bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022‒06‒19
78 papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development
  1. Recent updates in curcumin delivery.
  2. Nano-Based Drug Delivery of Anticancer Chemotherapeutic Drugs Targeting Breast Cancer.
  3. The Role of Photodynamic Therapy in Triggering Cell Death and Facilitating Antitumor Immunology.
  4. Targeting the methionine addiction of cancer.
  5. Nano-drug delivery system for the treatment of acute myelogenous leukemia.
  6. Nanoarchitectured Graphene Organic Framework for Drug Delivery and Chemo-photothermal Synergistic Therapy.
  7. Autoxidation-Resistant, ROS-Scavenging, and Anti-Inflammatory Micellar Nanoparticles Self-Assembled from Poly(acrylic acid)-Green Tea Catechin Conjugates.
  8. Recent Trends in Composite Nanozymes and Their Pro-Oxidative Role in Therapeutics.
  9. Deletion of Lactate Dehydrogenase-A Impairs Oncogene-Induced Mouse Hepatocellular Carcinoma Development.
  10. Cisplatin and paclitaxel co-delivery nanosystem for ovarian cancer chemotherapy.
  11. Mitochondria-Targeted Degradable Nanocomposite Combined with Laser and Ultrasound for Synergistic Tumor Therapies.
  12. Progress of Nanomaterials in Photodynamic Therapy Against Tumor.
  13. Dissecting dietary and semisynthetic volatile phenylpropenes: A compile of their distribution, food properties, health effects, metabolism and toxicities.
  14. Traditional Chinese medicine active ingredients-based selenium nanoparticles regulate antioxidant selenoproteins for spinal cord injury treatment.
  15. Cisplatin and oleanolic acid Co-loaded pH-sensitive CaCO3 nanoparticles for synergistic chemotherapy.
  16. Transferrin receptor-mediated liposomal drug delivery: recent trends in targeted therapy of cancer.
  17. Synergistic therapy for orthotopic gliomas via biomimetic nanosonosensitizer-mediated sonodynamic therapy and ferroptosis.
  18. Dendrimers as nanoscale vectors: Unlocking the bars of cancer therapy.
  19. Loading Drugs in Natural Phospholipid Bilayers of Cell Membrane Shells to Construct Biomimetic Nanocomposites for Enhanced Tumor Therapy.
  20. Highly Active Nano-Reactor for Responding Tumor Microenvironment and Antitumor Therapy.
  21. Taxanes prodrug-based nanomedicines for cancer therapy.
  22. Inhibitory Effects and Gene Expression Analysis of Chemotherapeutic Photodynamic Therapy by using a Liposomally Formulated Indocyanine Green Derivative.
  23. Solubilized chlorin e6-layered double hydroxide complex for anticancer photodynamic therapy.
  24. Metabolic Symbiosis-Blocking Nano-combination for Tumor Vascular Normalization Treatment.
  25. Nanoscale bioconjugates: A review of the structural attributes of drug-loaded nanocarrier conjugates for selective cancer therapy.
  26. Bioadhesive Nanoparticles as Potent Drug Delivery Carriers.
  27. Bimodal Treatment of Hepatocellular Carcinoma by Targeted Minimally Interventional Photodynamic/Chemotherapy Using Glyco-Covalent-Organic Frameworks-Guided Porphyrin/Sorafenib.
  28. Treatment of triple negative breast cancer by near infrared light triggered mild temperature photothermal therapy combined with oxygen-independent cytotoxic free radicals.
  29. A Multifunctional Vanadium-Iron-Oxide Nanoparticle Eradicates Hepatocellular Carcinoma via Targeting Tumor and Endothelial Cells.
  30. Health benefits of polyphenols: A concise review.
  31. Ethosomal (-)-epigallocatechin-3-gallate as a novel approach to enhance antioxidant, anti-collagenase and anti-elastase effects.
  32. The improved killing of both androgen-dependent and independent prostate cancer cells by etoposide loaded SPIONs coupled with NIR irradiation.
  33. Tumor Microenvironments-Adaptive Apoptotic Effects of Cytidine 5'-monophosphate-Capped Gold Nanoclusters.
  34. Characterizing the KRAS G12C mutation in metastatic colorectal cancer: a population-based cohort and assessment of expression differences in The Cancer Genome Atlas.
  35. Recent Advances in Chitosan and its Derivatives in Cancer Treatment.
  36. Potentiality of raloxifene loaded melittin functionalized lipidic nanovesicles against pancreatic cancer cells.
  37. Application of curcumin nanoformulations in Alzheimer's disease: prevention, diagnosis and treatment.
  38. Meta analysis of bioactive compounds, miRNA, siRNA and cell death regulators as sensitizers to doxorubicin induced chemoresistance.
  39. Breaking the niche: multidimensional nanotherapeutics for tumor microenvironment modulation.
  40. Approaches to Address PK-PD Challenges of Conventional Liposome Formulation with Special Reference to Cancer, Alzheimer's, Diabetes, and Glaucoma: An Update on Modified Liposomal Drug Delivery System.
  41. Drug delivery of natural products through nanocarriers for effective vitiligo therapy: A compendia Review.
  42. Flavonoids a Bioactive Compound from Medicinal Plants and Its Therapeutic Applications.
  43. New dawn for cancer cell death: emerging role of lipid metabolism.
  44. Recent Advances in Oral Mucoadhesive Drug Delivery.
  45. Anti-tumor pharmacology of natural products targeting mitosis.
  46. Novel selenium-containing photosensitizers for near-infrared fluorescence imaging-guided photodynamic therapy.
  47. Anti-cancer peptides: their current trends in the development of peptide-based therapy and anti-tumor drugs.
  48. The role of glutathione peroxidase-1 in health and disease.
  49. A Nucleus-Targeted Nanosystem Integrated with Photodynamic Therapy and Chemotherapy.
  50. Nanoinformatics and Personalized Medicine: An advanced cumulative approach for Cancer Management.
  51. Ethosomes as dermal/transdermal drug delivery systems: applications, preparation and characterization.
  52. Construction of chitooligosaccharide-based nanoparticles of pH/redox cascade responsive for co-loading cyclosporin A and AZD9291.
  53. Improving Photodynamic Therapy Anticancer Activity of a Mitochondria-Targeted Coumarin Photosensitizer Using a Polyurethane-Polyurea Hybrid Nanocarrier.
  54. Exploring Liposomes for Lung Cancer Therapy.
  55. Facile Synthesis of Three Types of Mesoporous Silica Microspheres as Drug Delivery Carriers and Their Sustained-Release Properties.
  56. A comparative study between olive oil and corn oil on oxidative metabolism.
  57. p53-Mediated Indirect Regulation on Cellular Metabolism: From the Mechanism of Pathogenesis to the Development of Cancer Therapeutics.
  58. Systematic review of the registered clinical trials for oncological hyperthermia treatment.
  59. Nanocrystals: An Approachable Delivery System for Anticancer Therapeutics.
  60. Combining metabolic phenotype determination with metabolomics and transcriptional analyses to reveal pathways regulated by hydroxycarboxylic acid receptor 2.
  61. Curcumin and metformin synergistically modulate peripheral and central immune mechanisms of pain.
  62. Transferrin-Modified Mangiferin-Loaded SLNs: Preparation, Characterization, and Application in A549 Lung Cancer Cell.
  63. Therapeutic Effects of Zoledronic Acid-Loaded Hyaluronic Acid/Polyethylene Glycol/Nano-Hydroxyapatite Nanoparticles on Osteosarcoma.
  64. MXene-Assisted Ablation of Cells with a Pulsed Near-Infrared Laser.
  65. An all-in-one biomimetic iron-small interfering RNA nanoplatform induces ferroptosis for cancer therapy.
  66. Novel Bicyclic Dione Compounds as KRAS Inhibitors for Treating Cancer.
  67. Bioactives and functional food ingredients with promising potential for the management of cerebral and myocardial ischemia: a comprehensive mechanistic review.
  68. Potential of Pectin for Biomedical Applications: A Comprehensive Review.
  69. Repurposing chia seed oil: A versatile novel functional food.
  70. A much-needed treatment for HER2-low breast cancer.
  71. Construction of reduction-sensitive heterodimer prodrugs of doxorubicin and dihydroartemisinin self-assembled nanoparticles with antitumor activity.
  72. A Hypoxia-Sensitive Drug Delivery System Constructed by Nitroimidazole and its Application in the Treatment of Hepatocellular Carcinoma.
  73. Mesoporous silica nanocarriers as drug delivery systems for anti-tubercular agents: a review.
  74. Chitosan: Applications in Drug Delivery System.
  75. Editorial: Mitochondria-Targeted Nanocarriers for Enhanced Efficacy of Cancer Therapy.
  76. Research Progress on Improving the Efficiency of CDT by Exacerbating Tumor Acidification.
  77. Stepwise responsive carboxymethyl chitosan-based nanoplatform for effective drug-resistant breast cancer suppression.
  78. Investigation of wound healing potential of photo-active curcumin-ZnO-nanoconjugates in excisional wound model.
  1. J Liposome Res. 2022 Jun 14. 1-12
    Recent updates in curcumin delivery.
    Mohammad A Obeid, Manal Alsaadi, Alaa A Aljabali.
      Curcumin is a natural component extracted from the rhizomes of turmeric (Curcuma longa), a natural plat with known medicinal uses for more than 4000 years. Most turmeric therapeutic effects are attributed to curcumin, a yellow-coloured extract. Curcumin has received considerable attention due to its biological activities, such as its use in arthritis, liver and neurodegenerative diseases, obesity, and several types of cancers. Most of these curcumin therapeutic activities are related to its antioxidant and anti-inflammatory effects. However, the clinical application of curcumin is hampered by some limitations that prevent its extensive clinical application. Curcumin high hydrophobicity of curcumin and limited water solubility are among the most important limitations. This poor solubility will result in low bioavailability due to its poor absorption into plasma and the target tissues. Curcumin also has rapid metabolism, which will significantly lower its bioavailability and shorten its half-life. Moreover, curcumin is photosensitive with limited chemical stability during manufacturing and storage. These limitations have been overcome by applying nanotechnology using several types of nanoparticles (NPs). This includes using NPs such as liposomes, niosomes, gold nanoparticles, and many others to improve the curcumin solubility and bioavailability. This review focuses on the different types of NPs investigated and the outcomes generated by their use in the most recent studies in this field. To follow the latest advances in the field of site-specific drug delivery using nanomaterials, an electronic databases search was conducted using PubMed, Google scholar and Scopus using the following keywords: lipid-based nanoparticles, curcumin delivery, niosomes, and liposomes.
    Keywords:  Curcumin; clinical trial; drug delivery; liposomes; niosomes nanoparticle
    DOI:  https://doi.org/10.1080/08982104.2022.2086567
  2. Recent Pat Anticancer Drug Discov. 2022 Jun 10.
    Nano-Based Drug Delivery of Anticancer Chemotherapeutic Drugs Targeting Breast Cancer.
    Akanksha Behl, Anil K Chhillar.
      BACKGROUND: Chemotherapeutic drugs are principally intended to treat breast cancer. However, sooner or later in tumor drug resistance developed. These chemo drugs are effectual, but with numerous side effects. Breast cancer care may be extremely difficult since recurring cancer is frequently pre-treated with powerful agents, and cancer cells acquire high resistance to earlier therapies, necessitating the use of alternative and more powerful drugs. Nanoparticles(NPs) as a medication delivery technology can overcome medication resistance in breast cancer and significantly reduce the effective dose. The off-targeted nature of chemo drugs can be resolved by encapsulating or attaching chemo drugs in nanocarrier which targets specifically breast cancer cells.OBJECTIVES: In this review, we highlight various chemo drugs for breast cancer and their encapsulation or bioconjugation with nanoparticles for its targeted delivery.
    CONCLUSION: Nanoparticles may subsist valuable abet in breast cancer management in this regard. Given that traditional chemotherapy, approaches have been demonstrated to have several side effects and defects during treatment, the NPs-mediated Drug delivery mechanism is a possible contender for replacement as a new technique.
    Keywords:  Breast Cancer; Chemotherapeutic drugs; Nanoparticles; Targeted delivery
    DOI:  https://doi.org/10.2174/157489281703220610170559
  3. Front Oncol. 2022 ;12 863107
    The Role of Photodynamic Therapy in Triggering Cell Death and Facilitating Antitumor Immunology.
    Liuchang Tan, Xiaoxiao Shen, Zhiqiang He, Yuangang Lu.
      Cancer is a major threat to human health because of its high mortality, easy recurrence, strong invasion, and metastasis. Photodynamic therapy (PDT) is a promising minimally invasive treatment for tumor. Compared with traditional treatment methods, PDT is less invasive and does not easily damage normal tissues. Most of the effects of this treatment are due to the direct effects of singlet oxygen together with reactive oxygen species. PDT can provide the source of active oxygen for the Fenton reaction, which enhances ferroptosis and also improves the efficacy of PDT in antitumor therapy. Additionally, in contrast to chemotherapy and radiotherapy, PDT has the effect of stimulating the immune response, which can effectively induce immunogenic cell death (ICD) and stimulate immunity. PDT is an ideal minimally invasive treatment method for tumors. In this paper, according to the characteristics of anti-tumor immunity of PDT, some tumor treatment strategies of PDT combined with anti-tumor immunotherapy are reviewed.
    Keywords:  cell death; immune response; immunotherapy; photodynamic therapy; tumor
    DOI:  https://doi.org/10.3389/fonc.2022.863107
  4. Am J Cancer Res. 2022 ;12(5): 2249-2276
    Targeting the methionine addiction of cancer.
    Joni C Sedillo, Vincent L Cryns.
      Methionine is the initiator amino acid for protein synthesis, the methyl source for most nucleotide, chromatin, and protein methylation, and the carbon backbone for various aspects of the cellular antioxidant response and nucleotide biosynthesis. Methionine is provided in the diet and serum methionine levels fluctuate based on dietary methionine content. Within the cell, methionine is recycled from homocysteine via the methionine cycle, which is linked to nutrient status via one-carbon metabolism. Unlike normal cells, many cancer cells, both in vitro and in vivo, show high methionine cycle activity and are dependent on exogenous methionine for continued growth. However, the molecular mechanisms underlying the methionine dependence of diverse malignancies are poorly understood. Methionine deprivation initiates widespread metabolic alterations in cancer cells that enable them to survive despite limited methionine availability, and these adaptive alterations can be specifically targeted to enhance the activity of methionine deprivation, a strategy we have termed "metabolic priming". Chemotherapy-resistant cell populations such as cancer stem cells, which drive treatment-resistance, are also sensitive to methionine deprivation, suggesting dietary methionine restriction may inhibit metastasis and recurrence. Several clinical trials in cancer are investigating methionine restriction in combination with other agents. This review will explore new insights into the mechanisms of methionine dependence in cancer and therapeutic efforts to translate these insights into enhanced clinical activity of methionine restriction in cancer.
    Keywords:  Methionine; cancer therapy; epigenetics; metabolism; nutrition; one-carbon; oxidative stress
  5. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021 Dec 25.
    Nano-drug delivery system for the treatment of acute myelogenous leukemia.
    Shaoqi Zhang, Jie Sun.
      Administration of therapeutic drugs has been the core strategy for acute myelogenous leukemia (AML), but it is generally limited by its low bioavailability, toxic side effects and intravenous administration. The nano-drug delivery system significantly improves the anti-AML activity through targeted optimization of the drug delivery system. Organic nanocarriers include polymers, liposomes, nanoemulsion, nanomicelle and proteins, which have the advantages of high loading capacity, biocompatibility and functionalization. Inorganic nanocarriers include gold nanoparticles, silicon nanoparticles, iron nanoparticles and other inorganic nanoparticles, which exhibit diverse physical and chemical properties, and have a wide range of biomedical applications including drug carriers. Both organic and inorganic nanocarriers exhibit the potential to alter the pharmacokinetics and pharmacodynamics of drugs. This article reviews the recent progress of nanocarriers as drug delivery system in clinical applications of AML treatment.
    Keywords:  Acute myelogenous leukemia; Drug delivery system; Nanocarrier; Review; Therapy
    DOI:  https://doi.org/10.3724/zdxbyxb-2022-0084
  6. J Biomater Appl. 2022 Jun 14. 8853282221108482
    Nanoarchitectured Graphene Organic Framework for Drug Delivery and Chemo-photothermal Synergistic Therapy.
    Chengfeng Xu, Shuting Yao, Peng Jiang, Cui Wang, Jinhua Hu, Junmin Wan, Zhiwen Hu, Bing Wang.
      The combination of phototherapy and chemotherapy has received extensive attention in the field of cancer therapy. Hence, graphene organic framework (GOF) with a large d-spacing was prepared by solvothermal method, and a novel nanocomposite based on bovine serum albumin (BSA) and the anticancer drug doxorubicin (DOX) was developed, which effectively achieved a photothermal-chemotherapy synergistic treatment. When the feeding ratio was 1:1.6, the DOX loading capacity was 18.51%, and the GOF-BSA/DOX nanocomposite possessed unobvious pH response characteristic, as well as the cumulative release of DOX reached 54.17% at 42°C in the acidic environment (pH = 5.0). The nanocarriers also showed excellent photothermal property and photothermal stability in vitro. In addition, under 808 nm near-infrared laser (NIR) irradiation, the GOF-BSA/DOX nanocomposites generated a large amount of heat, which significantly enhanced the synergistic antitumor effect of in vitro photothermal-chemotherapy. Furthermore, the GOF-BSA/DOX nanocomposites exhibited significantly increased cytotoxicity in the NIR compared with chemotherapy or photothermal therapy alone, suggesting that the combination of chemotherapy and photothermal therapy has excellent antitumor capacity. Therefore, porous GOF nanocarriers may have great potential in combined anti-tumour therapy.
    Keywords:  d-spacing; drug carriers; graphene organic framework; photothermal therapy; synergetic therapy
    DOI:  https://doi.org/10.1177/08853282221108482
  7. ACS Macro Lett. 2022 Jun 17. 835-840
    Autoxidation-Resistant, ROS-Scavenging, and Anti-Inflammatory Micellar Nanoparticles Self-Assembled from Poly(acrylic acid)-Green Tea Catechin Conjugates.
