. [Epub ahead of print]15(4):
    Development of Astaxanthin-Loaded Nanosized Liposomal Formulation to Improve Bone Health.
    Hsin-I Chang, Chu-Wen Shao, Evelyn Huang, Kuo-Yuan Huang.
      Astaxanthin is a xanthophyll carotenoid commonly found in marine organisms. Due to its super antioxidative ability, astaxanthin has been widely applied as a human nutraceutical supplement for health benefits. In order to enhance the bioavailability of astaxanthin, we used soybean phosphatidylcholine to encapsulate astaxanthin for liposomal formation. The physical properties of astaxanthin (asta)-loaded liposomes were determined by particle size, encapsulation efficiency and polydispersity index. The results revealed that the particle sizes of asta-loaded liposomes with various concentrations exhibited mean diameters in the range of 109 to 134 nm and had a narrow PDI value. As expected, the entrapment efficiency of liposomes loaded with a low concentration of astaxanthin (0.05 μg/mL) was 89%, and that was reduced to 29% for 1.02 μg/mL asta loading. Alizarin red staining and calcium content measurement showed that there was a significant reduction in calcium deposition for 7F2 osteoblasts treated with asta-loaded liposomes (0.25-1.02 μg/mL) in comparison with the cells treated with drug-free liposomes and mineralization medium (MM). Although liposomal formulation can reduce the cytotoxicity of astaxanthin and possess antioxidant, anti-inflammatory and anti-osteoclastogenic activities in RAW264.7 macrophages, asta-loaded liposomes with high concentrations may suppress ALP activity and mineralization level in 7F2 osteoblasts. Therefore, astaxanthin extract may be able to protect bones against oxidative stress and inflammation through liposomal formulation.
    Keywords:  anti-inflammation; astaxanthin; liposomes; marine natural product; osteoblast mineralization
    DOI:  https://doi.org/10.3390/ph15040490
  118. Pharmaceutics. 2022 Mar 28. pii: 728. [Epub ahead of print]14(4):
    Emerging Albumin-Binding Anticancer Drugs for Tumor-Targeted Drug Delivery: Current Understandings and Clinical Translation.
    Hanhee Cho, Seong Ik Jeon, Cheol-Hee Ahn, Man Kyu Shim, Kwangmeyung Kim.
      Albumin has shown remarkable promise as a natural drug carrier by improving pharmacokinetic (PK) profiles of anticancer drugs for tumor-targeted delivery. The exogenous or endogenous albumin enhances the circulatory half-lives of anticancer drugs and passively target the tumors by the enhanced permeability and retention (EPR) effect. Thus, the albumin-based drug delivery leads to a potent antitumor efficacy in various preclinical models, and several candidates have been evaluated clinically. The most successful example is Abraxane, an exogenous human serum albumin (HSA)-bound paclitaxel formulation approved by the FDA and used to treat locally advanced or metastatic tumors. However, additional clinical translation of exogenous albumin formulations has not been approved to date because of their unexpectedly low delivery efficiency, which can increase the risk of systemic toxicity. To overcome these limitations, several prodrugs binding endogenous albumin covalently have been investigated owing to distinct advantages for a safe and more effective drug delivery. In this review, we give account of the different albumin-based drug delivery systems, from laboratory investigations to clinical applications, and their potential challenges, and the outlook for clinical translation is discussed. In addition, recent advances and progress of albumin-binding drugs to move more closely to the clinical settings are outlined.
    Keywords:  albumin; cancer-targeted therapy; drug delivery system; prodrug
    DOI:  https://doi.org/10.3390/pharmaceutics14040728
  119. Pharmaceutics. 2022 Apr 10. pii: 826. [Epub ahead of print]14(4):
    Transdermal Glipizide Delivery System Based on Chitosan-Coated Deformable Liposomes: Development, Ex Vivo, and In Vivo Studies.
    Mohamed M Badran, Nadia N Alouny, Basmah N Aldosari, Ahlam M Alhusaini, Amal El Sayeh Abou El Ela.
