bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022‒05‒08
124 papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development
  1. Recent Developments of Nanostructures for the Ocular Delivery of Natural Compounds.
  2. Curcumin-loaded PEGylated mesoporous silica nanoparticles for effective photodynamic therapy.
  3. Phytofabricated Nanoparticle Formulation For Cancer Treatment: A Comprehensive Review.
  4. Research Progress on Nanoplatforms and Nanotherapeutic Strategies in Treating Glioma.
  5. Doxorubicin-loaded Cu2S/Tween-20 nanocomposites for light-triggered tumor photothermal therapy and chemotherapy.
  6. Theranostic nanosystem with supramolecular self-assembly for enhanced reactive oxygen species-mediated apoptosis guided by dual-modality tumor imaging.
  7. Highly-controllable drug release from core cross-linked singlet oxygen-responsive nanoparticles for cancer therapy.
  8. Two-photon responsive porphyrinic metal-organic framework involving Fenton-like reaction for enhanced photodynamic and sonodynamic therapy.
  9. Dual Inhibitions on Glucose/Glutamine Metabolisms for Nontoxic Pancreatic Cancer Therapy.
  10. Hypoxia responsive and tumor-targeted mixed micelles for enhanced cancer therapy and real-time imaging.
  11. Solvothermal synthesis of Nb-doped TiO2 nanoparticles with enhanced sonodynamic effects for destroying tumors.
  12. The biological activities of 5,15-diaryl-10,20-dihalogeno porphyrins for photodynamic therapy.
  13. An in vitro investigation of the hepatic toxicity of PEGylated polymeric redox responsive nanoparticles.
  14. Lipid-coated CaCO3-PDA nanoparticles as a versatile nanocarrier to enable pH-responsive dual modal imaging-guided combination cancer therapy.
  15. A mutually beneficial macrophages-mediated delivery system realizing photo/immune therapy.
  16. Polydopamine-modified ZIF-8 nanoparticles as a drug carrier for combined chemo-photothermal osteosarcoma therapy.
  17. Regulation of Nucleotide Metabolism with Nutrient-Sensing Nanodrugs for Cancer Therapy.
  18. The dimerization of methyl vanillate improves its effect against breast cancer cells via pro-oxidant effect.
  19. Improved therapeutic efficacy of quercetin-loaded polymeric nanoparticles on triple-negative breast cancer by inhibiting uPA.
  20. An emerging role of KRAS in biogenesis, cargo sorting and uptake of cancer-derived extracellular vesicles.
  21. Inhibition of the HIF-1 Survival Pathway as a Strategy to Augment Photodynamic Therapy Efficacy.
  22. Tumor microenvironment triggered biodegradation of inorganic nanoparticles for enhanced tumor theranostics.
  23. The Emerging Potential of Parthenolide Nanoformulations in Tumor Therapy.
  24. Excited state and reactive oxygen species against cancer and pathogens: a review on sonodynamic and sono-photodynamic therapy.
  25. Chemico-biological aspects of (-)-epigallocatechin-3-gallate (EGCG) to improve its stability, bioavailability and membrane permeability: Current status and future prospects.
  26. Strategies of targeting KRAS, challenging drug target.
  27. Enhanced Cancer Starvation Therapy Enabled by an Autophagy Inhibitors-Encapsulated Biomimetic ZIF-8 Nanodrug: Disrupting and Harnessing Dual Pro-Survival Autophagic Responses.
  28. Australian native fruits and vegetables: Chemical composition, nutritional profile, bioactivity and potential valorization by industries.
  29. Natural products: Potential therapeutic agents to prevent skeletal muscle atrophy.
  30. Quercetin loaded folate targeted plasmonic silver nanoparticles for light activated chemo-photothermal therapy of DMBA induced breast cancer in Sprague Dawley rats.
  31. An efficient photothermal-chemotherapy platform based on a polyacrylamide/phytic acid/polydopamine hydrogel.
  32. Epigallocatechin-3-Gallate Delivery in Lipid-Based Nanoparticles: Potentiality and Perspectives for Future Applications in Cancer Chemoprevention and Therapy.
  33. Nanomaterials in cancer: Reviewing the combination of hyperthermia and triggered chemotherapy.
  34. Dual or multiple drug loaded nanoparticles to target breast cancer stem cells.
  35. Enhanced delivery of theranostic liposomes through NO-mediated tumor microenvironment remodeling.
  36. Stimulus-responsive self-assembled prodrugs in cancer therapy.
  37. Architecting polyelectrolyte hydrogels with Cu-assisted polydopamine nanoparticles for photothermal antibacterial therapy.
  38. Dermal and Transdermal Drug Delivery through Vesicles and Particles: Preparation and Applications.
  39. A Space-Time Conversion Vehicle for Programmed Multi-Drugs Delivery into Pancreatic Tumor to Overcome Matrix and Reflux Barriers.
  40. An updated and comprehensive review on the potential health effects of curcumin-encapsulated micro/nanoparticles.
  41. How Advancing are Mesoporous Silica Nanoparticles? A Comprehensive Review of the Literature.
  42. ROS Modulating Inorganic Nanoparticles: A Novel Cancer Therapeutic Tool.
  43. Disulfur-bridged polyethyleneglycol/DOX nanoparticles for the encapsulation of photosensitive drugs: a case of computational simulations on the redox-responsive chemo-photodynamic drug delivery system.
  44. Oxidative stress-amplified nanomedicine for intensified ferroptosis-apoptosis combined tumor therapy.
  45. Synergistic photothermal-photodynamic-chemotherapy toward breast cancer based on a liposome-coated core-shell AuNS@NMOFs nanocomposite encapsulated with gambogic acid.
  46. Biomimetic Nanoparticle Drug Delivery Systems to Overcome Biological Barriers for Therapeutic Applications.
  47. Engineering Chemotherapeutic-Augmented Calcium Phosphate Nanoparticles for Treatment of Intraperitoneal Disseminated Ovarian Cancer.
  48. Hybrid PEGylated chitosan/PLGA nanoparticles designed as pH-responsive vehicles to promote intracellular drug delivery and cancer chemotherapy.
  49. Self-assembled bilosomes with stimuli-responsive properties as bioinspired dual-tunable nanoplatform for pH/temperature-triggered release of hybrid cargo.
  50. Open-Source and Reduced-Expenditure Nanosystem with ROS Self-Amplification and Glutathione Depletion for Simultaneous Augmented Chemodynamic/Photodynamic Therapy.
  51. Curcumin loaded zinc oxide nanoparticles for activity-enhanced antibacterial and anticancer applications.
  52. H2O2-independent chemodynamic therapy initiated from magnetic iron carbide nanoparticle-assisted artemisinin synergy.
  53. Synchronous Disintegration of Ferroptosis Defense Axis via Engineered Exosome-Conjugated Magnetic Nanoparticles for Glioblastoma Therapy.
  54. Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives.
  55. Exploring the role of senescence inducers and senotherapeutics as targets for anticancer natural products.
  56. Simple weak-acid derivatives of paclitaxel for remote loading into liposomes and improved therapeutic effects.
  57. Use of mesoporous polydopamine nanoparticles as a stable drug-release system alleviates inflammation in knee osteoarthritis.
  58. Photosensitization of pancreatic cancer cells by cationic alkyl-porphyrins in free form or engrafted into POPC liposomes: The relationship between delivery mode and mechanism of cell death.
  59. Ultrasound-mediated delivery of RGD-conjugated nanobubbles loaded with fingolimod and superparamagnetic iron oxide nanoparticles: targeting hepatocellular carcinoma and enhancing magnetic resonance imaging.
  60. Functionalized PAMAM-Based Nanoformulation for Targeted Delivery of 5-Fluorouracil in Hepatocellular Carcinoma.
  61. Natural antioxidants as additional weapons in fight against malarial parasite.
  62. Bromelain Loaded Lipid-Polymer Hybrid Nanoparticles for Oral Delivery: Formulation and Characterization.
  63. Combination of Vitamin C and Curcumin Safeguards Against Methotrexate-Induced Acute Liver Injury in Mice by Synergistic Antioxidant Effects.