    Ki Hyun Bae, Kiat Hwa Chan, Motoichi Kurisawa.
      (-)-Epigallocatechin-3-O-gallate (EGCG), the most bioactive catechin in green tea, has drawn significant interest as a potent antioxidant and anti-inflammatory compound. However, the application of EGCG has been limited by its rapid autoxidation at physiological pH, which generates cytotoxic levels of reactive oxygen species (ROS). Herein, we report the synthesis of poly(acrylic acid)-EGCG conjugates with tunable degrees of substitution and their spontaneous self-assembly into micellar nanoparticles with enhanced resistance against autoxidation. These nanoparticles not only exhibited superior oxidative stability and cytocompatibility over native EGCG, but also showed excellent ROS-scavenging and anti-inflammatory effects. This work presents a potential strategy to overcome the stability and cytotoxicity issues of EGCG, making it one step closer toward its widespread application.
    DOI:  https://doi.org/10.1021/acsmacrolett.2c00239
  8. Front Bioeng Biotechnol. 2022 ;10 880214
    Recent Trends in Composite Nanozymes and Their Pro-Oxidative Role in Therapeutics.
    Shilpa Maddheshiya, Seema Nara.
      Nanozymes are inorganic nanostructures whose enzyme mimic activities are increasingly explored in disease treatment, taking inspiration from natural enzymes. The catalytic ability of nanozymes to generate reactive oxygen species can be used for designing effective antimicrobials and antitumor therapeutics. In this context, composite nanozymes are advantageous, particularly because they integrate the properties of various nanomaterials to offer a single multifunctional platform combining photodynamic therapy (PDT), photothermal therapy (PTT), and chemodynamic therapy (CDT). Hence, recent years have witnessed great progress in engineering composite nanozymes for enhanced pro-oxidative activity that can be utilized in therapeutics. Therefore, the present review traverses over the newer strategies to design composite nanozymes as pro-oxidative therapeutics. It provides recent trends in the use of composite nanozymes as antibacterial, antibiofilm, and antitumor agents. This review also analyzes various challenges yet to be overcome by pro-oxidative composite nanozymes before being used in the field.
    Keywords:  antibacterial; antitumor; nanozyme; pro-oxidative; therapeutic
    DOI:  https://doi.org/10.3389/fbioe.2022.880214
  9. Cell Mol Gastroenterol Hepatol. 2022 Jun 14. pii: S2352-345X(22)00102-3. [Epub ahead of print]
    Deletion of Lactate Dehydrogenase-A Impairs Oncogene-Induced Mouse Hepatocellular Carcinoma Development.
    Marina Serra, Mario Di Matteo, Jens Serneels, Rajesh Pal, Sarah Trusso Cafarello, Martina Lanza, Carlos Sanchez-Martin, Matthias Evert, Alessandra Castegna, Diego Francesco Calvisi, Massimiliano Mazzone, Amedeo Columbano.
      BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a multistep process whereby abnormally proliferating cancer cells undergo extensive metabolic reprogramming. Metabolic alterations in hepatocarcinogenesis depend on the activation of specific oncogenes, thus partially explaining HCC heterogeneity. C-Myc oncogene overexpression, frequently observed in human HCCs, leads to a metabolic rewiring toward a Warburg phenotype and production of lactate, resulting in the acidification of the extracellular space, favoring the emergence of an immune-permissive tumor microenvironment. Here, we investigated whether Lactate dehydrogenase alpha (Ldha) genetic ablation interferes with metabolic reprogramming and HCC development in the mouse.METHODS: We characterized the metabolic reprogramming in tumors induced in C57BL/6J mice hydrodynamically co-transfected with c-Myc and h-Ras. Using the same experimental model, we investigated the effect of Ldha inhibition - gained through the inducible and hepatocyte-specific Ldha knockout - on cancer cell metabolic reprogramming, number and size of HCC lesions, and TME alterations.
    RESULTS: C-Myc/h-Ras driven tumors display a striking glycolytic metabolism, suggesting a switch to a Warburg phenotype. The tumors also exhibited enhanced pentose phosphate pathway activity, the switch of glutamine to sustain glutathione synthesis instead of Tricarboxylic acid cycle, and the impairment of oxidative phosphorylation. In addition, Ldha abrogation significantly hampered tumor number and size together with an evident inhibition of the Warburg-like metabolic feature and a remarkable increase of CD4+ lymphocytes compared to Ldha wild-type livers.
    CONCLUSIONS: These results demonstrate that Ldha deletion significantly impairs mouse HCC development and suggest LDH as a potential target to enhance the efficacy of the current therapeutic options.
    Keywords:  C-Myc; HCC; Ldha; Metabolic Reprogramming; TME
    DOI:  https://doi.org/10.1016/j.jcmgh.2022.06.003
  10. Regen Biomater. 2021 Jun;8(3): rbab015
    Cisplatin and paclitaxel co-delivery nanosystem for ovarian cancer chemotherapy.
    Qiaoying Wang, Changqiang Wu, Xiaoting Li, Dixiao Yang, Liangjun Shi.
      We have designed and developed an effective drug delivery system using biocompatible polymer of poly (ethylene glycol)-polyaspartic acid (mPEG-PAsp) for co-loading the chemotherapy drugs paclitaxel (PTX) and cisplatin (CP) in one nano-vehicle. This study aimed to improve the anti-cancer efficacy of combinations of chemotherapy drugs and reduce their side effects. mPEG-PAsp-(PTX/Pt) nano-micelles disperse well in aqueous solution and have a narrow size distribution (37.8 ± 3.2 nm) in dynamic light scattering (DLS). Drug release profiles found that CP released at pH 5.5 was significantly faster than that at pH 7.4. MPEG-PAsp-(PTX/Pt) nano-micelles displayed a significantly higher tumor inhibitory effect than mPEG-PAsp-PTX nano-micelles when the polymer concentrations reached 50 μg/mL. Our data indicated that polymer micelles of mPEG-PAsp loaded with the combined drug exert synergistic anti-tumor efficacy on SKOV3 ovarian cells via different action mechanisms. Results from our studies suggested that mPEG-PAsp-(PTX/Pt) nano-micelles are promising alternatives for carrying and improving the delivery of therapeutic drugs with different water solubilities.
    Keywords:  co-delivery nanosystem; combination chemotherapy; drug delivery; ovarian cancer; paclitaxel
    DOI:  https://doi.org/10.1093/rb/rbab015
  11. J Biomed Nanotechnol. 2022 Mar 01. 18(3): 763-777
    Mitochondria-Targeted Degradable Nanocomposite Combined with Laser and Ultrasound for Synergistic Tumor Therapies.
    Shuang Zhu, De-Qiang Wang, Xue-Hua Sun, Xin-Yu Li, Hui-Fang Xiao, Wan-Ru Sun, Xing-Tao Wang, You-Jie Li, Ping-Yu Wang, Shu-Yang Xie, Ran-Ran Wang.
      Although the development of safe and efficient cancer therapeutic agents is essential, this process remains challenging. In this study, a mitochondria-targeted degradable nanoplatform (PDA-MnO₂-IR780) for synergistic photothermal, photodynamic, and sonodynamic tumor treatment was investigated. PDA-MnO₂-IR780 exhibits superior photothermal properties owing to the integration of polydopamine, MnO₂, and IR780. IR780, a photosensitizer and sonosensitizer, was used for photodynamic therapy and sonodynamic therapy. When PDA-MnO₂-IR780 was delivered to the tumor site, MnO₂ was decomposed by hydrogen peroxide, producing Mn2+ and oxygen. Meanwhile, alleviating tumor hypoxia promoted the production of reactive oxygen species during photodynamic therapy and sonodynamic therapy. Moreover, large amounts of reactive oxygen species could reduce the expression of heat shock proteins and increase the heat sensitivity of tumor cells, thereby improving the photothermal treatment effect. In turn, hyperthermia caused by photothermal therapy accelerated the production of reactive oxygen species in photodynamic therapy. IR780 selectively accumulation in mitochondria also promoted tumor apoptosis. In this system, the mutual promotion of photothermal therapy and photodynamic therapy/sonodynamic therapy had an enhanced therapeutic effect. Moreover, the responsive degradable characteristic of PDA-MnO₂-IR780 in the tumor microenvironment ensured excellent biological safety. These results reveal a great potential of PDA-MnO₂-IR780 for safe and highly-efficiency synergistic therapy for cancer.
    DOI:  https://doi.org/10.1166/jbn.2022.3287
  12. Front Bioeng Biotechnol. 2022 ;10 920162
    Progress of Nanomaterials in Photodynamic Therapy Against Tumor.
    Lei Chen, Jiahui Huang, Xiaotong Li, Miaoting Huang, Shaoting Zeng, Jiayi Zheng, Shuyi Peng, Shiying Li.
      Photodynamic therapy (PDT) is an advanced therapeutic strategy with light-triggered, minimally invasive, high spatiotemporal selective and low systemic toxicity properties, which has been widely used in the clinical treatment of many solid tumors in recent years. Any strategies that improve the three elements of PDT (light, oxygen, and photosensitizers) can improve the efficacy of PDT. However, traditional PDT is confronted some challenges of poor solubility of photosensitizers and tumor suppressive microenvironment. To overcome the related obstacles of PDT, various strategies have been investigated in terms of improving photosensitizers (PSs) delivery, penetration of excitation light sources, and hypoxic tumor microenvironment. In addition, compared with a single treatment mode, the synergistic treatment of multiple treatment modalities such as photothermal therapy, chemotherapy, and radiation therapy can improve the efficacy of PDT. This review summarizes recent advances in nanomaterials, including metal nanoparticles, liposomes, hydrogels and polymers, to enhance the efficiency of PDT against malignant tumor.
    Keywords:  nanomaterials; photodynamic therapy; photosensitizers; tumor microenvironment; tumor-targeting
    DOI:  https://doi.org/10.3389/fbioe.2022.920162
  13. Crit Rev Food Sci Nutr. 2022 Jun 16. 1-20
    Dissecting dietary and semisynthetic volatile phenylpropenes: A compile of their distribution, food properties, health effects, metabolism and toxicities.
    Ahmed Zayed, Mansour Sobeh, Mohamed A Farag.
      Phenylpropenes represent a major subclass of plant volatiles, including eugenol, and (E)-anethole. They contribute to the flavor and aroma of many chief herbs and spices, to exert distinct notes in food, i.e., spicy anise- and clove-like to fruit. Asides from their culinary use, they appear to exert general health effects, whereas some effects are specific, e.g., eugenol being a natural local anesthetic. This review represents the most comprehensive overview of phenylpropenes with respect to their chemical structures, different health effects, and their food applications as flavor and food preservatives. Side effects and toxicities of these compounds represent the second main part of this review, as some were reported for certain metabolites generated inside the body. Several metabolic reactions mediating for phenylpropenes metabolism in rodents via cytochrome P450 (CYP450) and sulfotransferase (SULT) enzymes are presented being involved in their toxicities. Such effects can be lessened by influencing their pharmacokinetics through a matrix-derived combination effect via administration of herbal extracts containing SULT inhibitors, i.e., nevadensin in sweet basil. Moreover, structural modification of phenylpropanes appears to improve their effects and broaden their applications. Hence, such review capitalizing on phenylpropenes can help optimize their applications in nutraceuticals, cosmeceuticals, and food applications.
    Keywords:  Aromatic plants; bioactivities; carcinogenicity; genotoxicity; metabolism; phenylpropanoids
    DOI:  https://doi.org/10.1080/10408398.2022.2087175
  14. J Nanobiotechnology. 2022 Jun 14. 20(1): 278
    Traditional Chinese medicine active ingredients-based selenium nanoparticles regulate antioxidant selenoproteins for spinal cord injury treatment.
    Siyuan Rao, Yongpeng Lin, Rui Lin, Jinggong Liu, Hongshen Wang, Weixiong Hu, Bolai Chen, Tianfeng Chen.
      BACKGROUND: As Traditional Chinese Medicine (TCM) drugs, Huangqi and Danshen are always applied in combination for spinal cord injury (SCI) treatment based on the compatibility theory of TCM. Astragalus Polysaccharidesis (APS) and Tanshinone IIA (TSIIA) are the main active ingredients of Huangqi and Danshen, and they both possess neuroprotective effects through antioxidant activities. However, low solubility and poor bioavailability have greatly limited their application. In recent years, selenium nanoparticles (SeNPs) have drawn enormous attention as potential delivery carrier for antioxidant drugs.RESULTS: In this study, TCM active ingredients-based SeNPs surface decorated with APS and loaded with TSIIA (TSIIA@SeNPs-APS) were successfully synthesized under the guidance of the compatibility theory of TCM. Such design improved the bioavailability of APS and TSIIA with the benefits of high stability, efficient delivery and highly therapeutic efficacy for SCI treatment illustrated by an improvement of the antioxidant protective effects of APS and TSIIA. The in vivo experiments indicated that TSIIA@SeNPs-APS displayed high efficiency of cellular uptake and long retention time in PC12 cells. Furthermore, TSIIA@SeNPs-APS had a satisfactory protective effect against oxidative stress-induced cytotoxicity in PC12 cells by inhibiting excessive reactive oxygen species (ROS) production, so as to alleviate mitochondrial dysfunction to reduce cell apoptosis and S phase cell cycle arrest, and finally promote cell survival. The in vivo experiments indicated that TSIIA@SeNPs-APS can protect spinal cord neurons of SCI rats by enhancing GSH-Px activity and decreasing MDA content, which was possibly via the metabolism of TSIIA@SeNPs-APS to SeCys2 and regulating antioxidant selenoproteins to resist oxidative stress-induced damage.
    CONCLUSIONS: TSIIA@SeNPs-APS exhibited promising therapeutic effects in the anti-oxidation therapy of SCI, which paved the way for developing the synergistic effect of TCM active ingredients by nanotechnology to improve the efficacy as well as establishing novel treatments for oxidative stress-related diseases associated with Se metabolism and selenoproteins regulation.
    Keywords:  Antioxidant selenoproteins; Selenium nanoparticles; Spinal cord injury; Traditional Chinese Medicine active ingredients
    DOI:  https://doi.org/10.1186/s12951-022-01490-x
  15. RSC Adv. 2022 May 12. 12(23): 14808-14818
    Cisplatin and oleanolic acid Co-loaded pH-sensitive CaCO3 nanoparticles for synergistic chemotherapy.
    Muhammad Waseem Khan, Chenming Zou, Said Hassan, Fakhar Ud Din, Mahaman Yacoubou Abdoul Razak, Asif Nawaz, Alam Zeb, Abdul Wahab, Sudhair Abbas Bangash.
      Despite being one of the most potent anticancer agents, cisplatin (CDDP) clinical usage is limited owing to the acquired resistance and severe adverse effects including nephrotoxicity. The current work has offered a unique approach by designing a pH-sensitive calcium carbonate drug delivery system for CDDP and oleanolic acid (OA) co-delivery, with an enhanced tumor efficacy and reduced unwanted effects. Micro emulsion method was employed to generate calcium carbonate cores (CDDP encapsulated) followed by lipid coating along with the OA loading resulting in the generation of lipid-coated cisplatin/oleanolic acid calcium carbonate nanoparticles (CDDP/OA-LCC NPs). In vitro biological assays confirmed the synergistic apoptotic effect of CDDP and OA against HepG2 cells. It was further verified in vivo through the tumor-bearing nude mice model where NPs exhibited enhanced satisfactory antitumor efficacy in contrast to free drug solutions. In vivo pharmacokinetic study demonstrated that a remarkable long circulation time with a constant therapeutic concentration for both drugs could be achieved via this drug delivery system. In addition, the in vivo imaging study revealed that DiR-loaded NPs were concentrated more in tumors for a longer period of time as compared to other peritoneal tissues in tumor bearing mice, demonstrating the site specificity of the delivery system. On the other hand, hematoxylin and eosin (H&E) staining of Kunming mice kidney tissue sections revealed that OA greatly reduced CDDP induced nephrotoxicity in the formulation. Overall, these results confirmed that our pH-sensitive dual loaded drug delivery system offers a handy direction for effective and safer combination chemotherapy.
    DOI:  https://doi.org/10.1039/d2ra00742h
  16. Expert Opin Drug Deliv. 2022 Jun 13. 1-21
    Transferrin receptor-mediated liposomal drug delivery: recent trends in targeted therapy of cancer.
    Solmaz Mojarad-Jabali, Somayeh Mahdinloo, Masoud Farshbaf, Muhammad Sarfraz, Yousef Fatahi, Fatemeh Atyabi, Hadi Valizadeh.
      INTRODUCTION: Compared to normal cells, malignant cancer cells require more iron for their growth and rapid proliferation, which can be supplied by a high expression level of transferrin receptor (TfR). It is well known that the expression of TfR on the tumor cells is considerably higher than that of normal cells, which makes TfR an attractive target in cancer therapy.AREAS COVERED: In this review, the primary focus is on the role of TfR as a valuable tool for cancer-targeted drug delivery, followed by the full coverage of available TfR ligands and their conjugation chemistry to the surface of liposomes. Finally, the most recent studies investigating the potential of TfR-targeted liposomes as promising drug delivery vehicles to different cancer cells are highlighted with emphasis on their improvement possibilities to become a part of future cancer medicines.
    EXPERT OPINION: Liposomes as a valuable class of nanocarriers have gained much attention toward cancer therapy. From all the studies that have exploited the therapeutic and diagnostic potential of TfR on cancer cells, it can be realized that the systematic assessment of TfR ligands applied for liposomal targeted delivery has yet to be entirely accomplished.
    Keywords:  Liposomes; active targeting; drug delivery; receptor-mediated endocytosis; transferrin
    DOI:  https://doi.org/10.1080/17425247.2022.2083106
  17. Biomater Sci. 2022 Jun 14.
    Synergistic therapy for orthotopic gliomas via biomimetic nanosonosensitizer-mediated sonodynamic therapy and ferroptosis.
    Mingting Zhu, Pengying Wu, Yan Li, Lei Zhang, Yujin Zong, Mingxi Wan.