      The current study aimed to develop and evaluate a sustained-release transdermal Glipizide (GLP) film to overcome its oral administration problems. Chitosan (CS)-coated deformable liposomes (DLs) were utilized to enhance the drug transdermal delivery. The formulations were characterized in terms of particle size, zeta potential, entrapment efficiency (EE%), vesicle deformability, morphology, stability, and in vitro release. Transdermal films of chosen formulations were prepared by the solvent casting technique, and an ex vivo study throughout rat skin was also performed. Moreover, a pharmacokinetics (PK) study was carried out and blood glucose levels were estimated. All the liposomes were in the nanometer range and a high EE% was obtained from DLs compared to conventional liposomes (CL). The prepared formulations showed a high stability and the DLs exhibited a high deformability compared to CL. The in vitro release study confirmed the sustained release of GLP from both CL and DL and a more pronounced sustained release of GLP was detected after coating with CS. Moreover, GLP was shown to efficiently permeate through the rat skin from transdermal films by an ex vivo permeation test. The transdermal films showed a promising PK profile in the rat as compared with oral GLP. Most importantly, GLP-CS-DL1 demonstrated a higher hypoglycemic effect, confirming the possibility of systemic action by the local topical delivery of GLP.
    Keywords:  chitosan; deformable liposomes; glipizide; glucose levels; pharmacokinetics; transdermal delivery
    DOI:  https://doi.org/10.3390/pharmaceutics14040826
  120. Pharmaceutics. 2022 Apr 13. pii: 852. [Epub ahead of print]14(4):
    Dual Responsive poly(vinyl caprolactam)-Based Nanogels for Tunable Intracellular Doxorubicin Delivery in Cancer Cells.
    Kummara Madhusudana Rao, Maduru Suneetha, Dachuru Vinay Kumar, Hyeon Jin Kim, Yong Joo Seok, Sung Soo Han.
      In this work, doxorubicin (Dox)-encapsulated poly(vinyl caprolactam) (PVCL)-based three-dimensional nanogel networks were developed and were crosslinked with disulfide linkages. The nanogels degrade rapidly to low molecular weight chains in the presence of the typical intracellular concentration of glutathione. Doxorubicin (Dox) was successfully encapsulated into these nanogels. The nanogels have a high drug loading of 49% and can be tailored to 182 nm to deliver themselves to the targeted cells and release Dox under dual stimuli conditions, such as redox and temperature. By evaluating cell viability in the HepG2 cell line, we observed that Dox-loaded nanogels effectively killed the cancer cell. Fluorescence microscopy results show that the nanogels could easily be internalized with HepG2 cells. The results confirm that the nanogels destabilized in intracellular cytosol via degradation of disulfide bonds in nanogels networks and release of the Dox nearby the nucleus. These carriers could be promising for cancer drug delivery.
    Keywords:  cancer cells; drug release; dual responsive; intracellular triggered; nanogels; poly(vinyl caprolactam)
    DOI:  https://doi.org/10.3390/pharmaceutics14040852
  121. Pharmaceutics. 2022 Apr 08. pii: 817. [Epub ahead of print]14(4):
    Polymerized β-Cyclodextrin-Based Injectable Hydrogel for Sustained Release of 5-Fluorouracil/Methotrexate Mixture in Breast Cancer Management: In Vitro and In Vivo Analytical Validations.
    Saud Almawash, Mohamed A El Hamd, Shaaban K Osman.
      An inclusion complexation, between polymerized β-cyclodextrin and cholesterol end-capping branched polyethylene glycol, was utilized for constructing a self-assembled hydrogel. The physicochemical properties, the in vitro release profiles of 5-Fluorouracil/methotrexate (anticancer drugs), and the surface morphology of the resulting hydrogel were studied. Moreover, in vivo studies were carried out on female rats bearing breast cancer. The results revealed that the prepared systems were white in color, rubbery, and homogenous. The in vitro release studies showed an efficient ability of the modified system for drug loading and release in a sustained release manner for 14 days. The surface morphology was spongy porous. Moreover, the tumors' healing was indicated from the analysis of tumor volume, plasma tumor markers, and histopathological analysis, compared to the controlled rats. The pharmacokinetic parameters appeared significant differences (p &lt; 0.05) in the Cmax and Tmax of the medicated hydrogel samples, as compared with sole or combined saline-injected samples. The whole AUC of each drug in the medicated hydrogel samples was five-fold more than the mixture administrated in PBS. In conclusion, the proposed work delivered a hydrogel system that has a convenient ability for localized sustained release of breast cancer management.