  64. Investigation of the Antioxidant Properties of the Quaternized Chitosan Modified with a Gallic Acid Residue Using Peroxidase that Produces Reactive Oxygen Species.
  65. A Possible Antidepressive Effect of Dietary Interventions: Emergent Findings and Research Challenges.
  66. Magnetic mesoporous bioactive glass for synergetic use in bone regeneration, hyperthermia treatment, and controlled drug delivery.
  67. Carrier free nanomedicine for synergistic cancer therapy by initiating apoptosis and paraptosis.
  68. Simultaneous glutamine metabolism and PD-L1 inhibition to enhance suppression of triple-negative breast cancer.
  69. Metabolism in the progression and metastasis of brain tumors.
  70. Rational Molecular Design of Efficient Heavy-Atom-Free Photosensitizers for Cancer Photodynamic Therapy.
  71. Understanding the relevance of protein corona in nanoparticle-based therapeutics and diagnostics.
  72. Activatable cancer sono-immunotherapy using semiconducting polymer nanobodies.
  73. Rational design of yolk-shell nanostructures for drug delivery.
  74. A tumor-microenvironment-responsive nanomaterial for cancer chemo-photothermal therapy.
  75. Effective in vitro delivery of paclitaxel by nanocargo of mesoporous polycaprolactone against triple negative breast cancer cells by minimalizing drug dose.
  76. Doxorubicin delivery performance of superparamagnetic carbon multi-core shell nanoparticles: pH dependence, stability and kinetic insight.
  77. Computational Design of Molecularly Imprinted Polymers in Drug Delivery Systems: A Comprehensive Review.
  78. Fucoidan-Mediated Anisotropic Calcium Carbonate Nanorods of pH-Responsive Drug Release for Antitumor Therapy.
  79. Recent Advances in Transition-Metal Based Nanomaterials for Noninvasive Oncology Thermal Ablation and Imaging Diagnosis.
  80. Terpenes and terpenoids as main bioactive compounds of essential oils, their roles in human health and potential application as natural food preservatives.
  81. Natural polysaccharide-based biodegradable polymeric platforms for transdermal drug delivery system: a critical analysis.
  82. Surfactin effectively improves bioavailability of curcumin by formation of nano-capsulation.
  83. Near-infrared and metal-free tetra(butylamino)phthalocyanine nanoparticles for dual modal cancer phototherapy.
  84. Folic Acid-Decorated pH-Responsive Nanoniosomes With Enhanced Endocytosis for Breast Cancer Therapy: In Vitro Studies.
  85. Photodynamic diagnosis and photodynamic therapy of colorectal cancer in vitro and in vivo.
  86. Microbial transglutaminase nanoflowers as an alternative nanomedicine for breast cancer theranostics.
  87. Detection of Paraptosis After Photodynamic Therapy.
  88. Photosensitized Oxidation of Intracellular Targets: Understanding the Mechanisms to Improve the Efficiency of Photodynamic Therapy.
  89. The origins of cancer cell dormancy.
  90. Photodynamic Treatments for Disseminated Cancer Metastases Using Fiber-Optic Technologies.
  91. Polysaccharide-Based Theranostic Systems for Combined Imaging and Cancer Therapy: Recent Advances and Challenges.
  92. Folic Acid and Chitosan-Functionalized Gold Nanorods and Triangular Silver Nanoplates for the Delivery of Anticancer Agents.
  93. Sphingomyelin-based PEGylation Cu(DDC)2 Liposomes Prepared via the Dual Function of Cu2+ for Cancer Therapy: Facilitating DDC Loading and Exerting Synergistic Antitumor Effects.
  94. Drug Self-delivery Nanorods Enhance Photodynamic Therapy of Triple-Negative Breast Cancer by inhibiting Oxidative Phosphorylation.
  95. The Antioxidant, Anti-Inflammatory and Immunomodulatory Effects of Camel Milk.
  96. Sulfobetaine methacrylate-functionalized graphene oxide-IR780 nanohybrids aimed at improving breast cancer phototherapy.
  97. Promising role of polymeric nanoparticles in the treatment of rheumatoid arthritis.
  98. SWCNT-porphyrin nano-hybrids selectively activated by ultrasound: an interesting model for sonodynamic applications.
  99. Recent developments in industrial applications of nanoemulsions.
  100. Xanthan gum derivatives: review of synthesis, properties and diverse applications.
  101. Development and evaluation of a pH-responsive and water-soluble drug delivery system based on smart polymer coating of graphene nanosheets: an in silico study.
  102. Size and Shape Directed Novel Green Synthesis of Plasmonic Nanoparticles Using Bacterial Metabolites and Their Anticancer Effects.
  103. The Challenge to Deliver Oxaliplatin (l-OHP) to Solid Tumors: Development of Liposomal l-OHP Formulations.
  104. Pharmacological and natural products diversity of the brown algae genus Sargassum.
  105. Effect of glycated HDL on oxidative stress and cholesterol homeostasis in a human bladder cancer cell line, J82.
  106. The bioactive components as well as the nutritional and health effects of sea buckthorn.
  107. No Back-up Plan: Loss of Isozyme Diversity as a Promising Therapeutic Strategy for Cancer.
  108. Acute acne flare following isotretinoin administration successfully treated by 5-aminolevulinic acid photodynamic therapy.
  109. Analgesic and Anti-Inflammatory Properties of Two Hydrogel Formulations Comprising Polyherbal Extract.
  110. Strategies for Improving Photodynamic Therapy Through Pharmacological Modulation of the Immediate Early Stress Response.
  111. KRAS Mutations in Colorectal Cancer: Relationship With Clinicopathological Characteristics and Impact on Clinical Outcomes in Saudi Arabia.
  112. Low Intensity Ultrasound as an Antidote to Taxane/Paclitaxel-induced Cytotoxicity.
  113. A Comprehensive Insight into the Phytochemical, Pharmacological Potential, and Traditional Medicinal Uses of Albizia lebbeck (L.) Benth.
  114. Pharmacological Properties of Bergapten: Mechanistic and Therapeutic Aspects.
  115. Salvianolic Acid B Suppresses Non-Small-Cell Lung Cancer Metastasis through PKM2-Independent Metabolic Reprogramming.
  116. Natural deep eutectic solvent supported targeted solid-liquid polymer carrier for breast cancer therapy.
  117. Natural terpenoids with anti-inflammatory activities: Potential leads for anti-inflammatory drug discovery.
  118. Recent progress in the early detection of cancer based on CD44 biomarker; nano-biosensing approaches.
  119. Fabrication, physicochemical characterization and In vitro anticancer activity of nerolidol encapsulated solid lipid nanoparticles in human colorectal cell line.
  120. Cytotoxicity of Metal-Based Photoactivated Chemotherapy (PACT) Compounds.
  121. Formulation development, in vitro and in vivo evaluation of chitosan engineered nanoparticles for ocular delivery of insulin.
  122. Emerging Strategies in Enhancing Singlet Oxygen Generation of Nano-Photosensitizers Toward Advanced Phototherapy.
  123. Nanozyme-natural enzymes cascade catalyze cholesterol consumption and reverse cancer multidrug resistance.
  124. Solid Lipid Nanoparticles of Lepidium Sativum L Seed Extract: Formulation, Optimization and In vitro Cytotoxicity Studies.
  1. Front Chem. 2022 ;10 850757
    Recent Developments of Nanostructures for the Ocular Delivery of Natural Compounds.
    Malihe Sadat Razavi, Pedram Ebrahimnejad, Yousef Fatahi, Antony D'Emanuele, Rassoul Dinarvand.