      Ferroptosis is an emerging form of programmed cell death, and its combination with sonodynamic therapy (SDT) for anti-tumor activity is gradually attracting attention. However, their application against gliomas has not been studied. Herein, multifunctional cancer homologous targeting biomimetic nanoparticles (PIOC@CM NPs) encapsulating both Fe3O4 and Ce6 were constructed as a nanosonosensitizer. Based on focused ultrasound (US) combined with circulating microbubbles (MBs) to open the blood-brain barrier (BBB) in a safe and transient manner, the development of a therapeutic strategy to integrate the biomimetic nanosonosensitizer-mediated SDT and ferroptosis could achieve synergistic therapeutic effects against gliomas. We demonstrated that the glioma C6 cell membrane (CM) on the surface of the NPs allowed the nanosonosensitizer to accumulate selectively in tumors through homologous targeting in vitro. After efficient internalization in C6 cells, the PIOC@CM NPs could significantly increase the level of reactive oxygen species (ROS) and deplete glutathione (GSH) upon ultrasonic irradiation, resulting in the loss of glutathione peroxidase-4 (GPX4) activity, which facilitated SDT and ferroptosis to kill glioma C6 cells. Furthermore, the PIOC@CM NPs were intravenously injected after noninvasively opening the BBB via US-MBs, which enhanced the accumulation of the nanosonosensitizer in tumor tissues. Crucially, an attractive phenomenon of the significant reduction in orthotopic gliomas after the second US pulse-triggered SDT and ferroptosis was observed. Taken together, this study presents a novel combinatorial glioma therapeutic strategy based on noninvasive BBB opening with a biomimetic sonotheranostic system-mediated SDT and ferroptosis.
    DOI:  https://doi.org/10.1039/d2bm00562j
  18. Semin Cancer Biol. 2022 Jun 11. pii: S1044-579X(22)00137-7. [Epub ahead of print]
    Dendrimers as nanoscale vectors: Unlocking the bars of cancer therapy.
    Asmita Deka Dey, Ashkan Bigham, Yasaman Esmaeili, Milad Ashrafizadeh, Farnaz Dabbagh Moghaddam, Shing Cheng Tan, Satar Yousefiasl, Saurav Sharma, Aziz Maleki, Navid Rabiee, Alan Prem Kumar, Vijay Kumar Thakur, Gorka Orive, Esmaeel Sharifi, Arun Kumar, Pooyan Makvandi.
      Chemotherapy is the first choice in the treatment of cancer and is always preferred to other approaches such as radiation and surgery, but it has never met the need of patients for a safe and effective drug. Therefore, new advances in cancer treatment are now needed to reduce the side effects and burdens associated with chemotherapy for cancer patients. Targeted treatment using nanotechnology are now being actively explored as they could effectively deliver therapeutic agents to tumor cells without affecting normal cells. Dendrimers are promising nanocarriers with distinct physiochemical properties that have received considerable attention in cancer therapy studies, which is partly due to the numerous functional groups on their surface. In this review, we discuss the progress of different types of dendrimers as delivery systems in cancer therapy, focusing on the challenges, opportunities, and functionalities of the polymeric molecules. The paper also reviews the various role of dendrimers in their entry into cells via endocytosis, as well as the molecular and inflammatory pathways in cancer. In addition, various dendrimers-based drug delivery (e.g., pH-responsive, enzyme-responsive, redox-responsive, thermo-responsive, etc.) and lipid-, amino acid-, polymer- and nanoparticle-based modifications for gene delivery, as well as co-delivery of drugs and genes in cancer therapy with dendrimers, are presented. Finally, biosafety concerns and issues hindering the transition of dendrimers from research to the clinic are discussed to shed light on their clinical applications.
    Keywords:  cancer; chemotherapy; dendrimers; drug and gene delivery; targeted therapy
    DOI:  https://doi.org/10.1016/j.semcancer.2022.06.003
  19. ACS Appl Mater Interfaces. 2022 Jun 15.
    Loading Drugs in Natural Phospholipid Bilayers of Cell Membrane Shells to Construct Biomimetic Nanocomposites for Enhanced Tumor Therapy.
    Siyu Chi, Miaomiao Zuo, Mengting Zhu, Zijun Wang, Zhihong Liu.
      Drug-based oncotherapy is seriously challenged by insufficient drug accumulation at tumor sites, mainly resulting from low drug loading efficiency and poor tumor-targeting ability of drug carriers. We herein proposed a "one-stone, two-bird" strategy to circumvent both obstacles, utilizing the source cancer cell membrane (CM) as a dual-function carrier to simultaneously achieve sufficient drug loading and homologous tumor targeting. Combining the use of TPGS (d-α-tocopherol polyethylene glycol 1000 succinate) to inhibit the drug efflux process of drug-resistant tumor, we constructed core-shell-structured nanocomposites CMGNPs consisting of ICG (indocyanine green)/DOX (doxorubicin)-loaded, TPGS/OA (oleic acid)-stabilized upconversion nanoparticles as the core and ICG-loaded MCF7/ADR CMs as the shell, for combined chemo/phototherapy of MCF7/ADR tumor. The employment of phospholipid bilayers of CMs as natural pockets for extra drug loading while preserving the homologous targeting ability greatly enhanced drug concentration at tumor sites, endowing CMGNPs with excellent therapeutic efficacy. Our effort provides a versatile approach for facilitating drug delivery in diverse therapeutic systems.
    Keywords:  biomimetic drug delivery; drug resistant; homologous targeting; phospholipid bilayer; synergetic therapy
    DOI:  https://doi.org/10.1021/acsami.2c08587
  20. Technol Cancer Res Treat. 2022 Jan-Dec;21:21 15330338221095670
    Highly Active Nano-Reactor for Responding Tumor Microenvironment and Antitumor Therapy.
    Shuangxia Zhang, Yan Liu, Bo Liu.
      The tumor microenvironment is complex and changeable, so the design of a nano-delivery system for the tumor microenvironment has attracted wide attention. Based on this, we designed an intelligent nano-reactor for the characteristics of acidic pH and hypoxia in the tumor microenvironment. Firstly, the silver nano-balls were synthesized by the biological template method, which exhibited a good photothermal conversion efficiency and can realize the photothermal treatment of tumor sites. Subsequently, the hypoxic prodrug tirapazamine (TPZ) and polydopamine (PDA) for chemotherapy were self-assembled. After PDA arrived at the tumor site (pH 5.5) from the normal physiological environment (pH 7.4), the hypoxic prodrug TPZ was released in pH response by PDA. Subsequently, TPZ selectively induced obvious cell damage under tumor hypoxia stimulation but had no toxic effect on normal cells under normal oxygen. In addition, the nano-converter was loaded with iRGD on the surface, which enhanced the targeted delivery of the nano-reactor to achieve a highly effective antitumor effect. The nano-reactor was capable of combining photothermal/chemotherapy therapy. Importantly, it can selectively kill tumor cells without damaging normal cells based on the characteristics of the tumor microenvironment, with high bio-safety and clinical transformation potential.
    Keywords:  photothermal therapy; tirapazamine; tumor microenvironment
    DOI:  https://doi.org/10.1177/15330338221095670
  21. J Control Release. 2022 Jun 09. pii: S0168-3659(22)00334-0. [Epub ahead of print]
    Taxanes prodrug-based nanomedicines for cancer therapy.
    Linlin Sun, Pan Zhao, Menghan Chen, Jiayi Leng, Yixin Luan, Baoxiang Du, Jia Yang, Yong Yang, Rong Rong.
      Malignant tumor remains a huge threat to human health and chemotherapy still occupies an important place in clinical tumor treatment. As a kind of potent antimitotic agent, taxanes act as the first-line broad-spectrum cancer drug in clinical use. However, disadvantages such as prominent hydrophobicity, severe off-target toxicity or multidrug resistance lead to unsatisfactory therapeutic effects, which restricts its wider usage. The efficient delivery of taxanes is still quite a challenge despite the rapid developments in biomaterials and nanotechnology. Great progress has been made in prodrug-based nanomedicines (PNS) for cancer therapy due to their outstanding advantages such as high drug loading efficiency, low carrier induced immunogenicity, tumor stimuli-responsive drug release, combinational therapy and so on. Based on the numerous developments in this filed, this review summarized latest updates of taxanes prodrugs-based nanomedicines (TPNS), focusing on polymer-drug conjugate-based nanoformulations, small molecular prodrug-based self-assembled nanoparticles and prodrug-encapsulated nanosystems. In addition, the new trends of tumor stimuli-responsive TPNS were also discussed. Moreover, the future challenges of TPNS for clinical translation were highlighted. We here expect this review will inspire researchers to explore more practical taxanes prodrug-based nano-delivery systems for clinical use.
    Keywords:  Biomedical nanotechnology; Cancer therapy; Prodrug; Taxanes
    DOI:  https://doi.org/10.1016/j.jconrel.2022.06.004
  22. Photodiagnosis Photodyn Ther. 2022 Jun 11. pii: S1572-1000(22)00247-2. [Epub ahead of print] 102961
    Inhibitory Effects and Gene Expression Analysis of Chemotherapeutic Photodynamic Therapy by using a Liposomally Formulated Indocyanine Green Derivative.
    Yoshiharu Okamoto, Mariko Ishizuka, Fusao Sumiyama, Hisashi Kosaka, Akiko Suganami, Yutaka Tamura, Mitsugu Sekimoto, Masaki Kaibori.
      BACKGROUND: Photodynamic therapy (PDT) utilizes the enhanced permeability retention effect of photosensitizers and is less invasive and more selective than traditional chemotherapy. We constructed a chemotherapeutic PDT (chemo-PDT) nanoscale drug delivery system using a liposomally formulated indocyanine green derivative (ICG-Lipo) that encapsulated carboplatin and docetaxel (ICG-Lipo-C&D).METHODS: The antitumor effect of chemo-PDT mediated by ICG-Lipo-C&D was evaluated in a murine colon 26 CDF1 mouse model. Gene expression in tumor tissues was analyzed by RNA sequencing.
    RESULTS: Chemo-PDT using ICG-Lipo-C&D demonstrated an even stronger PDT-enhancing effect than did ICG-Lipo due to the synergistic effect of carboplatin and docetaxel. In addition, gene expression analysis showed that PDT with ICG-Lipo-C&D increased the expression of immune-related genes and decreased the expression of cytoskeleton-related genes.
    CONCLUSIONS: Chemo-PDT using ICG-Lipo as a photosensitizer as well as a drug delivery system with an enhanced permeability retention effect may be a promising cancer therapy.
    Keywords:  Indocyanine green (ICG); RNA sequencing; drug delivery system (DDS); near-infrared (NIR); photodynamic therapy (PDT)
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.102961
  23. Biomater Res. 2022 Jun 11. 26(1): 23
    Solubilized chlorin e6-layered double hydroxide complex for anticancer photodynamic therapy.
    Young-Um Jo, HyunJune Sim, Chung-Sung Lee, Kyoung Sub Kim, Kun Na.
      BACKGROUND: Layered double hydroxides (LDHs) are one type of 2-dimensional material with unique structure and strongly positive surface charge. Particularly, LDHs can be exfoliated by mono-layered double hydroxides (MLHs) as a single layer, showing an increased surface area. Therefore, there is a large focus on LDHs for drug delivery applications. Furthermore, most photosensitizers are hydrophobic that they cannot be soluble in aqueous solvents. Herein, we designed a simple way to solubilize hydrophobic photosensitizers by MLH with electrostatic interactions for anticancer photodynamic therapy (PDT), which has tremendous therapeutic advantages. The photosensitizer solubilized via loading on the MLH exhibited fluorescence and singlet oxygen-generation activities in aqueous solvent without chemical modification, resulting in photo-mediated anticancer treatment.METHODS: Negatively charged hydrophobic photosensitizers, chlorin e6 (Ce6) were solubilized by loading on the MLHs through the electrostatic interaction between positively charged MLHs. MLH/Ce6 complexes evaluated for physico-chemical characterization, pH-sensitive release property, in vitro photocytotoxicity, and in vivo tumor ablation.
    RESULTS: The photosensitizer solubilized via MLH exhibited fluorescence intensity and singlet-oxygen generation activities in aqueous solvent without chemical modification, resulting photocytotoxicity in cancer cells. The encapsulation efficiency of Ce6 increased to 21.2% through MLH compared to 0.6% when using LDH. In tumor-bearing mice, PDT with solubilized MLH/Ce6 indicated a tumor-suppressing effect approximately 3.4-fold greater than that obtained when Ce6 was injected alone.
    CONCLUSIONS: This study provided the solubilized Ce6 by the MLH in a simple way without chemical modification. We demonstrated that MLH/Ce6 complexes would have a great potential for anticancer PDT.
    Keywords:  Anticancer photodynamic therapy; Layered double hydroxide; Mono-layered double hydroxide; Photosensitizer; Solubilization
    DOI:  https://doi.org/10.1186/s40824-022-00272-8
  24. Adv Healthc Mater. 2022 Jun 16. e2102724
    Metabolic Symbiosis-Blocking Nano-combination for Tumor Vascular Normalization Treatment.
    Hui Xiong, Xiaoyan Liu, Zuohan Xie, Linyuan Zhu, Haipeng Lu, Cheng Wang, Jing Yao.
      The clinical anti-vascular endothelial growth factor (anti-VEGF) drugs and metronomic chemotherapy (MET) induced tumor vascular normalization treatment (TVNT) was easily antagonized by tumor microenvironment metabolic cross-talk between tumor cells and endothelial cells. To overcome this dilemma, nanodrug with the ability of endothelial cells targeted glycolysis inhibition and nanodrug with the ability of tumor cell glycolysis inhibition, anti-VEGF and MET were combined to prepare Nano-combination for TVNT. Besides blocking the metabolic cross-talk between tumor cells and endothelial cells, Nano-combination also induced extensive regulations-widely obstructing the pathways related to angiogenesis, tumor cell proliferation and immunosuppression and breaking the negative sugar-lipid-protein metabolism balance in tumor microenvironment. Thus, stronger and more lasting normalized tumor vascular network and remarkable antitumor efficacy were obtained after treatment, constructing a positive feedback loop between TVNT and anti-tumor therapy. Above all, our study provided a new insight for solving the bottleneck of clinical TVNT. This article is protected by copyright. All rights reserved.
    Keywords:  Targeted drug delivery; Tumor vascular normalization therapy; glycolysis inhibition; tumor microenvironment remodeling
    DOI:  https://doi.org/10.1002/adhm.202102724
  25. Heliyon. 2022 Jun;8(6): e09577
    Nanoscale bioconjugates: A review of the structural attributes of drug-loaded nanocarrier conjugates for selective cancer therapy.
    Wenjie Zhang, Reza Taheri-Ledari, Fatemeh Ganjali, Fereshte Hassanzadeh Afruzi, Zoleikha Hajizadeh, Mahdi Saeidirad, Fateme Sadat Qazi, Amir Kashtiaray, Samin Sadat Sehat, Michael R Hamblin, Ali Maleki.
      Nanobioconjugates are nanoscale drug delivery vehicles that have been conjugated to or decorated with biologically active targeting ligands. These targeting ligands can be antibodies, peptides, aptamers, or small molecules such as vitamins or hormones. Most research studies in this field have been devoted to targeting cancer. Moreover, the nanostructures can be designed with an additional level of targeting by being designed to be stimulus-responsive or "smart" by a judicious choice of materials to be incorporated into the hybrid nanostructures. This stimulus could be an acidic pH, raised temperature, enzyme, ultrasound, redox potential, an externally applied magnetic field, or laser irradiation. In this case, the smart capability can increase the accumulation at the tumor site or the on-demand drug release, while the ligand ensures selective binding to the tumor cells. The present review highlights some interesting studies classified according to the nanostructure material. These materials include natural substances (polysaccharides), multi-walled carbon nanotubes (and halloysite nanotubes), metal-organic frameworks and covalent-organic frameworks, metal nanoparticles (gold and silver), and polymeric micelles.
    Keywords:  Biotechnology; High-tech nanostructures; Ligands for molecular recognition; Nanotechnology; Synergistic therapeutic effects; Targeted cancer therapy
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e09577
  26. Curr Med Chem. 2022 Jun 13.
    Bioadhesive Nanoparticles as Potent Drug Delivery Carriers.
    Seda Rençber, Ece Özcan Bülbül, Zeynep Ay Senyigit, Neslihan Üstündağ Okur, Panoraia I Siafaka.
      BACKGROUND: Last years, nanotechnology-based systems have gained the interest of numerous scientists, especially for biomedical applications. Then, as called, nanocarriers present tunable abilities, can be easily functionalized to target specific epithelial cells, tissues, and organs while various materials can be chosen and generate nanosized particles. At the present, nanoparticles that possess bioadhesion have been studied as potent drug carriers since they can easier penetrate and target organs.OBJECTIVE: Aim of this study was to explore the various applications of the bioadhesive nanoparticles found in the literature.
    METHOD: Authors have studied the literature finding that bioadhesive nanoparticles can be administered via routes such as oral, topical, ocular, dermal, vaginal, etc according to the clinician's opinion and treatment choice. Therefore, the knowledge of general characteristics of bioadhesive nanoparticles, the bioadhesion theory, and other properties of nanoparticles should be known for the development of innovative bioadhesive drug nanocarriers.
    RESULTS: In this review article, the authors state the current knowledge of bioadhesion theories. In addition, the present categories of nanoparticles and their basic characteristics are also discussed. Finally, the biomedical applications of bioadhesive nanocarriers and the several administration routes are extensively reviewed.
    CONCLUSION: The review article aims to cover the most current bioadhesive nanoparticles for drug delivery to assist any scientist who desires to study or develop innovative bioadhesive formulations.
    Keywords:  Administration routes; Applications.; Bioadhesive formulations; Bioadhesive molecules; Bioadhesive nanoparticles; Biodhesion
    DOI:  https://doi.org/10.2174/0929867329666220613111635
  27. Acta Biomater. 2022 Jun 10. pii: S1742-7061(22)00350-6. [Epub ahead of print]
    Bimodal Treatment of Hepatocellular Carcinoma by Targeted Minimally Interventional Photodynamic/Chemotherapy Using Glyco-Covalent-Organic Frameworks-Guided Porphyrin/Sorafenib.