    Keywords:  branched PEG; cell viability; cholesterol; controlled release; pharmacokinetics; self-assembling hydrogel; tumor markers
    DOI:  https://doi.org/10.3390/pharmaceutics14040817
  122. Int J Mol Sci. 2022 Apr 14. pii: 4280. [Epub ahead of print]23(8):
    Drug Repurposing in Cancer Therapy: Influence of Patient's Genetic Background in Breast Cancer Treatment.
    Rafaela Rodrigues, Diana Duarte, Nuno Vale.
      Cancer is among the leading causes of death worldwide and it is estimated that in 2040 more than 29 million people will be diagnosed with some type of cancer. The most prevalent type of cancer in women, worldwide, is breast cancer, a type of cancer associated with a huge death rate. This high mortality is mainly a consequence of the development of drug resistance, which is one of the major challenges to overcome in breast cancer treatment. As a result, research has been focused on finding novel therapeutical weapons, specifically ones that allow for a personalized treatment, based on patients' characteristics. Although the scientific community has been concerned about guaranteeing the quality of life of cancer patients, researchers are also aware of the increasing costs related to cancer treatment, and efforts have been made to find alternatives to the development of new drugs. The development of new drugs presents some disadvantages as it is a multistep process that is time- and money-consuming, involving clinical trials that commonly fail in the initial phases. A strategy to overcome these disadvantages is drug repurposing. In this review, we focused on describing potential repurposed drugs in the therapy of breast cancer, considering their pharmacogenomic profile, to assess the relationship between patients' genetic variations and their response to a certain therapy. This review supports the need for the development of further fundamental studies in this area, in order to investigate and expand the knowledge of the currently used and novel potential drugs to treat breast cancer. Future clinical trials should focus on developing strategies to group cancer patients according to their clinical and biological similarities and to discover new potential targets, to enable cancer therapy to be more effective and personalized.
    Keywords:  anticancer drugs; cancer drug resistance; genetic influence; personalized medicine; pharmacology; repurposed drugs; therapeutic strategies
    DOI:  https://doi.org/10.3390/ijms23084280
  123. Biochem J. 2022 Apr 14. 479(7): 857-866
    Ferroptosis in plants: regulation of lipid peroxidation and redox status.
    Ayelén Mariana Distéfano, Gabriel Alejandro López, Victoria Bauer, Eduardo Zabaleta, Gabriela Carolina Pagnussat.
      Regulated cell death (RCD) is an essential process that plays key roles along the plant life cycle. Unlike accidental cell death, which is an uncontrolled biological process, RCD involves integrated signaling cascades and precise molecular-mediated mechanisms that are triggered in response to specific exogenous or endogenous stimuli. Ferroptosis is a cell death pathway characterized by the iron-dependent accumulation of lipid reactive oxygen species. Although first described in animals, ferroptosis in plants shares all the main core mechanisms observed for ferroptosis in other systems. In plants as in animals, oxidant and antioxidant systems outline the process of lipid peroxidation during ferroptosis. In plants, cellular compartments such as mitochondria, chloroplasts and cytosol act cooperatively and coordinately to respond to changing redox environments. This particular context makes plants a unique model to study redox status regulation and cell death. In this review, we focus on our most recent understanding of the regulation of redox state and lipid peroxidation in plants and their role during ferroptosis.
    Keywords:  cell death; ferroptosis; redox signalling
    DOI:  https://doi.org/10.1042/BCJ20210682
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