      Ocular disorders comprising various diseases of the anterior and posterior segments are considered as the main reasons for blindness. Natural products have been identified as potential treatments for ocular diseases due to their anti-oxidative, antiangiogenic, and anti-inflammatory effects. Unfortunately, most of these beneficial compounds are characterised by low solubility which results in low bioavailability and rapid systemic clearance thus requiring frequent administration or requiring high doses, which hinders their therapeutic applications. Additionally, the therapeutic efficiency of ocular drug delivery as a popular route of drug administration for the treatment of ocular diseases is restricted by various anatomical and physiological barriers. Recently, nanotechnology-based strategies including polymeric nanoparticles, micelles, nanofibers, dendrimers, lipid nanoparticles, liposomes, and niosomes have emerged as promising approaches to overcome limitations and enhance ocular drug bioavailability by effective delivery to the target sites. This review provides an overview of nano-drug delivery systems of natural compounds such as thymoquinone, catechin, epigallocatechin gallate, curcumin, berberine, pilocarpine, genistein, resveratrol, quercetin, naringenin, lutein, kaempferol, baicalin, and tetrandrine for ocular applications. This approach involves increasing drug concentration in the carriers to enhance drug movement into and through the ocular barriers.
    Keywords:  eye; nanoparticles; nanotechnology; natural products; ocular drug delivery
    DOI:  https://doi.org/10.3389/fchem.2022.850757
  2. RSC Adv. 2020 Jun 24. 10(41): 24624-24630
    Curcumin-loaded PEGylated mesoporous silica nanoparticles for effective photodynamic therapy.
    Gaizhen Kuang, Qingfei Zhang, Shasha He, Ying Liu.
      Curcumin (Cur) can be used as a photosensitizer in the photodynamic therapy (PDT) of cancer, but its low bioavailability limits further clinical application. A mesoporous silica-based drug delivery system (PEGylated mesoporous silica nanoparticles, MSN-PEG@Cur) was designed to solve the problem. The successful preparation of MSN-PEG@Cur was characterized by several physico-chemistry techniques. The endocytosis, ROS generation and in vitro anti-cancer efficacy of MSN-PEG@Cur were evaluated in detail step by step. The results indicated that MSN-PEG@Cur could be effectively endocytosed into cells and release Cur, which can promptly generate ROS upon irradiation, achieving effective PDT in cancer treatment. This MSNs-based drug delivery system provides an alternative strategy for Cur loading and PDT of cancer.
    DOI:  https://doi.org/10.1039/d0ra04778c
  3. Curr Drug Metab. 2022 Apr 27.
    Phytofabricated Nanoparticle Formulation For Cancer Treatment: A Comprehensive Review.
    Mahima Verma, Shireen Fatima, Irfan Ahmad Ansari.
      Nanotechnology is the science of the nanoscale, which is one billionth of a metre in size. Nanotechnology is a broad term that refers to a variety of technologies, materials, and production methods that are used to create and/or improve a variety of goods, including pharmaceuticals. In recent times, this technique has made significant development in the field of cancer. The majority of chemotherapeutic drugs are not selective to the cancer cells they are supposed to cure, and they might cause side effects and damage to healthy cells, resulting in a variety of negative effects. Having a thorough understanding of nanoparticles may hold the key to improve medication targeting and administration. Nano-engineering of pharmacological and natural compounds can improve diagnosis and treatment. Polymeric micelles, Liposomes, and dendrimers are examples of innovative cancer therapeutic nano-formulations. It has been demonstrated that quantum dots, nano-suspensions, and gold nanoparticles can improve delivery. The nanomedicines may be delivered more effectively, focusing on cancerous cells instead of healthy tissue, which minimizes undesirable side effects and drug resistance to chemotherapeutic agents. However, limited water solubility, low stability, poor absorption, and quick metabolism limit their therapeutic effectiveness. Nanotechnology has generated unique formulations to optimise the potential use of phytochemicals in anticancer therapy. Nanocomposites can improve phytochemical solubility and bioavailability, extend their half-life in the circulation, and even transport phytochemicals to specific locations. The progress in using phytochemical based nanoparticles in cancer treatment is summarized in this paper.
    Keywords:  Anti-cancerous; multidrug resistance; nanoparticles.; nanotechnology; phytochemical
    DOI:  https://doi.org/10.2174/1389200223666220427101427
  4. Mol Pharm. 2022 May 02.
    Research Progress on Nanoplatforms and Nanotherapeutic Strategies in Treating Glioma.
    Li Qiao, Huishu Yang, Xin-Xin Shao, Qiuyan Yin, Xian-Jun Fu, Qingcong Wei.
      Glioma is the most common and aggressive primary intracranial tumor within the central nervous system. The blood-brain barrier (BBB) has been a great hurdle for an effective glioma treatment. To effectively treat glioma, various strategies have been applied to deliver drugs to the brain by crossing the BBB. Nanocarrier-mediated drug delivery is emerging as an effective and noninvasive system to treat glioma, showing great potential in glioma therapy. In this review, we will provide a comprehensive overview on nanocarrier-mediated drug delivery and related glioma therapy. Following an initial overview of the BBB and blood-brain-tumor barrier (BBTB) structure and characteristics, nanocarrier-mediated drug delivery strategies (liposomes, micelles, inorganic systems, polymeric nanoparticles, nanogel system, biomimetic nanoparticles, and exosomes) for crossing the BBB are discussed. Finally, nanotherapeutic techniques (imaging-mediated chemotherapy, photothermal therapy, photodynamic therapy, gene therapy, immunotherapy, ferroptosis therapy, sonodynamic therapy, chemodynamic therapy, and combination therapy) in treating glioma are summarized. In addition, this review provides some perspectives on the clinical applications of nanomedicines.
    Keywords:  blood−brain barrier; drug delivery; glioma; nanocarrier; nanotherapy
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.1c00856
  5. RSC Adv. 2020 Jul 09. 10(44): 26059-26066
    Doxorubicin-loaded Cu2S/Tween-20 nanocomposites for light-triggered tumor photothermal therapy and chemotherapy.
    Shuwei Liu, Lu Wang, Bin Zhao, Ze Wang, Yinyu Wang, Bin Sun, Yi Liu.
      In clinical tumor therapy, traditional treatments such as surgery, radiotherapy and chemotherapy all have their own limitations. With the development of nanotechnology, new therapeutic methods based on nanomaterials such as photothermal therapy (PTT) have also emerged. PTT takes advantage of the poor thermal tolerance of tumor cells and uses the heat generated by photothermal reagents to kill tumor cells. A transition metal sulfide represented as Cu2S is an ideal photothermal reagent because of its easy preparation, high extinction coefficient and photothermal conversion efficiency. Surface modification of nanoparticles (NPs) is also necessary, which not only can reduce toxicity and improve colloidal stability, but also can provide the possibility of further chemotherapeutic drug loading. In this work, we report the fabrication of Tween-20 (Tw20)-modified and doxorubicin (Dox)-loaded Cu2S NPs (Cu2S/Dox@Tw20 NPs), which significantly improves the performance in tumor therapy. Apart from the enhancement of colloidal stability and biocompatibility, the drug loading rate of Dox in Tw20 reaches 11.3%. Because of the loading of Dox, Cu2S/Dox@Tw20 NPs exhibit chemotherapeutic behaviors and the tumor inhibition rate is 76.2%. Further combined with a near-infrared laser, the high temperature directly leads to the apoptosis of a large number of tumor cells, while the release of chemotherapeutic drugs under heat can not only continue to kill residual tumor cells, but also inhibit tumor recurrence. Therefore, with the combination of PTT and chemotherapy, the tumor was completely eliminated. Both hematological analysis and histopathological analysis proved that our experiments are safe.
    DOI:  https://doi.org/10.1039/d0ra03069d
  6. Pharmacol Res. 2022 May 02. pii: S1043-6618(22)00186-4. [Epub ahead of print] 106241
    Theranostic nanosystem with supramolecular self-assembly for enhanced reactive oxygen species-mediated apoptosis guided by dual-modality tumor imaging.