    Jun Hu, Jing Hu, Wenrui Wu, Yufei Qin, Junjie Fu, Chao Liu, Peter H Seeberger, Jian Yin.
      Very limited treatment options are available to fight hepatocellular carcinoma (HCC), a serious global health concern with high morbidity and mortality. The integration of multiple therapies into one nanoplatform to exert synergistic therapeutic effects offers advantages over monotherapies. Here, we describe the construction of the nanoplatform Sor@GR-COF-366 for synergistic chemotherapy and photodynamic therapy (PDT) for HCC using a porphyrin-based covalent organic framework (COF-366) coated with N-acetyl-galactosamine (GalNAc) and rhodamine B (RhB), and loaded with the first-line agent, Sorafenib (Sor). The nanoplatform is targeted towards ASGPR-overexpressed HCC cells and liver tissues by GalNAc and observed by real-time imaging of RhB in vitro and in vivo. The nanoplatform Sor@GR-COF-366 exerts an enhanced synergistic tumor suppression effect in a subcutaneous HCC mouse model with a tumor inhibition rate (TGI) of 97% while significantly prolonging survival at very low toxicity. The potent synergistic therapeutic outcome is confirmed in an orthotopic mouse model of HCC with the TGI of 98% with a minimally invasive interventional PDT (IPDT). Sor@GR-COF-366 is a promising candidate to be combined with chemo-IPDT for the treatment of HCC. STATEMENT OF SIGNIFICANCE: This work describes the construction of covalent-organic frameworks (COFs) modified with glyco-moieties to serve as hepato-targeted multitherapy delivery systems. They combine minimally invasive interventional photodynamic therapy (IPDT) triggered synergism with chemotherapy treatment for hepatocellular carcinoma (HCC). With the aid of minimally invasive intervention, PDT can elicit potent anti-cancer activity for deep solid tumors. This platform shows strong therapeutic outcomes in both subcutaneous and orthotopic mouse models, which can significantly prolong survival. This work showed an effective combination of a biomedical nano-formulation with the clinical operational means in cancer treatment, which is greatly promising in clinical translation.
    Keywords:  Bimodal therapy; Chemotherapy; Covalent-organic frameworks; Hepatocellular carcinoma; Interventional photodynamic therapy
    DOI:  https://doi.org/10.1016/j.actbio.2022.06.012
  28. Acta Biomater. 2022 Jun 12. pii: S1742-7061(22)00351-8. [Epub ahead of print]
    Treatment of triple negative breast cancer by near infrared light triggered mild temperature photothermal therapy combined with oxygen-independent cytotoxic free radicals.
    Ruihao Li, Xiaochun Hu, Fangjian Shang, Wenjing Wu, Haijun Zhang, Yixuan Wang, Jiawei Pan, Shuo Shi, Chunyan Dong.
      Triple negative breast cancer (TNBC) is highly malignant and prone to recurrence and metastasis. Patients with TNBC usually have poor prognosis. Hence, it is urgent to develop new comprehensive treatments for TNBC. The combination of heat shock protein (HSP) inhibitor and the photothermal agent can reduce the temperature required to kill tumor cells, thus achieving mild-temperature photothermal therapy (PTT). Compared with traditional PTT, mild-temperature PTT not only decreases tumor thermoresistance introduced by the overexpression of HSP, but also reduces the damage to normal tissues. Meanwhile, Azo initiator 2,2-azobis[2-(2-imidazolin-2-yl) propane]-dihydroch-loride (AIPH) can be thermally decomposed to generate oxygen-independent free radicals. Herein, a new therapeutic multifunctional nanoplatform (M-17AAG-AIPH) by loading heat shock protein 90 (HSP90) inhibitor (17AAG) and AIPH incorporated into mesoporous polydopamine (MPDA) was successfully constructed for mild-temperature PTT combined with oxygen-independent cytotoxic free radicals against TNBC. Under 808 nm laser irradiation, the mild-temperature PTT arising from the combined effects of 17AAG and MPDA induced a rapid release and decomposition of AIPH, promoting the apoptosis of cancer cells in hypoxic microenvironments. Both in vitro and in vivo results showed that the designed nanoplatform can significantly inhibit tumor growth and provided an efficient new therapeutic strategy for TNBC. STATEMENT OF SIGNIFICANCE: There is still an urgent need for new strategies for the treatment of triple negative breast cancer (TNBC). In this work, we successfully constructed a new therapeutic multifunctional nanoplatform (M-17AAG-AIPH) by co-carrying heat shock protein 90 (HSP90) inhibitor (17AAG) and AIPH on mesoporous polydopamine (MPDA). MPDA owned good biocompatibility and outstanding photothermal-conversion ability. The loading of 17AAG can reduce the heat resistance of tumor cells via specifically inhibiting the activity of HSP90, so as to achieve mild-temperature PTT. Meanwhile, 17AAG and MPDA mediated mild-temperature PTT promoted the decomposition of AIPH into oxygen-independent cytotoxic free radicals. Both in vitro and in vivo results showed that M-17AAG-AIPH can significantly inhibit tumor growth and provided an efficient new therapeutic strategy for TNBC.
    Keywords:  AIPH; Free radicals; HSP90 inhibitor; Mild-temperature PTT
    DOI:  https://doi.org/10.1016/j.actbio.2022.06.011
  29. ACS Appl Mater Interfaces. 2022 Jun 13.
    A Multifunctional Vanadium-Iron-Oxide Nanoparticle Eradicates Hepatocellular Carcinoma via Targeting Tumor and Endothelial Cells.
    Xiaoming Yang, Jianmin Xiao, Lingyu Jiang, Lang Ran, Yangyang Fan, Minghui Zhang, Yuxue Xu, Cuifang Yao, Baijiao An, Yang Yang, Chunhua Yang, Geng Tian, Guilong Zhang, Yin Zhang.
      Nanoparticles are widely used in biological research and cancer therapy. In hepatocellular carcinoma, several nanoplatforms have been synthesized and studied to improve the drug efficacy; however, these nanoplatforms are still insufficient to eradicate tumors. Herein, we have synthesized a novel vanadium (V)-iron-oxide (ION) nanoparticle (VIO) that combines chemodynamic, photothermal, and diagnostic capacities to enhance the tumor suppression effect in one agent with multiple functions. In the in vitro models, hepatocellular carcinoma cells are significantly inhibited by VIO-based nanoagents. The mechanistic study validates that VIO increases reactive oxygen species (ROS), which led to apoptosis and ferroptosis resulting in cell death. To our surprise, VIO targets not only tumor cells but also endothelial cells. In addition to inducing cell death, VIO also blocks tube formation and cell migration in human umbilical vein endothelial cell (HUVEC) and C166 models, indicating an antiangiogenic potential. In mouse tumor models, VIO retards tumor growth and induces apoptosis in tumor tissues. Furthermore, a significant blood vessel regression is seen in VIO-treated groups accompanied with larger necrotic areas. More interestingly, the activation of photothermal therapy completely eradicates tumor tissues. Taken together, this VIO nanoplatform could be a powerful anticancer candidate for nanodrug development.
    Keywords:  MRI; V doping iron oxide nanoparticle; antiangiogenesis; cancer therapy; ferroptosis
    DOI:  https://doi.org/10.1021/acsami.2c03474
  30. J Food Biochem. 2022 Jun 13. e14264
    Health benefits of polyphenols: A concise review.
    Ananya Rana, Mrinal Samtiya, Tejpal Dhewa, Vijendra Mishra, Rotimi E Aluko.
      Plants produce polyphenols, which are considered highly essential functional foods in our diet. They are classified into several groups according to their diverse chemical structures. Flavanoids, lignans, stilbenes, and phenolic acids are the four main families of polyphenols. Several in vivo and in vitro research have been conducted so far to evaluate their health consequences. Polyphenols serve a vital function in the protection of the organism from external stimuli and in eliminating reactive oxygen species (ROS), which are instigators of several illnesses. Polyphenols are present in tea, chocolate, fruits, and vegetables with the potential to positively influence human health. For instance, cocoa flavan-3-ols have been associated with a decreased risk of myocardial infarction, stroke, and diabetes. Polyphenols in the diet also help to improve lipid profiles, blood pressure, insulin resistance, and systemic inflammation. Quercetin, a flavonoid, and resveratrol, a stilbene, have been linked to improved cardiovascular health. Dietary polyphenols potential to elicit therapeutic effects might be attributed, at least in part, to a bidirectional association with the gut microbiome. This is because polyphenols are known to affect the gut microbiome composition in ways that lead to better human health. Specifically, the gut microbiome converts polyphenols into bioactive compounds that have therapeutic effects. In this review, the antioxidant, cytotoxicity, anti-inflammatory, antihypertensive, and anti-diabetic actions of polyphenols are described based on findings from in vivo and in vitro experimental trials. PRACTICAL APPLICATIONS: The non-communicable diseases (NCDs) burden has been increasing worldwide due to the sedentary lifestyle and several other factors such as smoking, junk food, etc. Scientific literature evidence supports the use of plant-based food polyphenols as therapeutic agents that could help to alleviate NCD's burden. Thus, consuming polyphenolic compounds from natural sources could be an effective solution to mitigate NCDs concerns. It is also discussed how natural antioxidants from medicinal plants might help prevent or repair damage caused by free radicals, such as oxidative stress.
    Keywords:  antioxidant; functional foods; gut microbiome; polyphenols
    DOI:  https://doi.org/10.1111/jfbc.14264
  31. Beilstein J Nanotechnol. 2022 ;13 491-502
    Ethosomal (-)-epigallocatechin-3-gallate as a novel approach to enhance antioxidant, anti-collagenase and anti-elastase effects.
    Çiğdem Yücel, Gökçe Şeker Karatoprak, Sena Yalçıntaş, Tuğba Eren Böncü.
      Controlled release systems containing natural compounds have been successfully applied in cosmetics as antiaging products to enhance the penetration of active compounds through the skin. In this study, we aimed to develop novel ethosomal formulations containing a potent antioxidant, epigallocatechin-3-gallate (EGCG), and to evaluate their potential for use in cosmetics by determining their antioxidant and antiaging effects. Ethosomes (ETHs) were prepared via mechanical dispersion and characterized in vitro in terms of particle size (PS), zeta potential (ZP), polydispersity index (PDI), encapsulation efficiency percentage (EE%), and in vitro release. The best ETH formulation was used to prepare the ethosome-based gel (ETHG) by using Carbopol 980 as a gelling agent at a ratio of 1:1 (v/v). The gel formulation was evaluated regarding organoleptic properties, pH values, and viscosity. Stability studies were conducted for three months and changes in characterization parameters and residual EGCG content of ETHs were examined. Besides, for ETHG, organoleptic properties, pH values (every two weeks), and viscosity (first and twelfth week) were determined for three months. The 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to test the cytotoxicity of the formulations and different EGCG solutions on the L929 cell line. The cell permeation properties and inhibitory effects of ETHs and ETHGs on collagenase and elastase enzymes were investigated compared to those of the solution form. Within the scope of antioxidant activity studies, 2,2-diphenyl-1-picrylhydrazyl (DPPH•) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+•) radical scavenging and β-carotene/linoleic acid co-oxidation inhibitory effects were carried out. The optimized EGCG-loaded ETHs (F3) were within the nanoscale range (238 ± 1.10 nm). The highest encapsulation efficiency and in vitro release values were 51.7 ± 1.15% and 50.8 ± 1.70%, respectively. The ETHG was successfully formulated with F3-coded ETHs and the cytotoxicity test revealed that the formulations and the EGCG solution at different concentrations were nontoxic. In terms of cell permeability, enzyme inhibition, and antioxidant activity, the ethosomal formulations yielded better results compared to the EGCG solution. It was observed that the formulations had a long-term effect due to the stability of EGCG. The findings of the study underline the potential of antioxidant and antiaging effects of the developed ethosomal formulations for use in the cosmetic field.
    Keywords:  antiaging effect; antioxidant effect; epigallocatechin gallate; ethosomal gel; ethosome
    DOI:  https://doi.org/10.3762/bjnano.13.41
  32. Biomater Sci. 2022 Jun 15.
    The improved killing of both androgen-dependent and independent prostate cancer cells by etoposide loaded SPIONs coupled with NIR irradiation.
    K Onbasli, M Erkısa, G Demirci, A Muti, E Ulukaya, A Sennaroglu, H Yagci Acar.
      Etoposide (Eto) is a toxic drug that shows promise in treating prostate cancer (PCa) but confers significant side effects, and has poor solubility and bioavailability. Nanoparticles are quite successful in overcoming such problems. Multifunctional nanoparticles that provide an opportunity to perform combination therapy have attracted great interest in recent years. Superparamagnetic iron oxide nanoparticles (SPIONs) are popular in various biomedical applications, including magnetic resonance imaging, drug delivery, magnetic hyperthermia and recently in photothermal therapy, combining imaging with therapy. Here, for the enhanced killing of PCa cells that are either androgen-dependent or not, the combination of SPION based Eto delivery and mild hyperthermia triggered by laser irradiation is proposed for the first time in the literature. For the encapsulation of Eto, highly stable, small, polyacrylic acid coated SPIONs were conjugated with bovine serum albumin (BSA) (Eto-BSA@PAA@SPION). Eto-BSA@PAA@SPION with 9% drug content produced better chemotherapeutic outcomes than free Eto on both androgen-dependent/castration sensitive LNCaP and androgen-independent/castration-resistant PC3 and DU145 PCa cells by enhancing drug internalization. Single and short irradiation of Eto-BSA@PAA@SPION treated cells at 808 nm improved the drug release and sensitized cells for Eto, hence, increasing the toxicity dramatically in all studied PCa cell lines. Caspase-mediated apoptosis, DNA damage, and ROS generation were detected in the treated cells, increasing with the Eto dose and laser treatment. The IC50 for Eto is reduced to 0.08 μg mL-1, 0.13 μg mL-1 and 2.8 μg mL-1 with laser/Eto-BSA@PAA@SPION for LNCaP, DU145 and PC3 cells, respectively. These are the lowest IC50 values seen in the literature for Eto on these cell lines so far, suggesting that the demonstrated nanoparticles and treatment approaches have great potential to treat various PCa cells at low doses of the drug under mild laser treatment conditions.
    DOI:  https://doi.org/10.1039/d2bm00107a
  33. ACS Appl Bio Mater. 2022 Jun 17.
    Tumor Microenvironments-Adaptive Apoptotic Effects of Cytidine 5'-monophosphate-Capped Gold Nanoclusters.
    Chun-Xia Zhang, Hong-Wei Li, Renwen Zhang, Zhongyuan Ren, Yuqing Wu.
      In the present work, cytidine 5'-monophosphate capped gold nanoclusters (AuNCs@CMP) are reported as a catalyst for redox reactions, which show both oxidase- and excellent peroxidase-like activity. When employing 3,3',5,5'-tetramethylbenzidine (TMB) as a substrate in the presence of hydrogen peroxide (H2O2), the maximum velocity (Vmax) was 175 × 10-8 M s-1 in vitro. Besides, the AuNCs@CMP exhibited high catalytic activity for reactive oxygen species (ROS) generation with H2O2. Particularly, they also displayed excellent catalytic activity for ROS generation in tumor cells, being activated and promoted by the tumor microenvironment (TME). Consequently, the AuNCs@CMP show an excellent antitumor effect on HeLa and SW480 cells as assayed by flow cytometry. The antitumor mechanism of AuNCs@CMP was attributed to the high ROS generation based on the specific environments of the TME. Therefore, the present study provides TME-adaptive AuNCs@CMP with excellent mimetic peroxidase activity, producing significant ROS to kill the tumor cells in TME.
    Keywords:  antitumor; cytidine 5′-monophosphate; gold nanoclusters; nanoenzyme; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1021/acsabm.2c00380
  34. Ther Adv Med Oncol. 2022 ;14 17588359221097940
    Characterizing the KRAS G12C mutation in metastatic colorectal cancer: a population-based cohort and assessment of expression differences in The Cancer Genome Atlas.
    Meredith Li, Faeze Keshavarz-Rahaghi, Gale Ladua, Lucas Swanson, Caroline Speers, Daniel J Renouf, Howard J Lim, Janine M Davies, Sharlene Gill, Heather C Stuart, Stephen Yip, Jonathan M Loree.
      Introduction: In metastatic colorectal cancer (mCRC), RAS mutations impart inferior survival and resistance to anti-epidermal growth factor receptor (EGFR) antibodies. KRAS G12C inhibitors have been developed and we evaluated how KRAS G12C differs from other RAS mutations.Patients and Methods: This retrospective review evaluated patients in British Columbia, Canada with mCRC and RAS testing performed between 1 January 2016 and 31 December 2018. Sequencing information from The Cancer Genome Analysis (TCGA) was also obtained and analysed.
    Results: Age at diagnosis, sex, anatomic location and stage at diagnosis did not differ by RAS mutation type. Progression free survival on first chemotherapy for patients with metastatic KRAS G12C tumours was 11 months. Median overall survival did not differ by RAS mutation type but was worse for both KRAS G12C (27 months) and non-G12C alterations (29 months) than wildtype (43 months) (p = 0.01). Within the TCGA, there was no differential gene expression between KRAS G12C and other RAS mutations. However, eight genes with copy number differences between the G12C and non-G12C RAS mutant groups were identified after adjusting for multiple comparisons (FITM2, PDRG1, POFUT1, ERGIC3, EDEM2, PIGU, MANBAL and PXMP4). We also noted that other RAS mutant mCRCs had a higher tumour mutation burden than those with KRAS G12C mutations (median 3.05 vs 2.06 muts/Mb, p = 4.2e-3) and that KRAS G12C/other RAS had differing consensus molecular subtype distribution from wildtype colorectal cancer (CRC) (p < 0.0001) but not each other (p = 0.14).
    Conclusion: KRAS G12C tumours have similar clinical presentation to other RAS mutant tumours, however, are associated with differential copy number alterations.
    Keywords:  RAS; cancer; colon; metastatic; rectal; signalling
    DOI:  https://doi.org/10.1177/17588359221097940
  35. Front Pharmacol. 2022 ;13 888740
    Recent Advances in Chitosan and its Derivatives in Cancer Treatment.
    Jingxian Ding, Yonghong Guo.
      Cancer has become a main public health issue globally. The conventional treatment measures for cancer include surgery, radiotherapy and chemotherapy. Among the various available treatment measures, chemotherapy is still one of the most important treatments for most cancer patients. However, chemotherapy for most cancers still faces many problems associated with a lot of adverse effects, which limit its therapeutic potency, low survival quality and discount cancer prognosis. In order to decrease these side effects and improve treatment effectiveness and patient's compliance, more targeted treatments are needed. Sustainable and controlled deliveries of drugs with controllable toxicities are expected to address these hurdles. Chitosan is the second most abundant natural polysaccharide, which has excellent biocompatibility and notable antitumor activity. Its biodegradability, biocompatibility, biodistribution, nontoxicity and immunogenicity free have made chitosan become a widely used polymer in the pharmacology, especially in oncotherapy. Here, we make a brief review of the main achievements in chitosan and its derivatives in pharmacology with a special focus on their agents delivery applications, immunomodulation, signal pathway modulation and antitumor activity to highlight their role in cancer treatment. Despite a large number of successful studies, the commercialization of chitosan copolymers is still a big challenge. The further development of polymerization technology may satisfy the unmet medical needs.
    Keywords:  anticancer drugs; cancer treatment; chitosan; drug delivery system; polysaccharides
    DOI:  https://doi.org/10.3389/fphar.2022.888740
  36. Drug Deliv. 2022 Dec;29(1): 1863-1877
    Potentiality of raloxifene loaded melittin functionalized lipidic nanovesicles against pancreatic cancer cells.
    Usama A Fahmy, Shaimaa M Badr-Eldin, Hibah M Aldawsari, Nabil A Alhakamy, Osama A A Ahmed, Mohamed F Radwan, Basma G Eid, Shaban R M Sayed, Gamal A El Sherbiny, Walaa Abualsunun.
      Pancreatic cancer (PC) frequency and incidence have grown rapidly in recent years. One of the most serious problems with PC is the existence of asymptotic manifestations, which frequently delays early detection, and until the diagnosis is established, tumor cells progress to the metastatic stage. Another significant concern with PC is the scarcity of well-defined pharmacotherapeutic drugs. The aim of this study was to develop an efficient nanocarrier system to augment the efficacy of raloxifene (RLX) against PC cells. As a result, the current investigation was carried out in order to give an effective treatment method, in which an optimum RLX loaded phospholipid-based vesicles with melittin (PL-MEL) was chosen using experimental design software, with particle size, zeta potential and entrapment efficiency % as dependent variables. Furthermore, anticancer activity against PANC1 cells was assessed. The optimized nanovesicle parameters were 172.5 nm for the measured size, zeta potential of -0.69 mV, and entrapment efficiency of 76.91% that were in good agreement with the expected ones. RLX-raw, plain formula, and optimized RLX-PL-MEL showed IC50 concentrations of 26.07 ± 0.98, 9.166 ± 0.34, and 1.24 ± 0.05 µg/mL, respectively. Furthermore, cell cycle analysis revealed that the nanovesicle was most effective in the G2-M phase, whereas Bax, and Bcl-2 estimates revealed that optimized RLX formula had the highest apoptotic activity among treatments investigated. However, as compared to RLX alone or plain formula alone, the optimized formula demonstrated higher expression of TNFα and Bax while a significant reduction of Bcl-2 and NF-κB expression was observed. mitochondrial membrane potential (MMP) analysis confirmed the apoptosis as well as the anticancer effect of the optimized formula. Thus, the present study results showed an improvement in the anti-PC effects of the RLX with phospholipid conjugated melittin, making it a novel treatment approach against PC.
    Keywords:  Liposomes; PANC1; apoptosis; membrane potential; ultrasonication
    DOI:  https://doi.org/10.1080/10717544.2022.2072544
  37. Nutr Neurosci. 2022 Jun 11. 1-16
    Application of curcumin nanoformulations in Alzheimer's disease: prevention, diagnosis and treatment.
    Hongqian Lv, Yan Wang, Xiaotong Yang, Guixia Ling, Peng Zhang.
      Objectives: Alzheimer's disease (AD) is a serious neurodegenerative disease. Although many therapeutic strategies have been studied, their clinical applications are immature. Moreover, these methods can only alleviate symptoms rather than cure it, posing a challenge to brain health in older adults worldwide. Curcumin (CUR) is a very promising natural compound for nerve protection and treatment. It can prevent and treat AD, and on the other hand, its fluorescence properties can be used in the diagnosis of AD. However, CUR is characterized by very low water solubility, fluid instability, rapid metabolism, low bioavailability and difficulty in penetrating the biological barriers, which limit its application. Nanocarriers are a potential material to improve the biocompatibility of CUR and its ability to cross biological barriers. Therefore, delivering CUR by nanocarriers is an effective method to achieve better efficacy. Methods: In this review, the preventive, therapeutic and diagnostic effects of CUR nanoformulations on AD, as well as various patents, clinical trials and experimental research progress in this field are discussed. The aim is to provide detailed reference and practical suggestions for future research. Results: CUR has a variety of pharmacological activities in the prevention and treatment of AD, and its nanoformulation can effectively improve solubility, bioavailability and the ability to penetrate the blood-brain barrier. Significant benefits have been observed in the current study. Discussion: CUR formulations have a good prospect in the prevention, diagnosis and treatment of AD, but the safety and principle of its administration need more detailed study in the future.
    Keywords:  Natural ingredient; drug delivery; nanocarriers; neurodegenerative disease; senile dementia
    DOI:  https://doi.org/10.1080/1028415X.2022.2084550
  38. Apoptosis. 2022 Jun 18.
    Meta analysis of bioactive compounds, miRNA, siRNA and cell death regulators as sensitizers to doxorubicin induced chemoresistance.
    Sruthi Sritharan, Sampurna Guha, Snoopy Hazarika, Nageswaran Sivalingam.
      Cancer has presented to be the most challenging disease, contributing to one in six mortalities worldwide. The current treatment regimen involves multiple rounds of chemotherapy administration, alone or in combination. The treatment has adverse effects including cardiomyopathy, hepatotoxicity, and nephrotoxicity. In addition, the development of resistance to chemo has been attributed to cancer relapse and low patient overall survivability. Multiple drug resistance development may be through numerous factors such as up-regulation of drug transporters, drug inactivation, alteration of drug targets and drug degradation. Doxorubicin is a widely used first line chemotherapeutic drug for a myriad of cancers. It has multiple intracellular targets, DNA intercalation, adduct formation, topoisomerase inhibition, iron chelation, reactive oxygen species generation and promotes immune mediated clearance of the tumor. Agents that can sensitize the resistant cancer cells to the chemotherapeutic drug are currently the focus to improve the clinical efficiency of cancer therapy. This review summarizes the recent 10-year research on the use of natural phytochemicals, inhibitors of apoptosis and autophagy, miRNAs, siRNAs and nanoformulations being investigated for doxorubicin chemosensitization.
    Keywords:  Cancer; Chemoresistance; Chemosensitization; Doxorubicin; miRNA; siRNA
    DOI:  https://doi.org/10.1007/s10495-022-01742-z
  39. Drug Deliv Transl Res. 2022 Jun 13.
    Breaking the niche: multidimensional nanotherapeutics for tumor microenvironment modulation.
    K Laxmi Swetha, Kavya Sree Maravajjala, Shyh-Dar Li, Manu Smriti Singh, Aniruddha Roy.
      Most of the current antitumor therapeutics were developed targeting the cancer cells only. Unfortunately, in the majority of tumors, this single-dimensional therapy is found to be ineffective. Advanced research has shown that cancer is a multicellular disorder. The tumor microenvironment (TME), which is made by a complex network of the bulk tumor cells and other supporting cells, plays a crucial role in tumor progression. Understanding the importance of the TME in tumor growth, different treatment modalities have been developed targeting these supporting cells. Recent clinical results suggest that simultaneously targeting multiple components of the tumor ecosystem with drug combinations can be highly effective. This type of "multidimensional" therapy has a high potential for cancer treatment. However, tumor-specific delivery of such multi-drug combinations remains a challenge. Nanomedicine could be utilized for the tumor-targeted delivery of such multidimensional therapeutics. In this review, we first give a brief overview of the major components of TME. We then highlight the latest developments in nanoparticle-based combination therapies, where one drug targets cancer cells and other drug targets tumor-supporting components in the TME for a synergistic effect. We include the latest preclinical and clinical studies and discuss innovative nanoparticle-mediated targeting strategies.
    Keywords:  Drug resistance; Multidimensional therapy; Nanoparticles; Tumor microenvironment; Tumor targeting
    DOI:  https://doi.org/10.1007/s13346-022-01194-7
  40. Curr Drug Metab. 2022 Jun 09.
    Approaches to Address PK-PD Challenges of Conventional Liposome Formulation with Special Reference to Cancer, Alzheimer's, Diabetes, and Glaucoma: An Update on Modified Liposomal Drug Delivery System.
    Payal Kesharwani, Kajal Kumari, Ritika Gururani, Smita Jain, Swapnil Sharma.
      Liposomes nowadays have become preferential drug delivery system, since it provides facilitating properties to drugs such as improved therapeutic index of encapsulated drug, target and controlled drug delivery, and less toxicity. However, conventional liposomes have shown some disadvantages such as less drug loading capacity, poor retention, clearance by kidney or reticuloendothelial system, and less release of hydrophilic drugs. Thus, to overcome these disadvantages recently, scientists have explored new approaches and methods viz. ligand conjugation, polymer coating, and liposomes-hybrid including surface-modified liposomes, biopolymer-incorporated liposomes, guest-in-cyclodextrin-in-liposome, liposome-in-hydrogel, liposome-in-film, and liposome-in-nanofiber, etc. These approaches have been shown to improve the physiochemical and pharmacokinetic properties of encapsulated drugs. Lately, Pharmacokinetic-pharmacodynamic (PK-PD) computational modeling has emerged as a beneficial tool for analyzing the impact of formulation- and system-specific factors on the target disposition and therapeutic efficacy of liposomal drugs. There has been an increasing number of liposome-based therapeutic drugs, both FDA approved and undergoing clinical trials having application in anticancer, Alzheimer's, diabetes, and glaucoma. To meet the continuous demand of health sectors and to produce the desired product, it is important to perform pharmacokinetic studies. This review focuses on the physical, physicochemical, and chemical factors of drugs that influence the target delivery of drugs. It also explains various physiological barriers such as systemic clearance, and extravasation. A novel approach, liposomal-hybrid complex: an innovative approach as a vesicular drug delivery system to overcome limited membrane permeability and bioavailability has been discussed in the review. Moreover, this review highlights the pharmacokinetic considerations and challenges of poorly absorbed drugs along with the applications of a liposomal delivery system in improving PKPD in various diseases such as cancer, Alzheimer's, diabetes, and glaucoma.
    Keywords:  Therapeutic efficacy; bioavailability; hybrid; polymer; poorly water-soluble drugs
    DOI:  https://doi.org/10.2174/1389200223666220609141459
  41. J Cosmet Dermatol. 2022 Jun 14.
    Drug delivery of natural products through nanocarriers for effective vitiligo therapy: A compendia Review.
    Abdul Qadir, Shehla Nasar Mir Najib Ullah, Samreen Jahan, Asad Ali, Nausheen Khan.
      Vitiligo is a depigmenting illness that causes white areas on the skin. Vitiligo's pathogenetic genesis is based on the melanocyte's autoimmune destruction, in which oxidative stress causes melanocyte molecular, organelle, and exposure of antigen, as well as melanocyte cell death, and so plays a role in vitiligo progression. Natural compounds have recently shown a wide range of therapeutic bioactivities against a number of skin disorders, and this study focuses on natural compounds' effects and processes on vitiligo models. Although topical therapy plays an important role in vitiligo treatment, its utility and patient compliance are hampered by adverse effects or inadequate efficacy. Novel drug delivery techniques can help improve topical medication delivery by improving epidermal localization, reducing side effects, and increasing effectiveness. This paper covers the significant potential of herbal derived active compounds as anti-vitiligo drugs, as well as new drug delivery as a viable carrier and future possibilities to investigate.
    Keywords:  Herbal drug used; Nanoformulation; Pathogenesis; Therapeutics approaches; Vitiligo
    DOI:  https://doi.org/10.1111/jocd.15158
  42. Biomed Res Int. 2022 ;2022 5445291
    Flavonoids a Bioactive Compound from Medicinal Plants and Its Therapeutic Applications.
    Arpita Roy, Ariba Khan, Irfan Ahmad, Saad Alghamdi, Bodour S Rajab, Ahmad O Babalghith, Mohammad Y Alshahrani, Saiful Islam, Md Rabiul Islam.
      Plants generally secrete secondary metabolites in response to stress. These secondary metabolites are very useful for humankind as they possess a wide range of therapeutic activities. Secondary metabolites produced by plants include alkaloids, flavonoids, terpenoids, and steroids. Flavonoids are one of the classes of secondary metabolites of plants found mainly in edible plant parts such as fruits, vegetables, stems, grains, and bark. They are synthesized by the phenylpropanoid pathway. Flavonoids possess antibacterial, antiviral, antioxidant, anti-inflammatory, antimutagenic, and anticarcinogenic properties. Due to their various therapeutic applications, various pharmaceutical companies have exploited different plants for the production of flavonoids. To overcome this situation, various biotechnological strategies have been incorporated to improve the production of different types of flavonoids. In this review, we have highlighted the various types of flavonoids, their biosynthesis, properties, and different strategies to enhance the production of flavonoids.
    DOI:  https://doi.org/10.1155/2022/5445291
  43. Mol Metab. 2022 Jun 14. pii: S2212-8778(22)00098-9. [Epub ahead of print] 101529
    New dawn for cancer cell death: emerging role of lipid metabolism.
    Chanjuan Zhang, Neng Zhu, Hongfang Li, Yongzhen Gong, Jia Gu, Yaning Shi, Duanfang Liao, Wei Wang, Aiguo Dai, Li Qin.
      BACKGROUND: Resistance to cell death, a protective mechanism for removing damaged cells, is a "Hallmark of Cancer" that is essential for cancer progression. Increasing attention to cancer lipid metabolism has revealed a number of pathways that induce cancer cell death.SCOPE OF REVIEW: We summarize emerging concepts regarding lipid metabolic reprogramming in cancer that is mainly involved in lipid uptake and trafficking, de novo synthesis and esterification, fatty acid synthesis and oxidation, lipogenesis, and lipolysis. During carcinogenesis and progression, continuous metabolic adaptations are co-opted by cancer cells, to maximize their fitness to the ever-changing environmental. Lipid metabolism and the epigenetic modifying enzymes interact in a bidirectional manner which involves regulating cancer cell death. Moreover, lipids in the tumor microenvironment play unique roles beyond metabolic requirements that promote cancer progression. Finally, we posit potential therapeutic strategies targeting lipid metabolism to improve treatment efficacy and survival of cancer patient.
    MAJOR CONCLUSIONS: The profound comprehension of past findings, current trends, and future research directions on resistance to cancer cell death will facilitate the development of novel therapeutic strategies targeting the lipid metabolism.
    Keywords:  Lipid metabolism; cancer; cell death; therapeutic strategy
    DOI:  https://doi.org/10.1016/j.molmet.2022.101529
  44. J Pharm Pharm Sci. 2022 ;25 201-217
    Recent Advances in Oral Mucoadhesive Drug Delivery.
    Shiva Golshani, Alireza Vatanara, Mohsen Amin.
      The oral cavity is one of the most important routes for local and systemic drug delivery, as it has a large surface, high permeability, and rich blood supply. Oral mucosal drug delivery has some advantages, such as enhancing bioavailability, preventing first-pass metabolism, reducing dose frequency, and non-invasiveness. In recent years, notable oral mucoadhesive patents were introduced to the pharmaceutical field, which indicates promising potentials for therapeutic purposes. Oral mucosal drug delivery can play a key role to deliver the biological drugs, such as antimicrobial peptides. This article gives an overview of oral mucoadhesive drug delivery systems and provides basic principles for the researchers to overcome the problems associated with the formulation design.
    DOI:  https://doi.org/10.18433/jpps32705
  45. Cancer Biol Med. 2022 Jun 15. pii: j.issn.2095-3941.2022.0006. [Epub ahead of print]
    Anti-tumor pharmacology of natural products targeting mitosis.
    Manru Huang, Caiyan Liu, Yingying Shao, Shiyue Zhou, Gaoyong Hu, Shuangshuang Yin, Weiling Pu, Haiyang Yu.
      Cancer has been an insurmountable problem in the history of medical science. The uncontrollable proliferation of cancer cells is one of cancer's main characteristics, which is closely associated with abnormal mitosis. Targeting mitosis is an effective method for cancer treatment. This review summarizes several natural products with anti-tumor effects related to mitosis, focusing on targeting microtubulin, inducing DNA damage, and modulating mitosis-associated kinases. Furthermore, the main disadvantages of several typical compounds, including drug resistance, toxicity to non-tumor tissues, and poor aqueous solubility and pharmacokinetic properties, are also discussed, together with strategies to address them. Improved understanding of cancer cell mitosis and natural products may pave the way to drug development for the treatment of cancer.
    Keywords:  Tumor; mechanism; mitosis; natural products; pharmacology
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2022.0006
  46. J Photochem Photobiol B. 2022 Jun 02. pii: S1011-1344(22)00102-6. [Epub ahead of print]233 112488
    Novel selenium-containing photosensitizers for near-infrared fluorescence imaging-guided photodynamic therapy.
    Meiyu Jiang, Jiasheng Wu, Weimin Liu, Haohui Ren, Shuai Wang, Pengfei Wang.