    Dan Yan, Haili Zhang, Xiao Xu, Chunling Ren, Chao Han, Zhongrui Li.
      With the development of precision medicine, visual and traceable treatments are highly desirable for cancer therapy. However, researchers and clinicians remain confused regarding where the drug distributes and location of the tumor, when the drug is released and when to irradiate the tumor, and how the drug presents antitumor activity, all of which hinders assessment of the cancer patient's condition and formulation of a follow-up treatment scheme for clinicians. Here, a supramolecular self-assembly theranostic nanosystem (MWNs) was designed for enhanced reactive oxygen species (ROS)-mediated cell apoptosis guided by dual-modality tumor imaging. Specifically, merocyanine was introduced in cyanine dye to extend its conjugated π-scaffolds, which could preferentially self-assemble into nanovesicles owing to its amphipathy. Furthermore, withaferin A (WA), used as a chemotherapeutic drug, was loaded to construct MWNs. The assembled or disassembled MWNs behaved differently in photoacoustic (PA) intensity and fluorescence signal intensity. The MWNs exhibited stronger PA signals and quenched fluorescence, which monitors their distribution and images the tumor location in vivo, while the disassembled MWNs showed weak PA signals and recovered fluorescence, indicating the release of drug and instructing the appropriate time to irradiate for photodynamic therapy (PDT). Thus, ROS generation introduced by PDT and released WA led to cell apoptosis. This intelligent nanosystem for precise cancer therapy that reveals where the tumor is, when to irradiate the tumor, and how the tumor is cured might establish the basis for biomedical applications of finely controlled platform.
    Keywords:  Dual-modality tumor imaging; Photodynamic therapy; Reactive oxygen species; Supramolecular self-assembly; Theranostic nanoparticle; Withaferin A
    DOI:  https://doi.org/10.1016/j.phrs.2022.106241
  7. RSC Adv. 2020 May 26. 10(34): 19997-20008
    Highly-controllable drug release from core cross-linked singlet oxygen-responsive nanoparticles for cancer therapy.
    Jiayan Zhou, Chunyang Sun, Chunshui Yu.
      Highly-controllable release consisting of preventing unnecessary drug leakage at physiologically normal tissues and triggering sufficient drug release at tumor sites is the main aim of nanoparticle-based tumor therapy. Developing drug-conjugation strategies with covalent bonds in response to a characteristic stimulus, such as reactive oxygen species (ROS) generated by photodynamic therapy (PDT) has attracted much attention. ROS can not only cause cytotoxicity, but also trigger the cleavage of ROS-responsive linkers. Therefore, it is feasible to design a new model of controlled drug release via the breakage of ROS-responsive linkers and degradation of nanoparticles. The self-supply of the stimulus and highly-controllable drug release can be achieved by encapsulation of photosensitizer (PS) and chemotherapeutic drugs simultaneously without any support of tumor endogenous stimuli. Therefore, we used thioketal (TK) linkers as the responsive linkers due to their reaction with singlet oxygen (1O2, SO), a type of ROS. They were conjugated to the side groups of polyphosphoesters (PPE) via click chemistry to acquire the core cross-linked SO-responsive PPE nanoparticles poly(thioketal phosphoesters) (TK-PPE). TK-PPE coated with the photosensitizer chlorin e6 (Ce6) and chemotherapeutic drug doxorubicin (DOX) simultaneously were prepared and named as TK-PPECe6&DOX. TK-PPECe6&DOX kept stable due to the high stability of the TK-linkers in the normal physiological environment. With self-production of SO as the stimulating factor from the encapsulated Ce6, highly-controlled drug release was achieved. After incubation of tumor cells, 660 nm laser irradiation induced SO generation, resulting in the cleavage of TK-linkers and boosted-release of DOX. Highly-controllable drug release of TK-PPECe6&DOX through self-production of stimulus increased antitumor efficacy, offering a promising avenue for clinical on-demand chemotherapy.
    DOI:  https://doi.org/10.1039/d0ra02053b
  8. J Nanobiotechnology. 2022 May 06. 20(1): 217
    Two-photon responsive porphyrinic metal-organic framework involving Fenton-like reaction for enhanced photodynamic and sonodynamic therapy.
    Wenyao Duan, Bo Li, Wen Zhang, Jiaqi Li, Xin Yao, Yupeng Tian, Jun Zheng, Dandan Li.
      Designing new oxygenation nanomaterials by oxygen-generating or oxygen-carrying strategies in hypoxia-associated anti-tumor therapy is a high priority target yet challenge. In this work, we fabricated a nanoplatform involving Fenton-like reaction, Pd@MOF-525@HA, to relieve tumor hypoxia via oxygen-generating strategy for enhanced oxygen-dependent anti-tumor therapy. Thereinto, the porphyrinic MOF-525 can produce singlet oxygen (1O2) via light or ultrasonic irradiation for photodynamic and sonodynamic therapy. Notably, the well-dispersed Pd nanocubes within MOF-525 can convert H2O2 into O2 to mitigate the hypoxic environment for enhanced therapy outcome. Moreover, the two-photon activity and cancer cell specific targeting capability of Pd@MOF-525@HA gave rise to deeper tissue penetration and near-infrared light-induced fluorescence imaging to achieve precise guidance for cancer therapy. This work provides a feasible way in designing new oxygenation nanomaterials to relieve tumor hypoxia for enhanced cancer treatment.
    Keywords:  Hypoxia; Metal-organic framework; Photodynamic therapy; Sonodynamic therapy; Two-photon
    DOI:  https://doi.org/10.1186/s12951-022-01436-3
  9. ACS Appl Mater Interfaces. 2022 May 05.
    Dual Inhibitions on Glucose/Glutamine Metabolisms for Nontoxic Pancreatic Cancer Therapy.
    Yingying Xu, Zhiguo Yu, Hao Fu, Yuedong Guo, Ping Hu, Jianlin Shi.
      Glucose and glutamine are two principal nutrients in mammalian cells that provide energy and biomass for cell growth and proliferation. Especially in cancer cells, glutamine could be a main alternative for energy and biomass supply once glucose metabolism is suppressed. Therefore, single inhibition of enzymes in either glucose metabolism or glutaminolysis, though maybe efficient in vitro, is far from being satisfactory for efficient in vivo cancer therapy. Here, we proposed a new strategy for dual inhibitions on both glucose and glutamine metabolisms concurrently by silencing mutated gene Kras and glutaminase 1 (GLS1) via nanomaterial-based siKras and siGLS1 delivery, rather than conventional highly toxic chemodrugs. Such a combination therapy could overcome the challenge that glucose and glutamine are alternatives to each other in the biosynthesis and energy production for cancer cells, resulting in much elevated treatment efficacy. In addition, layered double hydroxide (LDH), the siRNA carrier, enables an enhanced gene delivery efficiency compared to the commercial transfection agent Lipofectamine 2000. Briefly, Mg-Al LDH nanosheets, loaded with siKras and siGLS1 onto their surfaces by electrostatic adsorption, could release siRNA from lysosomes into the cytoplasm via the proton sponge effect of LDH, favoring the siRNA stability and gene silencing efficiency enhancements. The thus released siRNA could downregulate the expressions of Kras, GLS1, and other enzymes involved in glucose metabolism, resulting in the downregulations of ATP and other metabolites. Such a biosafe LDH/siRNA nanomedicine is able to efficiently suppress the growth of xenografts through cancer cell proliferation suppression, displaying its great potential as a simultaneous glucose/glutamine metabolism coinhibitor for treating pancreatic cancer.
    Keywords:  GLS1; Kras; glucose metabolism inhibition; glutamine metabolism inhibition; layered double hydroxide nanoparticles; pancreatic cancer; siRNA
    DOI:  https://doi.org/10.1021/acsami.2c00111
  10. Colloids Surf B Biointerfaces. 2022 Apr 28. pii: S0927-7765(22)00209-0. [Epub ahead of print]215 112526
    Hypoxia responsive and tumor-targeted mixed micelles for enhanced cancer therapy and real-time imaging.