      Benzopyran nitrile dyes cannot be used as qualified photosensitizers due to the low quantum yield of triplet state. The benzopyran derivatives containing selenium instead of oxygen atom based on the heavy atom effect are expected to become potential agents for photodynamic therapy. In this paper, a series of selenium-containing photosensitizers (PSX) were prepared according to this strategy. PSX can effectively produce both singlet oxygen and superoxide anions upon laser irradiation. PSX exhibited the emission wavelength at 500-800 nm and near-infrared (NIR) fluorescence imaging in HeLa cells. Excellent biocompatibility and phototoxicity further indicated that PSX could be used as efficient photosensitizers for NIR fluorescence imaging and photodynamic therapy.
    Keywords:  NIR fluorescence imaging; Photodynamic therapy; Photosensitizer; Selenium
    DOI:  https://doi.org/10.1016/j.jphotobiol.2022.112488
  47. Biotechnol Genet Eng Rev. 2022 Jun 14. 1-40
    Anti-cancer peptides: their current trends in the development of peptide-based therapy and anti-tumor drugs.
    Amit Lath, Anita Rani Santal, Nameet Kaur, Poonam Kumari, Nater Pal Singh.
      Human cancer remains a cause of high mortality throughout the world. The conventional methods and therapies currently employed for treatment are followed by moderate-to-severe side effects. They have not generated curative results due to the ineffectiveness of treatments. Besides, the associated high costs, technical requirements, and cytotoxicity further characterize their limitations. Due to relatively higher presidencies, bioactive peptides with anti-cancer attributes have recently become treatment choices within the therapeutic arsenal. The peptides act as potential anti-cancer agents explicitly targeting tumor cells while being less toxic to normal cells. The anti-cancer peptides are isolated from various natural sources, exhibit high selectivity and high penetration efficiency, and could be quickly restructured. The therapeutic benefits of compatible anti-cancer peptides have contributed to the significant expansion of cancer treatment; albeit, the mechanisms by which bioactive peptides inhibit the proliferation of tumor cells remain unclear. This review will provide a framework for assessing anti-cancer peptides' structural and functional aspects. It shall provide appropriate information on their mode of action to support and strengthen efforts to improve cancer prevention. The article will mention the therapeutic health benefits of anti-cancer peptides. Their importance in clinical studies is elaborated for reducing cancer incidences and developing sustainable treatment models.
    Keywords:  Anti-cancer peptides; anti-tumor; bioactive peptides; cytotoxicity; therapeutic benefits
    DOI:  https://doi.org/10.1080/02648725.2022.2082157
  48. Free Radic Biol Med. 2022 Jun 09. pii: S0891-5849(22)00224-6. [Epub ahead of print]
    The role of glutathione peroxidase-1 in health and disease.
    Diane E Handy, Joseph Loscalzo.
      Glutathione peroxidase 1 (GPx1) is an important cellular antioxidant enzyme that is found in the cytoplasm and mitochondria of mammalian cells. Like most selenoenzymes, it has a single redox-sensitive selenocysteine amino acid that is important for the enzymatic reduction of hydrogen peroxide and soluble lipid hydroperoxides. Glutathione provides the source of reducing equivalents for its function. As an antioxidant enzyme, GPx1 modulates the balance between necessary and harmful levels of reactive oxygen species. In this review, we discuss how selenium availability and modifiers of selenocysteine incorporation alter GPx1 expression to promote disease states. We review the role of GPx1 in cardiovascular and metabolic health, provide examples of how GPx1 modulates stroke and provides neuroprotection, and consider how GPx1 may contribute to cancer risk. Overall, GPx1 is protective against the development and progression of many chronic diseases; however, there are some situations in which increased expression of GPx1 may promote cellular dysfunction and disease owing to its removal of essential reactive oxygen species.
    Keywords:  Angiogenesis; Atherosclerosis; Cancer; Cardiac protection; Endothelial dysfunction; Glutathione peroxidase 1; Inflammation; Neurodegeneration; Oxidative stress; Selenium; Selenocysteine; Stroke
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.06.004
  49. J Biomed Nanotechnol. 2022 Mar 01. 18(3): 837-848
    A Nucleus-Targeted Nanosystem Integrated with Photodynamic Therapy and Chemotherapy.
    Jing Xin, Sijia Wang, Jing Wang, Lei Fu, Zhenxi Zhang, Cuiping Yao.
      Minimally invasive photodynamic therapy, destroying lesions with a light-activated photosensitizer, has been increasingly performed since it is highly efficiency, safe, synergistically compatible, repeatable, and minimally-invasive, with few adverse reactions. However, the most present photosensitizer or nanodrug delivery system containing a photosensitizer can target tumor cells but rarely cell nuclei. In this regard, the nucleus-targeting drug delivery system has been developed aiming impair tumor cells in an efficient and direct manner. In this study, the cationic liposome (Clip) drug delivery system integrated with low dose nucleus-targeting chemotherapeutic drug Doxorubicin (DOX) and photosensitizer AlPcS4 (Clip-AlPcS4@DOX) was synthesized. Among them, Clip was used to efficiently load drugs into cells almost at the same time, low dose DOX was used to open the channel for the materials to enter the nucleus on the premise of ensuring low cytotoxicity and then introduced photosensitizer into the nucleus, AlPcS4 photosensitizer was used to damage directly and efficiently through the photodynamic therapy (PDT) effect after entering the nucleus. In summary, a nucleus-targeting nanodrug delivery system (Clip-AlPcS4@DOX) was designed and synthesized and could be induced cell apoptosis more quickly and efficiently. Therefore, it could be a promising nucleus-targeting nanosized reagent integrating the PDT and chemotherapy for gastric therapy.
    DOI:  https://doi.org/10.1166/jbn.2022.3286
  50. Curr Med Chem. 2022 Jun 10.
    Nanoinformatics and Personalized Medicine: An advanced cumulative approach for Cancer Management.
    Fariya Khan, Salman Akhtar, Mohammad Amjad Kamal.
      Background- Even though the battle against cancer has advanced remarkably in last few decades and the survival rate has improved very significantly, an ultimate cure for cancer treatment stills remains an undeterred problem. In such scenario, nanoinformatics, which is bioinformatics coupled with nanotechnology, endows with many novel research opportunities in the preclinical and clinical development of specially personalized nanosized drugs and carriers bestowing newer dimensions in anticancer research and therapy. Personalized nanomedicines tends to serve as a promising treatment option for cancer owing to their noninvasiveness and their novel approach. Explicitly, the field of personalized medicine is expected to have an enormous impact in clinical research owing to its diverse advantages and its versatility to adapt a drug to a cohort of patients. Objective- The current review attempts to explain the implications of nanoinformatics as a new emerging field in the field of pharmacogenomics and precision medicine. This review also recapitulates how nanoinformatics could accelerate the developments of personalized nanomedicine in anticancer research, which is undoubtedly the need of the hour. Conclusion- The approach and concept of personalized nanomedicine has been facilitated by humongous impending field of Nanoinformatics. The breakthrough progressions made through nanoinformatics have prominently changed the insight of the future personalized medicinal drug in cancer research. Nanoparticle based medicine has been developing and has created a center of attention in recent years, with a prime focus on proficient delivery mechanisms for various chemotherapy drugs. Nanoinformatics has allowed merging of all recent advances from creating nanosized particles that contain drugs targeting cell surface receptors to other potent molecules designed to kill cancerous cells and its subsequent application to personalize medicine.
    Keywords:  Cancer informatics; Nanoinformatics; Nanomedicine; Oncogenomics; Personalized medicine
    DOI:  https://doi.org/10.2174/0929867329666220610090405
  51. J Liposome Res. 2022 Jun 13. 1-19
    Ethosomes as dermal/transdermal drug delivery systems: applications, preparation and characterization.
    Atoosa Jafari, Saeid Daneshamouz, Parisa Ghasemiyeh, Soliman Mohammadi-Samani.
      Transdermal drug delivery systems (TDDSs) have gained substantial attention during the last decade. TDDS are versatile delivery systems in which active components are delivered to skin for local effects or systemic delivery of active pharmaceutical through the skin. Overcoming stratum corneum is the most challenging step of delivering drugs through the skin. Lipid-based vesicular delivery systems due to the capability of the delivery of both hydrophilic and hydrophobic drugs are becoming more popular during the recent years. Ethosomes are innovative, biocompatible, biodegradable and non-toxic form of lipid-based vesicles that efficiently enable to entrap drugs of various physicochemical properties. These are other forms of liposome which contain high amounts of ethanol in their structure that enabling ethosomes to efficiently penetrate through deeper layers of skin. Ethosomes have various compositions based on their type but are mainly composed of phospholipids, ethanol, water and the active components. Ethosomes are easily manufactured and they are superior compared to liposomes in terms of different aspects due to the presence of ethanol. The purpose of this review is to thoroughly focus on various aspects of ethosomes, including mechanism of penetration, advantages and disadvantages, characterisation and applications.
    Keywords:  Ethosome; dermal drug delivery systems; skin permeation; transdermal drug delivery systems; vesicular nanocarriers
    DOI:  https://doi.org/10.1080/08982104.2022.2085742
  52. Carbohydr Polym. 2022 Sep 01. pii: S0144-8617(22)00524-0. [Epub ahead of print]291 119619
    Construction of chitooligosaccharide-based nanoparticles of pH/redox cascade responsive for co-loading cyclosporin A and AZD9291.
    Shumin Chen, Xiaoguo Ji, Mengyao Zhao, Jiayang Jin, Haiping Zhang, Liming Zhao.
      AZD9291 can prolong the survival of patients with non-small cell lung cancer. Unfortunately, resistance to AZD9291 is inevitable and hinders effectiveness. Studies showed the combination of Cyclosporin A (CsA) and AZD9291 could increase the efficacy of AZD9291, but the delivery efficiency of free drugs was limited. A chitooligosaccharide (COS) -based nanoparticle with enhanced delivery efficiency and endocytosis was constructed in this study. The results showed that this pH/redox cascade responsive nanoparticles improved therapeutic effect. The system is small and the surface charge changed from negative to positive according to the weakly acidic tumor microenvironment. After endocytosis, the nanoparticles decomposed and released AZD9291 and CsA in redox-rich cytoplasm. Experiments in vitro and in vivo proved that the nanoparticles overcame the biological barrier and significantly enhanced the anti-tumor effect of AZD9291. The novel multifunctional nanoparticle provides a way to overcome the drug resistance and the possibility of clinical application.
    Keywords:  AZD9291; Chitooligosaccharides; Cyclosporin A; Drug delivery system; Nanoparticles
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119619
  53. Biomacromolecules. 2022 Jun 13.
    Improving Photodynamic Therapy Anticancer Activity of a Mitochondria-Targeted Coumarin Photosensitizer Using a Polyurethane-Polyurea Hybrid Nanocarrier.
    Joaquín Bonelli, Enrique Ortega-Forte, Anna Rovira, Manel Bosch, Oriol Torres, Cristina Cuscó, Josep Rocas, José Ruiz, Vicente Marchán.
      Integration of photosensitizers (PSs) within nanoscale delivery systems offers great potential for overcoming some of the "Achiles' heels" of photodynamic therapy (PDT). Herein, we have encapsulated a mitochondria-targeted coumarin PS into amphoteric polyurethane-polyurea hybrid nanocapsules (NCs) with the aim of developing novel nanoPDT agents. The synthesis of coumarin-loaded NCs involved the nanoemulsification of a suitable prepolymer in the presence of a PS without needing external surfactants, and the resulting small nanoparticles showed improved photostability compared with the free compound. Nanoencapsulation reduced dark cytotoxicity of the coumarin PS and significantly improved in vitro photoactivity with red light toward cancer cells, which resulted in higher phototherapeutic indexes compared to free PS. Importantly, this nanoformulation impaired tumoral growth of clinically relevant three-dimensional multicellular tumor spheroids. Mitochondrial photodamage along with reactive oxygen species (ROS) photogeneration was found to trigger autophagy and apoptotic cell death of cancer cells.
    DOI:  https://doi.org/10.1021/acs.biomac.2c00361
  54. Crit Rev Ther Drug Carrier Syst. 2022 ;39(4): 1-47
    Exploring Liposomes for Lung Cancer Therapy.
    Aisha Shahid, Mohd Muazzam Khan, Usama Ahmad, Md Faheem Haider, Asad Ali.
      Cancer is referred to as a pleiotropic disease-causing approximately 9.6 million deaths in 2018. Among all cancers, lung cancer was the leading cause of death in 2017, and 12% of fatalities were alone due to lung cancer. The associated risk factors in lung cancer include smoking (80-85%), chronic inflammation in the lungs, COPD, pulmonary fibrosis, environmental and occupational exposure to nickel, arsenic, chromates, etc. Early diagnosed patients' treatment plan includes chemotherapy, immunotherapy, radiotherapy, surgery, and tumor ablation. Many sorts of drug delivery carriers have been used in the past, usually in targeted chemotherapy. Liposomes are spherical shape vesicles containing a lipid bilayer and aqueous core, with potency to encapsulate both hydrophobic and hydrophilic drugs with minimal toxicity. These vesicles have a particle size of 0.02-1000 μm allowing selective passive targeting to the tumor's deeper tissues. Current publications on liposomes highlight their acceptance and best choice among all systems to deliver synthetic and herbal drugs to the lungs. This review focuses on many aspects, which include an in-depth analysis of potential anticancer drugs that have utilized the advantages of liposomes for effective lung carcinomatherapy and devices used to deliver the active agents to the pulmonary tissues. Investigations on ongoing, approved, and failed clinical trials and patents on products related to lung cancer have been highlighted to provide a critical review on the subject.
    DOI:  https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2021037912
  55. Curr Drug Deliv. 2022 Jun 16.
    Facile Synthesis of Three Types of Mesoporous Silica Microspheres as Drug Delivery Carriers and Their Sustained-Release Properties.
    Yameng Zhu, Boyao Wang, Jian Chen, Jun He, Xilong Qiu.
      BACKGROUND: Mesoporous silica nanoparticles (MSN) are one of the most promising carriers for drug delivery. MSNs have been widely used in pharmaceutical research as drug carriers because of their large pore volume, high surface area, excellent biocompatibility, nontoxicity, ease to functionalize, and sustained release effects. MSNs have attracted much attention during drug delivery because of their special structure.OBJECTIVE: The present study aimed to synthesize mesoporous silica nanoparticles (MSN), dendritic mesoporous silica nanoparticles (DMSN) and hollow mesoporous silica nanoparticles (HMSN) through facile methods, and to compare the drug release properties of nano-porous silica with different pore structures as a stroma for PUE drug.
    METHODS: MSN, DMSN, and HMSN were characterized by SEM, TEM, FT-IR, nitrogen adsorption-desorption isotherms, XRD, and zeta potential methods. Subsequently, puerarin (PUE) was used as the active ingredient and loaded into the three mesoporous materials, respectively. And the drug delivery behavior was measured in PBS solution with different pH values. The sustained-release properties of MSN, DMSN, and HMSN loaded with PUE were investigated. Finally, the biocompatibility and stability of MSN, DMSN, and HMSN were studied by MTT assay and hemolysis assay.
    RESULTS: Our results showed that MSN, DMSN, and HMSN were successfully synthesized and the three types of mesoporous silica nanoparticles had higher drug loading and encapsulation efficiency. According to the first-order release equation curve and Higuchi equation parameters, the results showed that the PUE-loaded MSN, DMSN, and HMSN exhibited sustained-release properties. Finally, MTT and hemolysis methods displayed that MSN, DMSN, and HMSN had good biocompatibility and stability.
    CONCLUSION: In this study, MSN, DMSN, and HMSN were successfully synthesized, and to compare the drug release properties of nano-porous silica with different pore structures as a stroma for PUE drug, we provided a theoretical and practical basis for the application of PUE.
    Keywords:  DMSN; HMSN; MSN; PUE; drug delivery; sustained-release
    DOI:  https://doi.org/10.2174/1567201819666220616121602
  56. Food Funct. 2022 Jun 14.
    A comparative study between olive oil and corn oil on oxidative metabolism.
    Eraci Drehmer, Mari Ángeles Navarro-Moreno, Sandra Carrera-Juliá, Mari Luz Moreno.
      Fats are an important part of diet, but not all lipids have the same structure and chemical properties. Unsaturated fatty acids have one or more double bonds in their structure and can be monounsaturated or polyunsaturated, respectively. Most vegetable oils, such as olive oil and corn oil, contain significant amounts of these fatty acids. The presence of double bonds in the molecule of a fatty acid constitutes vulnerable sites for oxidation reactions generating lipid peroxides, potentially toxic compounds that can cause cellular damage. In response to this oxidative damage, aerobic organisms have intracellular enzymatic antioxidant defense mechanisms. The aim of the present investigation was to study comparatively the effects of control liquid diets, of a defined composition, containing olive oil or corn oil as a lipid source respectively of monounsaturated and polyunsaturated fatty acids, on the oxidative metabolism of rats. Rats were divided into three groups which received a control animal feed diet (A.F.), olive oil liquid diet (O.O) and corn oil liquid diet (C.O) for 30 days. It was observed that the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), increased in the liver and white fat tissue of rats fed with olive oil when compared to the corn oil group. However, in brown fat tissue and blood cells, the enzyme activities showed a tendency to decrease in the olive oil group. In addition, the effect of olive oil and corn oil on several glucose metabolism parameters (pyruvate, lactate, LDH, acetoacetate and beta-hydroxybutyrate) showed that corn oil impairs to a greater extent the cellular metabolism. All these results helped in concluding that some body tissues are more adversely affected than others by the administration of corn oil or olive oil, and their antioxidant defenses and cellular metabolism respond differently too.
    DOI:  https://doi.org/10.1039/d2fo00919f
  57. Front Oncol. 2022 ;12 895112
    p53-Mediated Indirect Regulation on Cellular Metabolism: From the Mechanism of Pathogenesis to the Development of Cancer Therapeutics.
    Chen-Yun Wang, Chi-Hong Chao.