    Ying Xu, Peng Chen, Lei Tang, Xiaojun Zhang, Feng Shi, Xuyang Ning, Jingli Bi, Yang Qu, Hongfei Liu.
      Most chemotherapy agents have serious side effects due to lack of tumor targeting, which affects their clinical application. In addition, as an essential characteristic of malignant tumor, hypoxia is attracting exclusive research focus regarding its non-invasive real-time tracing in novel targeting delivery system. Herein, we designed a mixed micelle with tumor targeting and hypoxia responsiveness for tumor therapy and imaging. In particular, the dual-modified mix micelles were self-assembled by folic acid (FA) and 2-(2-nitroimidazole) ethylamine (NI) conjugated polymers, in which paclitaxel (PTX) and quantum dots (QDs) were co-loaded into the hydrophobic core. The drug loaded micelles showed satisfactory drug encapsulation, good storage stability, and sustained release properties. In vitro cell experiments showed that the mixed micelles exhibited enhanced cytotoxic effect and improved the cellular uptake, especially under hypoxic conditions, which was due to the FA mediated active targeting effect and NI induced hypoxic responsive release. In vivo experiments further proved that the mixed micelles possessed outstanding tumor targeting and hypoxia responsive properties. Furthermore, the drug loaded micelles showed excellent anti-tumor effect and can realize real-time in vivo imaging. This work demonstrates that the dual-modified mixed micelles co-loading with PTX and QDs might provide a novel approach for tumor therapy and imaging.
    Keywords:  Hypoxia responsiveness; Paclitaxel; Quantum dots; Real-time imaging; Targeted deliver
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112526
  11. RSC Adv. 2021 Nov 10. 11(58): 36920-36927
    Solvothermal synthesis of Nb-doped TiO2 nanoparticles with enhanced sonodynamic effects for destroying tumors.
    Wenjie Sun, Xiaojuan Dong, Pingping Huang, Jia Shan, Lei Qi, Jun Zhou.
      Titania (TiO2) nanomaterials have been proved to be biocompatible sonosensitizers for sonodynamic therapy (SDT) of various cancer cells, while they suffer from weak sonodynamic effects due to fast combination of excited carriers. In this work, to improve the therapeutic efficiency, we prepared PEGylated Nb-doped TiO2 (TiO2-x :Nb) nanoparticles by a simple solvothermal method and a subsequent surface modification process. The TiO2-x :Nb nanoparticles exhibited an average size of 11 nm and a polydisperse index of 0.12. The Nb doping had no obvious effect on the phase of TiO2 matrixes but released electrons to the conduction band of TiO2, resulting in high concentrations of deficiencies. As a result, the TiO2-x :Nb nanoparticles exhibited a higher efficiency of singlet oxygen (1O2) generation than that of pure TiO2 nanoparticles upon ultrasound irradiation. Importantly, the TiO2-x :Nb nanoparticles had high biocompatibility similar to pure TiO2 nanoparticles, while they could efficiently produce cytotoxic 1O2 to destroy cancer cells in vitro in comparison to the partially destroyed cancer cells by pure TiO2 nanoparticles upon ultrasound irradiation. More importantly, the TiO2-x :Nb nanoparticles displayed obvious tumor cellular injury in tumor-bearing mice in vivo through high SDT effects. Therefore, the synthesized PEGylated TiO2-x :Nb nanoparticles in this study exhibited higher therapeutic effects of SDT than that of the pure TiO2 nanoparticles, and the doping strategy would provide some insights for tuning traditional weak sonosensitizers into efficient ones.
    DOI:  https://doi.org/10.1039/d1ra06548c
  12. J Cancer Res Clin Oncol. 2022 May 06.
    The biological activities of 5,15-diaryl-10,20-dihalogeno porphyrins for photodynamic therapy.
    Man Yi Li, Le Mi, Gennady Meerovich, Thin Wut Soe, Ting Chen, Ni Ni Than, Yi Jia Yan, Zhi Long Chen.
      PURPOSE: Esophageal cancer is the most common gastrointestinal tumor and is difficult to be eradicated with conventional treatment. Porphyrin-based photosensitizers (PSs) mediated photodynamic therapy (PDT) could kill tumor cells with less damage to normal cells. As the most widely used porphyrin-based photosensitizer in clinics, Photofrin II has excellent anti-tumor effect. However, it has some disadvantages such as weak absorption at near infrared region, the complexity of components and prolonged skin photosensitivity. Here series novel 5,15-diaryl-10,20-dihalogeno porphyrin derivatives were afforded and evaluated to develop more effective and safer photosensitizers for tumor therapy.METHODS: The photophysical properties and singlet oxygen generation rates of 5,15-diaryl-10,20-dihalogeno porphyrins (I1-6, II1-4) were tested. The cytotoxicity of I1-6 and II1-4 were measured by MTT assay. The pathway of cell death was studied by flow cytometry. In vivo photodynamic efficacy of I3 and II2-4 in Eca-109 tumor-bearing BABL/c nude mice were measured and histopathological analysis were examined.
    RESULTS: 5,15-Diaryl-10,20-dihalogeno porphyrins I1-6 and II1-4 were synthesized. The longest absorption wavelength of these halogenated porphyrins (λmax = 660 nm) displayed a red shift around 30 nm compared to the unhalogenated porphyrins PS1 (λmax = 630 nm). The singlet oxygen generation rates of I1-6 and II1-4 were significantly higher than PS1 and HMME. All PSs mediated PDT showed obvious cytotoxic effect against Eca-109 cells compared to HMME in vitro and in vivo. Among these PSs, II4 exhibited appropriate absorption in the phototherapeutic window, higher 1O2 generation rate (k = 0.0061 s-1), the strongest phototoxicity (IC50 = 0.4 μM), lower dark toxicity, high generation of intracellular ROS in Eca-109 cells and excellent photodynamic anti-tumor efficacy in vivo. Besides, cell necrosis was induced by compound II4 mediated PDT.
    CONCLUSION: All new compounds have obvious photodynamic anti-esophageal cancer effects. Among them, the photosensitizer II4 showed excellent efficacy in vitro and in vivo, which has the potential to become a photodynamic anti-tumor drug.
    Keywords:  Anti-tumor; Halogenated porphyrin; Photodynamic therapy; Photosensitizer
    DOI:  https://doi.org/10.1007/s00432-022-04037-7
  13. RSC Adv. 2022 Apr 22. 12(20): 12860-12870
    An in vitro investigation of the hepatic toxicity of PEGylated polymeric redox responsive nanoparticles.
    Leagh G Powell, Cameron Alexander, Vicki Stone, Helinor J Johnston, Claudia Conte.
      It can be challenging to deliver drugs to cancer cells in a targeted manner at an effective dose. Polymeric nanoparticles (NPs) are promising drug delivery systems that can be targeted to cancer cells using redox responsive elements. More specifically, intracellular and extracellular levels of the antioxidant glutathione (GSH) are elevated in cancer cells and therefore the use of NPs with a cleavable GSH-responsive element allowing these NPs to target cancer cells and trigger the release of their cargo (e.g. anticancer drugs). The aim of this study was to assess the hepatotoxicity of polymeric NP delivery systems with and without a redox sensitive element. Copolymer poly (lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) NPs with (RR-NPs) and without (nRR-NPs) a redox responsive dithiylethanoate ester linker were synthesised and their toxicity assessed in vitro. As the liver is a primary site of NP accumulation, the C3A hepatocyte cell line was used to assess NP toxicity in vitro via investigation of cytotoxicity, cytokine production, genotoxicity, intracellular reactive oxygen species (ROS) production, intracellular calcium concentration, and hepatocyte function (albumin and urea production). The cellular uptake of NPs was also assessed as this may influence the cellular dose and, therefore, the cellular response. Both NPs had no detrimental impact on cell viability. However, both NPs stimulated an increase in cytokine (IL-1ra) and ROS production and decreased hepatocyte function, with the greatest effect observed for nRR-NPs. Only nRR-NPs caused DNA damage. Cells internalised both NPs and caused a (sub-lethal) increase in intracellular calcium levels. Therefore, whilst the NPs did not have a negative impact on cell viability, the NPs were able to elicit sub-lethal toxicity. By using a battery of tests we were able to demonstrate that RR-NPs may be less toxic than nRR-NPs. Our findings can therefore feed into the development of safer and more effective nanomedicines and into the design of testing strategies to assess polymeric NP safety based on knowledge of their mechanism of toxicity.
    DOI:  https://doi.org/10.1039/d2ra00395c
  14. J Mater Chem B. 2022 May 06.
    Lipid-coated CaCO3-PDA nanoparticles as a versatile nanocarrier to enable pH-responsive dual modal imaging-guided combination cancer therapy.
    XinXing Ma, Chunjie Wang, Ziliang Dong, Chunhong Hu, Liangzhu Feng.
      Development of an intelligent and versatile delivery system to achieve tumor-targeted delivery and controlled release of diverse functional moieties is of great significance to realize precise cancer theranostics. In this study, we use pH-dissociable calcium carbonate-polydopamine (pCaCO3) nanocomposites as a template to guide the formation of a lipid bilayer on their surface, yielding lipid-coated pCaCO3 nanoparticles with high loading efficacies towards gadolinium ions (Gd3+), doxorubicin (DOX) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR). The obtained liposomal nanotheranostics show excellent physiological stability and pH-dependent release of DOX and Gd3+; the latter could lead to pH-dependent T1 signal enhancement under magnetic resonance (MR) imaging, as well as efficient photothermal conversion efficacy. Then, we found that tumors in mice with intravenous injection of DiR-DOX-Gd@pCaCO3-PEG could be clearly visualized in a real-time manner by recording their near-infrared (NIR) fluorescence and T1 MR signal. Furthermore, treatment with such liposomal nanotheranostics injection and NIR laser irradiation could enable collective suppression of the growth of 4T1 tumors in Balb/c mice via combined chemo- and photothermal therapies. Therefore, this work highlights the concise preparation of lipid-coated pCaCO3 nanocomposites, which could be utilized for the construction of diverse cancer nanotheranostics by exploiting their versatile loading capacities.
    DOI:  https://doi.org/10.1039/d2tb00022a
  15. J Control Release. 2022 Apr 27. pii: S0168-3659(22)00234-6. [Epub ahead of print]
    A mutually beneficial macrophages-mediated delivery system realizing photo/immune therapy.
    Xiudan Wang, Junya Lu, Yuling Mao, Qinfu Zhao, Caishun Chen, Jianan Han, Meiqi Han, Huijuan Yuan, Siling Wang.
      The accumulation of nanomedicines in tumor tissues determines their therapeutic efficacy. We herein exploit the tropism of macrophages to improve the accumulation and retention time of nanomedicine at tumors. Interestingly, macrophages are not merely as transporters, but killers activated by nanomedicine. The system(M@C-HA/ICG) was established by decorating macrophages with hyaluronic acid-modified hollow mesoporous carbon (C) nanoparticles loading indocyanine green (ICG). Notably, C nanoparticles with superior photothermal conversion capability not merely guarantee the efficient delivery of ICG through high drug loading efficiency and inhibiting the premature leaky, but effectually activate the polarization of macrophages. The results exhibited that those activated macrophages could release pro-inflammatory cytokines (NO, TNF-α, IL-12), while M@C-HA/ICG afforded about 2-fold higher tumor accumulation compared with pure nanoparticle C-HA/ICG and produced heat and singlet oxygen (1O2) under irradiation of an 808 nm laser, realizing the combination of photodynamic therapy (PDT), photothermal therapy (PTT) and cytokines-mediated immunotherapy. Specially, we also investigated the relationship of singlet oxygen (1O2) or temperature and tumor-killing activity for understanding the specific effectual procedure of PDT/PTT synergistic therapy. Overall, we firstly established an "all active" delivery system integrating the features of nanomedicine with biological functions of macrophages, providing a novel insight for cell-mediated delivery platform and tumor targeted multimodality anti-cancer therapy.
    Keywords:  Cell-based delivery; Immunotherapy; Macrophage polarization; Mesoporous carbon nanoparticles; Phototherapy
    DOI:  https://doi.org/10.1016/j.jconrel.2022.04.038
  16. Colloids Surf B Biointerfaces. 2022 Apr 19. pii: S0927-7765(22)00190-4. [Epub ahead of print]216 112507
    Polydopamine-modified ZIF-8 nanoparticles as a drug carrier for combined chemo-photothermal osteosarcoma therapy.
    Xueling Yin, Siyi Ran, Haoyan Cheng, Meng Zhang, Wei Sun, Ying Wan, Chunsheng Shao, Zhihong Zhu.
      Single chemotherapy often causes severe adverse effects and chemoresistance which limits therapeutic efficacy. Recently, combination of chemotherapy with photothermal therapy (PTT) have received broad attention for synergistic treatment of osteosarcoma, ultimately resulting in the enhancement of therapeutic efficacy of anticancer drugs. In this study, we have developed a novel drug delivery system based on polydopamine (pDA)-modified ZIF-8 nanoparticles loaded with methotrexate (MTX) (pDA/MTX@ZIF-8 NPs). Herein, pDA modification avoided the explosive release of the drug, and improved the biocompatibility and near-infrared (NIR) light absorbance performance of nanoparticles. The as-prepared pDA/MTX@ZIF-8 NPs could be used as drug targeting delivery system and simultaneously displayed excellent photothermal effects under NIR irradiation. Biology assays in vitro indicated that the pDA/MTX@ZIF-8 NPs were able to efficiently induce MG63 cell apoptosis through reducing mitochondrial membrane potentials (MMPs), and the introduction of photothermal agents enhanced the antitumor effect and decreased the dose of chemotherapeutic drugs. Moreover, the optimized pDA/MTX@ZIF-8 NPs (40 μg/mL) exhibited better photothermal conversion performance and facilitated tumor cells death. These results triumphantly exhibit that the pDA/MTX@ZIF-8 NPs have a synergistic effect of chemo-photothermal therapy (combination index CI = 0.346) and excellent biocompatibility, which has unexceptionable prospects for the therapy of osteosarcoma.
    Keywords:  Chemotherapy; Methotrexate; Osteosarcoma; Photothermal therapy; Polydopamine
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112507
  17. Adv Sci (Weinh). 2022 May 04. e2200482
    Regulation of Nucleotide Metabolism with Nutrient-Sensing Nanodrugs for Cancer Therapy.
    Xinye Wang, Wen Su, Yongbin Jiang, Fuhao Jia, Wenping Huang, Jie Zhang, Yue Yin, Hai Wang.
      The continual growth of tumor cells requires considerable nutrient consumption. Methotrexate (MTX) is used to treat certain types of cancer by blocking the DNA and RNA productions through interfering one-carbon metabolism and de novo purine and pyrimidine synthesis. However, treatment of MTX may cause many serious adverse effects, which hamper its clinical application. Herein, the authors synthesize ferrous ions, histidine, and MTX assembled nanoparticles (FHM) to deliver MTX at tumor site and enhance the sensitivity of tumor cells to MTX with histidine catabolism. Furthermore, fasting-mimicking diet (FMD) is applied to intervene in the one-carbon metabolism and enhance the cytotoxicity of MTX. Meanwhile, FMD treatment can significantly augment the cellular uptake and tumor accumulation of FHM nanoparticles. Due to the triple inhibitions of the one-carbon metabolism, the proliferation of tumor cells is strongly disturbed, as which is highly replying on DNA and RNA production. Taken together, a 95% lower dose of MTX adopted in combined therapy significantly inhibits the growth of two types of murine tumors without evident systemic toxicity. This strategy may provide a promising nucleotide metabolism-based nanomedicine for cancer therapy.