      The transcription factor p53 is the most well-characterized tumor suppressor involved in multiple cellular processes, which has expanded to the regulation of metabolism in recent decades. Accumulating evidence reinforces the link between the disturbance of p53-relevant metabolic activities and tumor development. However, a full-fledged understanding of the metabolic roles of p53 and the underlying detailed molecular mechanisms in human normal and cancer cells remain elusive, and persistent endeavor is required to foster the entry of drugs targeting p53 into clinical use. This mini-review summarizes the indirect regulation of cellular metabolism by wild-type p53 as well as mutant p53, in which mechanisms are categorized into three major groups: through modulating downstream transcriptional targets, protein-protein interaction with other transcription factors, and affecting signaling pathways. Indirect mechanisms expand the p53 regulatory networks of cellular metabolism, making p53 a master regulator of metabolism and a key metabolic sensor. Moreover, we provide a brief overview of recent achievements and potential developments in the therapeutic strategies targeting mutant p53, emphasizing synthetic lethal methods targeting mutant p53 with metabolism. Then, we delineate synthetic lethality targeting mutant p53 with its indirect regulation on metabolism, which expands the synthetic lethal networks of mutant p53 and broadens the horizon of developing novel therapeutic strategies for p53 mutated cancers, providing more opportunities for cancer patients with mutant p53. Finally, the limitations and current research gaps in studies of metabolic networks controlled by p53 and challenges of research on p53-mediated indirect regulation on metabolism are further discussed.
    Keywords:  cancer treatment; indirect regulation; metabolism; mutant p53; synthetic lethality; wild-type p53
    DOI:  https://doi.org/10.3389/fonc.2022.895112
  58. Int J Hyperthermia. 2022 ;39(1): 806-812
    Systematic review of the registered clinical trials for oncological hyperthermia treatment.
    H Peeters, E M van Zwol, L Brancato, M G M C da Cunha, J Bogers.
      BACKGROUND: The use of heat to treat various diseases is called hyperthermia treatment (HT). Since the 1970s, the anti-cancer effects of HT have been investigated. Different HT techniques can be categorized as local, regional and whole-body hyperthermia treatment (WBHT). We aim to provide a summary of recent research done on HT to treat cancer.METHODS: In July 2020 ClinicalTrials.gov were systematically searched for all trials including hyperthermia and cancer registered between 2000 and 2020. Studies were excluded when they did not concern hyperthermal treatment, when they were not oncological studies, when they were observational or other non-interventional studies.
    RESULTS: Of 1654 identified trials, 235 were included. Of these 235 studies, 123 described the use of HIPEC (52.3%), 44 other types of regional HT (18.7%), 45 local HT (19.1%) and 15 WBHT (6.4%). A steady increase (720%) in research to hyperthermic intraperitoneal chemotherapy (HIPEC) can be observed in the last decade. Although HIPEC is the most researched HT modality, an evolution in other HT technologies could be observed during the past decade.
    CONCLUSIONS: Research to HT to treat cancer has expanded fast. Some techniques, for example HIPEC start to be used outside of research context, but overall, more research is needed to establish a clear effect of these HT techniques.
    Keywords:  Clinical trials; cancer; hyperthermia
    DOI:  https://doi.org/10.1080/02656736.2022.2076292
  59. Curr Drug Metab. 2022 Jun 10.
    Nanocrystals: An Approachable Delivery System for Anticancer Therapeutics.
    Pooja Khairnar, Mayank Handa, Rahul Shukla.
      Cancer accounts for the high mortality rate and limits the life expectancy of an individual. As per the WHO report of 2020, Cancer accounts for >10 million deaths globally. Scientists are continuously pitching toward the development of novel techniques to combat this menace and enhance the efficacy of prevailing molecules. In the early phases of the drug development process, >40% of promising new therapeutic molecules are hydrophobic. Low aqueous solubility results in compromised bioavailability on administration. This limitation is a major drawback for the therapeutic use of the anticancer drug. Drug nanocrystals (NCs) have sparked a lot of interest in drug delivery. This might be due to their excellent physicochemical characteristics like tailored dissolution, high drug loading efficiency, extended circulation period, and high structural stability. These are 'n' number of the characteristics that make drug nanocrystals a promising formulation for the treatment of cancer. In the last few years, many hydrophobic or lipophilic drugs like camptothecin, paclitaxel, cyclosporin, busulfan, and thymectacin had been formulated as drug nanocrystals against anticancer therapeutics. Various formulation technologies have been developed in conjunction with nanocrystal development. This includes top-down approaches, bottom-up approaches, as well as combination technology. In this article, we will focus on the various manufacturing processes, biological fate and therapeutic applications of NCs, and future perspectives in the management of cancer.
    Keywords:  anticancer drugs; biological fate; bottom-up approach; nanocrystals; top-down approach
    DOI:  https://doi.org/10.2174/1389200223666220610165850
  60. Discov Oncol. 2022 Jun 13. 13(1): 47
    Combining metabolic phenotype determination with metabolomics and transcriptional analyses to reveal pathways regulated by hydroxycarboxylic acid receptor 2.
    Philipp Rabe, Mareike Gehmlich, Anna Peters, Petra Krumbholz, Anders Nordström, Claudia Stäubert.
      BACKGROUND: The adaptation of cellular metabolism is considered a hallmark of cancer. Oncogenic signaling pathways support tumorigenesis and cancer progression through the induction of certain metabolic phenotypes associated with altered regulation of key metabolic enzymes. Hydroxycarboxylic acid receptor 2 (HCA2) is a G protein-coupled receptor previously shown to act as a tumor suppressor. Here, we aimed to unveil the connection between cellular metabolism and HCA2 in BT-474 cells. Moreover, we intend to clarify how well this metabolic phenotype is reflected in transcriptional changes and metabolite levels as determined by global metabolomics analyses.METHODS: We performed both, siRNA mediated knockdown of HCA2 and stimulation with the HCA2-specific agonist monomethyl fumarate. Seahorse technology was used to determine the role of HCA2 in BT-474 breast cancer cell metabolism and its potential to induce a switch in the metabolic phenotype in the presence of different energy substrates. Changes in the mRNA expression of metabolic enzymes were detected with real-time quantitative PCR (RT-qPCR). Untargeted liquid chromatography-mass spectrometry (LC-MS) metabolic profiling was used to determine changes in metabolite levels.
    RESULTS: Knockdown or stimulation of HCA2 induced changes in the metabolic phenotype of BT474 cells dependent on the availability of energy substrates. The presence of HCA2 was associated with increased glycolytic flux with no fatty acids available. This was reflected in the increased mRNA expression of the glycolytic enzymes PFKFB4 and PKM2, which are known to promote the Warburg effect and have been described as prognostic markers in different types of cancer. With exogenous palmitate present, HCA2 caused elevated fatty acid oxidation and likely lipolysis. The increase in lipolysis was also detectable at the transcriptional level of ATGL and the metabolite levels of palmitic and stearic acid.
    CONCLUSIONS: We combined metabolic phenotype determination with metabolomics and transcriptional analyses and identified HCA2 as a regulator of glycolytic flux and fatty acid metabolism in BT-474 breast cancer cells. Thus, HCA2, for which agonists are already widely used to treat diseases such as psoriasis or hyperlipidemia, may prove useful as a target in combination cancer therapy.
    Keywords:  Cancer metabolism; GPR109A; HCA2; LC-MS; Metabolite profile; Metabolite-sensing GPCR
    DOI:  https://doi.org/10.1007/s12672-022-00503-3
  61. Sci Rep. 2022 Jun 11. 12(1): 9713
    Curcumin and metformin synergistically modulate peripheral and central immune mechanisms of pain.
    Peththa Wadu Dasuni Wasana, Hasriadi, Chawanphat Muangnoi, Opa Vajragupta, Pranee Rojsitthisak, Pornchai Rojsitthisak, Pasarapa Towiwat.
      Metformin is a well-tolerated antidiabetic drug and has recently been repurposed for numerous diseases, including pain. However, a higher dose of metformin is required for effective analgesia, which can potentiate its dose-dependent gastrointestinal side effects. Curcumin is a natural polyphenol and has beneficial therapeutic effects on pain. Curcumin has been used as an analgesic adjuvant with several analgesic drugs, allowing synergistic antinociceptive effects. Nevertheless, whether curcumin can exert synergistic analgesia with metformin is still unknown. In the present study, the nature of curcumin-metformin anti-inflammatory interaction was evaluated in in vitro using lipopolysaccharide-induced RAW 264.7 macrophage and BV-2 microglia cells. In both macrophage and microglia, curcumin effectively potentiates the anti-inflammatory effects of metformin, indicating potential synergistic effects in both peripheral and central pathways of pain. The nature of the interaction between curcumin and metformin was further recapitulated using a mouse model of formalin-induced pain. Coadministration of curcumin and metformin at a 1:1 fixed ratio of their ED50 doses significantly reduced the dose required to produce a 50% effect compared to the theoretically required dose in phase II of the formalin test with a combination index value of 0.24. Besides, the synergistic interaction does not appear to involve severe CNS side effects indicated by no motor alterations, no alterations in short-term and long-term locomotive behaviors, and the general well-being of mice. Our findings suggest that curcumin exerts synergistic anti-inflammation with metformin with no potential CNS adverse effects.
    DOI:  https://doi.org/10.1038/s41598-022-13647-7
  62. Drug Des Devel Ther. 2022 ;16 1767-1778
    Transferrin-Modified Mangiferin-Loaded SLNs: Preparation, Characterization, and Application in A549 Lung Cancer Cell.
    Qi Zhou, Kezhu Hou, Zhiqiang Fu.
      Introduction: Mangiferin is a plant antitumor compound with poor water solubility and low bioavailability. In this study, transferrin-modified mangiferin-loaded solid lipid nanoparticles (Tf-modified MGF-SLNs) were prepared to overcome the above defects.Methods: Tf-modified MGF-SLNs were prepared by the emulsification-solvent evaporation method. The physicochemical properties of Tf-MGF-SLNs such as particle size, zeta potential and in vitro drug release were investigated. We also demonstrated the effect of Tf-MGF-SLNs in lung cancer.
    Results: The mean hydrodynamic diameter of the Tf-MGF-SLNs was 121.8±2.9 nm with a polydispersity index of 0.134±0.03. According to TEM micrographs, Tf-MGF-SLNs are spherical and uniform, and the EE% was found to be 72.5±2.4%. In vitro release, we identified an initial burst effect release, followed by controlled release, in SLNs at both pHs and the Tf-MGF-SLNs drug accumulation release percentages reached over 68% at pH 4.0 and 72% at pH 7.4 in 6 hours, respectively. In vivo studies showed that depending on surface modification, Tf-MGF-SLNs, which suggested that cell internalization was changed and more drugs entered the cells successfully.
    Discussion: Tf-MGF-SLNs were highly efficient in suppressing the tumor growth in xenograft tumor model. Sustained release of the drug delivery system and Tf-modified MGF-SLNs played a major role. Tf-MGF-SLNs would be a promising formulation for the treatment of lung cancer.
    Keywords:  A549 lung cancer cell; SLNs; mangiferin; transferrin
    DOI:  https://doi.org/10.2147/DDDT.S366531
  63. Front Bioeng Biotechnol. 2022 ;10 897641
    Therapeutic Effects of Zoledronic Acid-Loaded Hyaluronic Acid/Polyethylene Glycol/Nano-Hydroxyapatite Nanoparticles on Osteosarcoma.
    Yan Xu, Jingqi Qi, Wei Sun, Wu Zhong, Hongwei Wu.
      Zoledronic acid (ZOL) has been approved as the only bisphosphonate for the prevention and treatment of metastatic bone diseases with acceptable safety and tolerability. However, systemic or direct injection of ZOL often causes severe side effects, which limits its clinical application. Here, an innovative nano-drug delivery system, ZOL-loaded hyaluronic acid/polyethylene glycol/nano-hydroxyapatite nanoparticles (HA-PEG-nHA-ZOL NPs), has been found to effectively inhibit the proliferation of three types of human osteosarcoma cell lines (143b, HOS, and MG63) at 1-10 μmol/L, while with low cell cytotoxicity on normal cells. The NPs significantly enhanced the apoptosis-related protein expression and tumor cell apoptosis rate. The NPs could also inhibit the proliferation of osteosarcoma cells by blocking the S phase of the cell cycle. In the orthotopic osteosarcoma nude mice model, local injection of the HA-PEG-nHA-ZOL NPs stimulated tumor necrosis, apoptosis, and granulocyte infiltration in the blood vessels. Altogether, the ZOL nano-delivery system possesses great potential for local treatment to prevent local tumor recurrence and can be applied in clinical osteosarcoma therapy.
    Keywords:  nanoparticle; osteosarcoma; targeted therapy; tumor therapy; zoledronic acid
    DOI:  https://doi.org/10.3389/fbioe.2022.897641
  64. ACS Appl Mater Interfaces. 2022 Jun 15.
    MXene-Assisted Ablation of Cells with a Pulsed Near-Infrared Laser.
    Sergiy Kyrylenko, Oleksiy Gogotsi, Ivan Baginskiy, Vitalii Balitskyi, Veronika Zahorodna, Yevheniia Husak, Ilya Yanko, Mykolay Pernakov, Anton Roshchupkin, Mykola Lyndin, Bernhard B Singer, Volodymyr Buranych, Alexander Pogrebnjak, Oksana Sulaieva, Oleksandr Solodovnyk, Yury Gogotsi, Maksym Pogorielov.
      Innovative therapies are urgently needed to combat cancer. Thermal ablation of tumor cells is a promising minimally invasive treatment option. Infrared light can penetrate human tissues and reach superficial malignancies. MXenes are a class of 2D materials that consist of carbides/nitrides of transition metals. The transverse surface plasmons of MXenes allow for efficient light absorption and light-to-heat conversion, making MXenes promising agents for photothermal therapy (PTT). To date, near-infrared (NIR) light lasers have been used in PTT studies explicitly in a continuous mode. We hypothesized that pulsed NIR lasers have certain advantages for the development of tailored PTT treatment targeting tumor cells. The pulsed lasers offer a wide range of controllable parameters, such as power density, duration of pulses, pulse frequency, and so on. Consequently, they can lower the total energy applied and enable the ablation of tumor cells while sparing adjacent healthy tissues. We show for the first time that a pulsed 1064 nm laser could be employed for selective ablation of cells loaded with Ti3C2Tx MXene. We demonstrate both low toxicity and good biocompatibility of this MXene in vitro, as well as a favorable safety profile based on the experiments in vivo. Furthermore, we analyze the interaction of MXene with cells in several cell lines and discuss possible artifacts of commonly used cellular metabolic assays in experiments with MXenes. Overall, these studies provide a basis for the development of efficient and safe protocols for minimally invasive therapies for certain tumors.
    Keywords:  MXene; cancer cell; in vivo safety; photothermal therapy; pulsed near-infrared laser
    DOI:  https://doi.org/10.1021/acsami.2c08678
  65. Acta Biomater. 2022 Jun 13. pii: S1742-7061(22)00357-9. [Epub ahead of print]
    An all-in-one biomimetic iron-small interfering RNA nanoplatform induces ferroptosis for cancer therapy.
    Siming Huang, Hongbo Le, Guobin Hong, Guosheng Chen, Fang Zhang, Liejing Lu, Xiang Zhang, Ya Qiu, Zhe Wang, Qinyuan Zhang, Gangfeng Ouyang, Jun Shen.
      Iron-dependent ferroptosis is a promising therapeutic strategy for cancers. However, the sustained overexpression of the antioxidant glutathione (GSH) in cancer cells substantially limits its therapeutic effect. Seeking efficient approaches that can perform high GSH depletion efficiency remains a significant task. Herein, we construct an all-in-one nanoplatform with functions of tumor targeting, monitoring and treatment for cancer ferroptosis therapy by constructing a homotypic cancer cell membrane-camouflaged iron-small interfering RNA nanohybrid (CM-Fe-siR). The SLC7A11-targeted siRNA in the nanohybrid inhibits the biosynthesis of GSH by cutting off the supply of intracellular cystine, an essential ingredient in GSH synthesis, which subsequently results in the accumulation of reactive oxygen species (ROS) that are generated from Fenton reaction induced by iron. Meanwhile, the intracellular deficiency of GSH inactivates glutathione peroxidase 4 (GPX4, a lipid repair enzyme), which further increases the accretion of lipid peroxides to enhance iron-induced ferroptosis. This biomimetic nanohybrid shows a remarkable anti-cancer effect by triggering sustainable and efficient ferroptosis via these multiple synergistic actions. Besides, the nanohybrids enable in vivo magnetic resonance imaging (MRI) monitoring of therapy. The biomimetic CM-Fe-siR all-in-one nanoplatform may provide an efficient means of ferroptosis therapy for cancers. STATEMENT OF SIGNIFICANCE: Ferroptosis therapy based on the Fenton reaction of iron nanomaterials has aroused much attention in cancer treatment; however, the therapeutic efficacy is greatly inhibited by the sustained overexpression of the antioxidant GSH in cancer cells. It is of great importance to exploit more reagents or techniques performing high GSH depletion efficiency. Here, we facilely construct an all-in-one cancer cell membrane-camouflaged iron-siRNA nanoplatform, which possesses good biosafety, tumor-targeting, and noninvasive MRI monitoring capabilities. It effectively inhibits the GSH synthesis, and further simultaneously promotes the ROS accumulation and GPX4 inactivation, leading to enhanced cancer ferroptosis. This work highlights that the biomimetic iron-siRNA nanohybrids have a high potential in clinical application for imaging-guided cancer ferroptosis therapy.
    Keywords:  RNA interference; chemodynamic therapy; ferroptosis; iron-biomolecule coordination; magnetic resonance imaging
    DOI:  https://doi.org/10.1016/j.actbio.2022.06.017
  66. ACS Med Chem Lett. 2022 Jun 09. 13(6): 893-894
    Novel Bicyclic Dione Compounds as KRAS Inhibitors for Treating Cancer.
    Ram W Sabnis.
      
    DOI:  https://doi.org/10.1021/acsmedchemlett.2c00221
  67. Food Funct. 2022 Jun 14.
    Bioactives and functional food ingredients with promising potential for the management of cerebral and myocardial ischemia: a comprehensive mechanistic review.
    Eman Maher Zahran, Ahmed M Sayed, Rania Alaaeldin, Mahmoud A Elrehany, Amira R Khattab, Usama Ramadan Abdelmohsen.