    Keywords:  biomolecular nanoparticles; cancer therapy; dietary modification; tumor metabolism
    DOI:  https://doi.org/10.1002/advs.202200482
  18. Chem Biol Interact. 2022 May 03. pii: S0009-2797(22)00167-3. [Epub ahead of print] 109962
    The dimerization of methyl vanillate improves its effect against breast cancer cells via pro-oxidant effect.
    Adriano de Souza Pessoa, Cintia Kazuko Tokuhara, Vanessa Svizzero Fakhoury, Ana Lígia Pagnan, Gabriela Silva Neubern de Oliveira, Mariana Liessa Rovis Sanches, Kelly Karina Inacio, Bruna Carolina Costa, Valdecir Farias Ximenes, Rodrigo Cardoso de Oliveira.
      Phenolic phytochemicals are a group of organic compounds with potent antioxidant features but can also act as powerful pro-oxidants. These characteristics are effective in reducing metastatic potential in cancer cells, and this effect has been associated with reactive oxygen species (ROS). Methyl vanillate (MV) and its dimer, methyl divanillate (DMV), are potent antioxidants. In the present study, we investigated the effects of MV and DMV on breast cancer cell lines MCF-7 and MDA-MB-231 and compared the results using the non-tumor cell line HB4a. Our results indicated that the compounds performed a pro-oxidant action, increasing the generation of ROS. DMV decreased the viability cell, showing a higher apoptotic effect and inhibition of proliferation than MV on both cell lines, with significant differences between groups (p < 0.05). Some modulation of NOX4, NOX5, and DUOX were observed, but the results did not correlate with the intracellular production of ROS. The dimer showed more effectivity and pro-oxidant effect than MV, impacting cell line MCF-7 in higher extension than MDA-MB-231. In conclusion, and corroborating with reported works, the dimerization of natural phenolic compounds was associated with improved beneficial biological effects as a potential cytotoxic agent to tumor cells.
    Keywords:  Methyl Vanillate; Methyl divanillate; Pro-oxidant
    DOI:  https://doi.org/10.1016/j.cbi.2022.109962
  19. RSC Adv. 2020 Sep 16. 10(57): 34517-34526
    Improved therapeutic efficacy of quercetin-loaded polymeric nanoparticles on triple-negative breast cancer by inhibiting uPA.
    Yang Zhou, Dan Chen, Guangpu Xue, Shujuan Yu, Cai Yuan, Mingdong Huang, Longguang Jiang.
      Triple negative breast cancer (TNBC) is one kind of breast cancer that demonstrates highly aggressive tumor biology. The high heterogeneity of TNBC makes its individual clinical treatment extremely blind and limited, which also introduces more challenges into the diagnosis and treatment of diseases. Urokinase-type plasminogen activator (uPA) is a high level marker for breast cancer, which mediates tumor growth and metastasis. Quercetin is a plant-derived flavonoid in many plants, which inhibits uPA and has low bioavailability and mediocre pharmaceutical efficacy. Thus, we herein developed polymeric nanoparticulate systems from PLGA-TPGS (Qu-NPs) for quercetin oral delivery and evaluated the anticancer effect of this formulation on TNBC in vitro and in vivo. Qu-NPs have a uniform spherical morphology with a mean diameter of 198.4 ± 7.8 nm and good drug loading capacity (8.1 ± 0.4%). Moreover, Qu-NPs exhibited significantly improved inhibition on the growth and metastasis in TNBC cells. Following oral gavage, a remarkable antitumor effect of Qu-NPs on 4T1-bearing mice was observed with a tumor inhibition ratio of 67.88% and fewer lung metastatic colonies. Furthermore, the inhibitory effect of quercetin on the migration of uPA knockdown MDA-MB231 cells was greatly attenuated. Together, Qu-NPs improved the significant antitumor and antimetastatic effects by inhibiting uPA, which provides a new strategy for the treatment of TNBC.
    DOI:  https://doi.org/10.1039/d0ra04231e
  20. Future Med Chem. 2022 May 03.
    An emerging role of KRAS in biogenesis, cargo sorting and uptake of cancer-derived extracellular vesicles.
    Zhijack Fong, Wai-Leng Lee.
      Extracellular vesicles (EVs) are nanovesicles secreted for intercellular communication with endosomal network regulating secretion of small EVs (or exosomes) that play roles in cancer progression. As an essential oncoprotein, Kirsten rat sarcoma virus (KRAS) is tightly regulated by its endosomal trafficking for membrane attachment. However, the crosstalk between KRAS and EVs has been scarcely discussed despite its endocytic association. An overview of the oncogenic role of KRAS focusing on its correlation with cancer-associated EVs should provide important clues for disease prognosis and inspire novel therapeutic approaches for treating KRAS mutant cancers. Therefore, this review summarizes the relevant studies that provide substantial evidence linking KRAS mutation to EVs and discusses the oncogenic implication from the aspects of biogenesis, cargo sorting, and release and uptake of the EVs.
    Keywords:  KRAS; cancer; exosome; extracellular vesicle; intercellular signaling
    DOI:  https://doi.org/10.4155/fmc-2021-0332
  21. Methods Mol Biol. 2022 ;2451 285-403
    Inhibition of the HIF-1 Survival Pathway as a Strategy to Augment Photodynamic Therapy Efficacy.
    Photodynamic Therapy Study Group
      Photodynamic therapy (PDT) is a non-to-minimally invasive treatment modality that utilizes photoactivatable drugs called photosensitizers to disrupt tumors with locally photoproduced reactive oxygen species (ROS). Photosensitizer activation by light results in hyperoxidative stress and subsequent tumor cell death, vascular shutdown and hypoxia, and an antitumor immune response. However, sublethally afflicted tumor cells initiate several survival mechanisms that account for decreased PDT efficacy. The hypoxia inducible factor 1 (HIF-1) pathway is one of the most effective cell survival pathways that contributes to cell recovery from PDT-induced damage. Several hundred target genes of the HIF-1 heterodimeric complex collectively mediate processes that are involved in tumor cell survival directly and indirectly (e.g., vascularization, glucose metabolism, proliferation, and metastasis). The broad spectrum of biological ramifications culminating from the activation of HIF-1 target genes reflects the importance of HIF-1 in the context of therapeutic recalcitrance. This chapter elaborates on the involvement of HIF-1 in cancer biology, the hypoxic response mechanisms, and the role of HIF-1 in PDT. An overview of inhibitors that either directly or indirectly impede HIF-1-mediated survival signaling is provided. The inhibitors may be used as pharmacological adjuvants in combination with PDT to augment therapeutic efficacy.
    Keywords:  Hypoxia-inducible factor 1; Pharmacology, Inhibitor; Photobiology and photochemistry; Survival signaling; Tumor biology and biochemistry
    DOI:  https://doi.org/10.1007/978-1-0716-2099-1_19
  22. RSC Adv. 2020 Jul 15. 10(45): 26742-26751
    Tumor microenvironment triggered biodegradation of inorganic nanoparticles for enhanced tumor theranostics.
    Weitao Yang, Suhong Yang, Liping Jiang, Yujuan Zhou, Cuiling Yang, Cuijun Deng.
      Inorganic nanoparticles (NPs)-mediated tumor theranostics have attracted widespread attention due to their unique physicochemical properties, such as optical, electrical, magnetic, and thermal properties. In the past decade, great advancements have been made in inorganic NPs-associated drug delivery, multimodal tumor imaging, and tumor therapy. However, the potential toxicity of inorganic NPs due to their low biodegradability, background signals interference and treatment side effects limit their clinical application. Therefore, developing biodegradable and intelligent NPs is beneficial to avoid excessive metal ions deposition, specific tumor imaging and treatment. In this review, we summarize the recent advances in tumor microenvironment (TME)-triggered biodegradation of inorganic NPs accompanied by imaging signal amplification and the released ions-mediated tumor therapy. First, the feature characteristics of the TME are introduced, including mild acidity, hypoxia, overexpressed reactive oxygen species (ROS), glutathione (GSH), and enzymes et al.; then, the biodegradation of NPs in a TME-induced activation of imaging signals, such as magnetic resonance (MR) imaging and fluorescence imaging is described; furthermore, tumor therapies through "Fenton", "Fenton-like" reactions, and interference of biological effects in cells is presented. Finally, the challenges and outlook for improving the degradation efficiency, imaging, specificity and efficiency of tumor imaging and treatment are discussed.