      Ischemia is a deadly disease featured by restricted perfusion to different organs in the body. An increase in the accumulation of reactive oxygen species and cell debris is the driving force for inducing many oxidative, inflammatory and apoptotic signaling pathways. However, the number of therapeutics existing for ischemic stroke patients is limited and there is insufficient data on their efficiency, which warrants the search for novel therapeutic candidates from natural sources. Herein, a comprehensive survey was done on the reported functional food bioactives (ca. 152 compounds) to manage or protect against health consequences of myocardial and cerebral ischemia. Furthermore, we reviewed the reported mechanistic studies for their anti-ischemic potential. Subsequently, network pharmacology- and in silico-based studies were conducted using the reported myocardial and cerebral ischemia-relevant molecular targets to study their complex interactions and highlight key targets in disease pathogenesis. Subsequently, the most prominent 20 compounds in the literature were used in a comprehensive in silico-based analysis (inverse docking, ΔG calculation and molecular dynamics simulation) to determine other potential targets for these compounds and their probable interactions with different signaling pathways relevant to this disease. Many functional food bioactives, belonging to different chemical classes, i.e., flavonoids, saponins, phenolics, alkaloids, iridoids and carotenoids, were proven to exhibit multifactorial effects in targeting the complex pathophysiology of ischemic conditions. These merits make them valuable therapeutic agents that can outperform the conventional drugs, and hence they can be utilized as add-ons to the conventional therapy for the management of different ischemic conditions; however, their rigorous clinical assessment is necessary.
    DOI:  https://doi.org/10.1039/d2fo00834c
  68. J Biomater Sci Polym Ed. 2022 Jun 14. 1-33
    Potential of Pectin for Biomedical Applications: A Comprehensive Review.
    Nazlı Seray Bostancı, Senem Büyüksungur, Nesrin Hasirci, Ayşen Tezcaner.
      Pectin is a polysaccharide extracted from various plants, such as apples, oranges, lemons, and it possesses some beneficial effects on human health, including being hypoglycemic and hypocholesterolemic. Therefore, pectin is used in various pharmaceutical and biomedical applications. Meanwhile, its low mechanical strength and fast degradation rate limit its usage as drug delivery devices and tissue engineering scaffolds. To enhance these properties, it can be modified or combined with other organic molecules or polymers and/or inorganic compounds. These materials can be prepared as nano sized drug carriers in the form of spheres, capsules, hydrogels, self assamled micelles, etc. for treatment purposes (mostly cancer). Different composites or blends of pectin can also be produced as membranes, sponges, hydrogels, or 3D printed matrices for tissue regeneration applications. This review is concentrated on the properties of pectin based materials and focus especially on the utilization of these materials as drug carriers and tissue engineering scaffolds, including 3D printed and 3D bioprinted systems covering the studies in the last decade and especially in the last 5 years.
    Keywords:  3D bioprinting; 3D printing; biomaterial; drug delivery; pectin; scaffold; tissue engineering
    DOI:  https://doi.org/10.1080/09205063.2022.2088525
  69. J Food Sci. 2022 Jun 16.
    Repurposing chia seed oil: A versatile novel functional food.
    Yamini Tak, Manpreet Kaur, Rajendra Kumar, Chirag Gautam, Prabhjot Singh, Harjeet Kaur, Amanpreet Kaur, Surekha Bhatia, Niraj Kumar Jha, Piyush Kumar Gupta, Ryszard Amarowicz.
      Chia seed oil (CSO) has been recently gaining tremendous interest as a functional food. The oil is rich in with polyunsaturated fatty acids (PUFAs), especially, alpha linolenic acid (ALA), linoleic acid (LA), tocopherols, phenolic acids, vitamins, and antioxidants. Extracting CSO through green technologies has been highly efficient, cost-effective, and sustainable, which has also shown to improve its nutritional potential and proved to be eco-friendly than any other traditional or conventional processes. Due to the presence of valuable bioactive metabolites, CSO is proving to be a revolutionary source for food, baking, dairy, pharmaceutical, livestock feed, and cosmetic industries. CSO has been reported to possess antidiabetic, anticancer, anti-inflammatory, antiobesity, antioxidant, antihyperlipidemic, insect-repellent, and skin-healing properties. However, studies on toxicological safety and commercial potency of CSO are limited and therefore the need of the hour is to focus on large-scale molecular mechanistic and clinical studies, which may throw light on the possible translational opportunities of CSO to be utilized to its complete potential. In this review, we have deliberated on the untapped therapeutical possibilities and novel findings about this functional food, its biochemical composition, extraction methods, nutritional profiling, oil stability, and nutraceutical and pharmaceutical applications for its health benefits and ability to counter various diseases.
    Keywords:  chia seed oil; extraction; fatty acid; human health; nutrition; stabilization
    DOI:  https://doi.org/10.1111/1750-3841.16211
  70. Nat Med. 2022 Jun 16.
    A much-needed treatment for HER2-low breast cancer.
    Karen O'Leary.
      
    Keywords:  Breast cancer; Cancer therapy; Clinical trials; Targeted therapies
    DOI:  https://doi.org/10.1038/d41591-022-00070-8
  71. Colloids Surf B Biointerfaces. 2022 Jun 07. pii: S0927-7765(22)00297-1. [Epub ahead of print]217 112614
    Construction of reduction-sensitive heterodimer prodrugs of doxorubicin and dihydroartemisinin self-assembled nanoparticles with antitumor activity.
    Guolian Ren, Danyu Duan, Geng Wang, Rongrong Wang, Yujie Li, Hengtong Zuo, Qichao Zhang, Guoshun Zhang, Yongdan Zhao, Ruili Wang, Shuqiu Zhang.
      Doxorubicin (DOX) is used as a first-line chemotherapeutic drug, whereas dihydroartemisinin (DHA) also shows a certain degree of antitumor activity. Disulfide bonds (-SS-) in prodrug molecules can be degraded in highly reducing environments. Thus, heterodimer prodrugs of DOX and DHA linked by a disulfide bond was designed and subsequently prepared as reduction-responsive self-assembled nanoparticles (DOX-SS-DHA NPs). In an in vitro release study, DOX-SS-DHA NPs exhibited reduction-responsive activity. Upon cellular evaluation, DOX-SS-DHA NPs were found to have better selectivity toward tumor cells and less cytotoxicity to normal cells. Compared to free DiR, DOX-SS-DHA NPs showed improved accumulation at the tumor site and even had a longer clearance half-life. More importantly, DOX-SS-DHA NPs possessed a much higher tumor inhibition efficacy than DOX-sol and MIX-sol in 4T1 tumor-bearing mice. Our results suggested the superior antitumor efficacy of DOX-SS-DHA NPs with less cytotoxicity.
    Keywords:  Dihydroartemisinin; Doxorubicin; Heterodimer prodrugs; Reduction-sensitive; Self-assembled nanoparticles
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112614
  72. AAPS PharmSciTech. 2022 Jun 16. 23(6): 167
    A Hypoxia-Sensitive Drug Delivery System Constructed by Nitroimidazole and its Application in the Treatment of Hepatocellular Carcinoma.
    Tingting Meng, Yinghong Li, Ying Tian, Mingxing Ma, Kequan Shi, Xuwei Shang, Hong Yuan, Fuqiang Hu.
      Hypoxia is an important pathological phenomenon, and it can induce many tumor microenvironment changes, such as accumulations of intracellular lactic acid, decrease of tumor microenvironment pH value, and regulate a series of physiological and pathological processes such as adhesion, metastasis, and immune escape. Hypoxic tumor cells act as a key target for treating tumor. In this research, we designed and prepared PEG-nitroimidazole grafts, PEG-NI, and FA-PEG-NI. We first explored their physical and chemical properties to serve as a drug carrier. Then, the hypoxia-sensitive properties such as particle size changes and drug release were investigated. Finally, the tumor targeting ability was studied in vitro and in vivo, and anti-tumor capacity was determined. Both grafts showed excellent property as a nanodrug carrier and showed favorable drug encapsulation ability of sorafenib with the help of the hydrophobic chain of 6-(BOC-amino) hexyl bromide. The micelles responded to the hypoxic tumor environment with chemical and spatial structure changes leading to sensitive and fast drug release. With the modification of folic acid, FA-PEG-NI gained tumor targeting ability in vivo. FA-PEG-NI graft proved a potential targeting drug delivery system in the treatment of hypoxic hepatocellular carcinoma.
    Keywords:  PEG-nitroimidazole grafts; folic acid; hepatocellular carcinoma; hypoxia sensitive
    DOI:  https://doi.org/10.1208/s12249-022-02316-7
  73. R Soc Open Sci. 2022 Jun;9(6): 220013
    Mesoporous silica nanocarriers as drug delivery systems for anti-tubercular agents: a review.
    Josephine Oluwagbemisola Tella, Joseph Adeyemi Adekoya, Kolawole Oluseyi Ajanaku.
      The treatment and management of tuberculosis using conventional drug delivery systems remain challenging due to the setbacks involved. The lengthy and costly treatment regime and patients' non-compliance have led to drug-resistant tuberculosis, which is more difficult to treat. Also, anti-tubercular drugs currently used are poor water-soluble drugs with low bioavailability and poor therapeutic efficiency except at higher doses which causes drug-related toxicity. Novel drug delivery carrier systems such as mesoporous silica nanoparticles (MSNs) have been identified as nanomedicines capable of addressing the challenges mentioned due to their biocompatibility. The review discusses the sol-gel synthesis and chemistry of MSNs as porous drug nanocarriers, surface functionalization techniques and the influence of their physico-chemical properties on drug solubility, loading and release kinetics. It outlines the physico-chemical characteristics of MSNs encapsulated with anti-tubercular drugs.
    Keywords:  anti-tubercular agents; drug delivery; mesoporous silica nanoparticles; nanomedicine; tuberculosis
    DOI:  https://doi.org/10.1098/rsos.220013
  74. Mini Rev Med Chem. 2022 Jun 09.
    Chitosan: Applications in Drug Delivery System.
    Suresh Kumar, Ruby Dhiman, Carlos R Prudencio, Antonio Charlys da Costa, Arpana Vibhuti, Elcio Leal, Chung-Ming Chang, V Samuel Raj, Ramendra Pati Pandey.
      Chitin and chitosan have unique structures with significant functional groups carrying useful chemical capabilities. Chitin and chitosan are acknowledged as novel biomaterials with advantageous biocompatibility and biodegradability. Chitosan is a polysaccharide that is made from chitin. There have been several attempts to employ this biopolymer in the biomedical area. This material's application in the production of artificial skin, drug targeting, and other areas is explored. The most prevalent strategies for recovering chitin from sea organisms are described and various pharmacological and biological uses are discussed. This review article targets drug delivery with the help of chitosan derived nanomaterial. The drug delivery system applications through nonmaterial have encountered a considerable role in the pharmaceutical, medical, biological, and other sectors in recent years. Nanomaterials have advanced applications as novel drug delivery systems in many fields, especially in industry, biology, and medicine. In the biomedical and pharmaceutical arena, the natural polymer-based nanoparticulate method has now been widely studied as particulate vehicles. By mixing alginate with other biopolymers, by immobilizing specific molecules such as sugar molecules and peptides by chemical or physical cross-linking, different properties and structures such as biodegradability, gelling properties, mechanical strength, and cell affinity can be obtained. Owing to their inherent ability to deliver both hydrophilic and hydrophobic drug molecules, increase stability, decrease toxicity, and enhance commonly formulated medications, these particles are now widely used in imaging and molecular diagnostics, cosmetics, household chemicals, sunscreens, radiation safety, and novel drug delivery.
    Keywords:  Biopolymers; biological properties; nanomaterials; nanotoxicity; pharmaceutical nanotechnology; physicochemical properties; toxicological effect
    DOI:  https://doi.org/10.2174/1389557522666220609102010
  75. Front Bioeng Biotechnol. 2022 ;10 905999
    Editorial: Mitochondria-Targeted Nanocarriers for Enhanced Efficacy of Cancer Therapy.
    Yan Gao, Bing Xia.
      
    Keywords:  cancer therapy; chemotherapy; enhanced efficacy; mitochondria targeting; nanomedicine; phototherapy
    DOI:  https://doi.org/10.3389/fbioe.2022.905999
  76. Int J Nanomedicine. 2022 ;17 2611-2628
    Research Progress on Improving the Efficiency of CDT by Exacerbating Tumor Acidification.
    Wenting Chen, Jinxi Liu, Caiyun Zheng, Que Bai, Qian Gao, Yanni Zhang, Kai Dong, Tingli Lu.
      In recent years, chemodynamic therapy (CDT) has received extensive attention as a novel means of cancer treatment. The CDT agents can exert Fenton and Fenton-like reactions in the acidic tumor microenvironment (TME), converting hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (·OH). However, the pH of TME, as an essential factor in the Fenton reaction, does not catalyze the reaction effectively, hindering its efficiency, which poses a significant challenge for the future clinical application of CDT. Therefore, this paper reviews various strategies to enhance the antitumor properties of nanomaterials by modulating tumor acidity. Ultimately, the performance of CDT can be further improved by inducing strong oxidative stress to produce sufficient ·OH. In this paper, the various acidification pathways and proton pumps with potential acidification functions are mainly discussed, such as catalytic enzymes, exogenous acids, CAIX, MCT, NHE, NBCn1, etc. The problems, opportunities, and challenges of CDT in the cancer field are also discussed, thereby providing new insights for the design of nanomaterials and laying the foundation for their future clinical applications.
    Keywords:  Fenton/Fenton-like reactions; chemodynamic therapy; reactive oxygen specie; tumor microenvironment
    DOI:  https://doi.org/10.2147/IJN.S366187
  77. Carbohydr Polym. 2022 Sep 01. pii: S0144-8617(22)00459-3. [Epub ahead of print]291 119554
    Stepwise responsive carboxymethyl chitosan-based nanoplatform for effective drug-resistant breast cancer suppression.
    Hui Peng, Lei Qiao, Guisong Shan, Min Gao, Ruijie Zhang, Xiaoqing Yi, Xiaoyan He.
      Efficient delivery systems for co-delivery of P-glycoprotein (P-gp) inhibitors and chemotherapeutic drugs are essential for inhibiting multi-drug resistance (MDR) breast cancers. Herein, we present a multi-functional carboxymethyl chitosan (CMC) based core-shell nanoplatform to co-deliver MDR1 gene-silenced small interfering RNA (siMDR1) and doxorubicin (DOX) for optimal combinatorial therapy. DOX is linked to CMC through a disulfide bond to model redox-responsive prodrug (CMC-DOX) as the inner core. siMDR1 is encapsulated in oligoethylenimine (OEI), which is electrostatically adsorbed on CMC-DOX as the pH-responsive sheddable shielding shell. AS1411 aptamer and GALA peptide functionalised hyaluronic acid (AHA/GHA) are provided on the surface for tumour-targeting and endo/lysosomal escape. The nanoplatform could stepwise release payloads with acid/redox triggered fashion. AHA effectively improves nanoplatform intracellular uptake and tumour accumulation. GHA facilitates cargos escape from endo/lysosomes to cytoplasm. The multi-functional nanoplatform provides 86.3 ± 2.2% siMDR1 gene silencing and significantly downregulates P-gp expression. Moreover, it ensures 55.7 ± 1.6% MCF-7/ADR cell apoptosis at a low concentration of DOX (30 μg/mL) in vitro and performs synergistic therapeutic effects suppressing tumour growth in vivo. Overall, the multi-functional CMC-based biopolymers can be efficient siRNA/drug co-delivery carriers for cancer chemotherapy.
    Keywords:  Carboxymethyl chitosan; Combination cancer therapy; Controlled release; Multi-drug resistance; Stepwise responsive
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119554
  78. Photodiagnosis Photodyn Ther. 2022 Jun 14. pii: S1572-1000(22)00242-3. [Epub ahead of print] 102956
    Investigation of wound healing potential of photo-active curcumin-ZnO-nanoconjugates in excisional wound model.
    Zara Aslam, Talat Roome, Anam Razzak, Shazmeen Mohammad Aslam, Midhat Batool Zaidi, Tasmina Kanwal, Bushra Sikandar, Massimo F Bertino, Khadija Rehman, Muhammad Raza Shah.
      Wound healing, being a dynamic process consisting of hemostasis, inflammation, proliferation, and remodeling, involves the complicated interplay of various growth mediators and the cells associated repair system. Current wound healing therapies usually fail to completely regain skin integrity and functionality. Traditionally, curcumin is considered a potent natural wound healing agent as it possesses antibacterial, antioxidant, and anti-inflammatory properties. It is also known that zinc oxide (ZnO) nanoparticles (NPs) have photocatalytic properties, including the generation of reactive oxygen species. ZnO nanoaprticles are also Food and Drug Administration (FDA) approved as safe substances. While ZnO oxide requires illumination with ultraviolet light to become photocatalytically active, dye-sensitized ZnO can be activated by illumination with visible light. In the present study, we explored the wound healing potential of ZnO nanoparticles sensitized with curcumin (Cu+ZnO Nps) and illuminated with visible (blue) light generated by an array of high power LEDs. We studied the antibacterial effect of our conjugates by percentage reduction in bacterial growth and biofilm formation. The wound healing potential was analyzed by percentage wound contraction, biochemical parameters, and histopathological analysis of the wounded site. Additionally, angiogenesis and wound associated cytokines was evaluated by immunohistochemistry of CD31 and gene expression analysis of IL-1β, TNF-α, and MMP-9 after 16 days of post-wound treatment, respectively. Our study suggests that the therapeutic effect of Cu+ZnO NPs with LED illumination increases its wound healing potential by producing an antibacterial and anti-inflammatory effect. Moreover, the treatment strategy of using a nano formulation in combination with LED illumination further increases its efficacy. It was concluded that the anti-inflammatory and bactericidal effects of the LED illuminated Cu+ZnO Np showed accelerated wound healing with increased wound contraction, collagen deposition, angiogenesis, and re-epithelialization.
    Keywords:  Curcumin; anti-inflammatory; bactericidal; wound healing; zinc oxide nanoparticles
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.102956
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