    DOI:  https://doi.org/10.1039/d0ra04651e
  23. Drug Des Devel Ther. 2022 ;16 1255-1272
    The Emerging Potential of Parthenolide Nanoformulations in Tumor Therapy.
    Tao An, Huanhuan Yin, Yanting Lu, Feng Liu.
      Plant-derived sesquiterpene lactones are promising natural sources for the discovery of anti-cancer drugs. As an extensively studied sesquiterpene lactone, the tumor suppression effect of parthenolide (PTL) has been clarified by targeting a number of prominent signaling pathways and key protein regulators in carcinogenesis. Notably, PTL was also the first small molecule reported to eradicate cancer stem cells. Nevertheless, the clinical application of PTL as an antitumor agent remains limited, owing to some disadvantages such as low water solubility and poor bioavailability. Thus, nanomedicine has attracted much interest because of its great potential for transporting poorly soluble drugs to desired body sites. In view of the significant advantages over their free small-molecule counterparts, nanoparticle delivery systems appear to be a potential solution for addressing the delivery of hydrophobic drugs, including PTL. In this review, we summarized the key anticancer mechanisms underlined by PTL as well as engineered PTL nanoparticles synthesized to date. Therefore, PTL nanoformulations could be an alternative strategy to maximize the therapeutic value of PTL.
    Keywords:  cancer therapy; cellular processes; nanomedicine; parthenolide; signaling pathways
    DOI:  https://doi.org/10.2147/DDDT.S355059
  24. ChemMedChem. 2022 May 04.
    Excited state and reactive oxygen species against cancer and pathogens: a review on sonodynamic and sono-photodynamic therapy.
    Marcin Wysocki, Beata Czarczynska-Goslinska, Daniel Ziental, Maciej Michalak, Emre Güzel, Lukasz Sobotta.
      Photodynamic and sonodynamic therapy are therapies having great potential in the treatment of bacterial infections and cancer. Their background is associated with photo- and sonosensitizers - substances that can be excited when exposed to light or ultrasound. These sensitizers belong to a variety of compounds groups, including porphyrins, porphyrazines, and phthalocyanines. Releasing the energy when returning to the ground state can occur in the manner of transferring it to oxygen molecules, leading to reactive oxygen species able to disrupt membranes of bacterial and cancer cells, leaving the organism's cells unaffected. In recent years, the number of reports on numerous sensitizers being effective has been constantly growing. Therefore, the development of this field may prove beneficial for dealing with cancer and microbes. This review describes the development of photodynamic and sonodynamic therapy, as well as their combination, with emphasize on sonodynamic therapy and its potential in the treatment of cancer and bacterial infections.
    Keywords:  Singlet oxygen * Porphyrinoids * Sensitizers * Cancer * Pathogens * Antitumor agents * Nanoparticles
    DOI:  https://doi.org/10.1002/cmdc.202200185
  25. Crit Rev Food Sci Nutr. 2022 May 02. 1-30
    Chemico-biological aspects of (-)-epigallocatechin-3-gallate (EGCG) to improve its stability, bioavailability and membrane permeability: Current status and future prospects.
    Revathy Sahadevan, Satyam Singh, Anupama Binoy, Sushabhan Sadhukhan.
      Natural products have been a bedrock for drug discovery for decades. (-)-Epigallocatechin-3-gallate (EGCG) is one of the widely studied natural polyphenolic compounds derived from green tea. It is the key component believed to be responsible for the medicinal value of green tea. Significant studies implemented in in vitro, in cellulo, and in vivo models have suggested its anti-oxidant, anti-cancer, anti-diabetic, anti-inflammatory, anti-microbial, neuroprotective activities etc. Despite having such a wide array of therapeutic potential and promising results in preclinical studies, its applicability to humans has encountered with rather limited success largely due to the poor bioavailability, poor membrane permeability, rapid metabolic clearance and lack of stability of EGCG. Therefore, novel techniques are warranted to address those limitations so that EGCG or its modified analogs can be used in the clinical setup. This review comprehensively covers different strategies such as structural modifications, nano-carriers as efficient drug delivery systems, synergistic studies with other bioactivities to improve the chemico-biological aspects (e.g., stability, bioavailability, permeability, etc.) of EGCG for its enhanced pharmacokinetics and pharmacological properties, eventually enhancing its therapeutic potentials. We think this review article will serve as a strong platform with comprehensive literature on the development of novel techniques to improve the bioavailability of EGCG so that it can be translated to the clinical applications.
    Keywords:  (−)-Epigallocatechin-3-gallate; anti-bacterial; anti-cancer; anti-oxidant; anti-viral; bioavailability; green tea; membrane permeability; nano-carriers; polyphenol; pro-oxidant; stability
    DOI:  https://doi.org/10.1080/10408398.2022.2068500
  26. Curr Pharm Des. 2022 May 06.
    Strategies of targeting KRAS, challenging drug target.
    Abdul Wadood, Amar Ajmal, Ashfaq Ur Rehman.
      In the developed world, cancer is the most common cause of death. Among the 36 human genes of the RAS family, KRAS, NRAS, and HRAS play a prominent role in human cancer. KRAS belongs to the Rassuperfamily of proteins and is a small GTPase signal transduction protein. Among the RAS isoform, KRAS is the dominant mutant that induced approximately 86% of the RAS mutations. The most frequently mutated KRAS isoform is KRAS4B, about 90% of pancreatic cancer, 30-40% of colon cancer, and 15 to 20% of lung cancers are caused by mutations KRAS4B isoform. Liver cancer, bladder cancer, breast cancer, and myeloid leukaemia are also caused by mutations in KRAS but are rare. Currently, no FDA-approved drugs are available for KRAS-driven cancer. As the RAS proteins lack a right pocket accessible to the chemical inhibitors, the cancer-causing mutant proteins are almost identical to their essential wild-type counterparts. Therefore, it was considered undruggable. The structure and function of new insights in RAS have changed this understanding and encouraged the development of many drug candidates. This review provides information about the different strategies of targeting KRAS, a challenging drug target that might be valuable for the scientific community.
    Keywords:  KRAS oncogene; KRAS signalling; KRAS structure; KRAS4B isoform; drug target; targeted therapy
    DOI:  https://doi.org/10.2174/1381612828666220506144046
  27. ACS Appl Mater Interfaces. 2022 May 04.
    Enhanced Cancer Starvation Therapy Enabled by an Autophagy Inhibitors-Encapsulated Biomimetic ZIF-8 Nanodrug: Disrupting and Harnessing Dual Pro-Survival Autophagic Responses.
    Fenglan Li, Tao Chen, Fang Wang, Jinfa Chen, Yuanyuan Zhang, Danting Song, Ning Li, Xin-Hua Lin, Lisen Lin, Junyang Zhuang.
      Autophagy is an important protective mechanism in maintaining or restoring cell homeostasis under physiological and pathological conditions. Nanoparticles (NPs) with certain components and morphologies can induce autophagic responses in cancer cells, providing a new perspective for establishing cancer therapy strategies. Herein, a novel nanodrug system, cell membranes-coated zeolitic imidazolate framework-8 (ZIF-8) NPs encapsulating chloroquine (CQ) and glucose oxidase (GOx) (defined as mCG@ZIF), is designed to achieve an enhanced anticancer effect with the combination of starvation therapy and an autophagy regulation strategy. It is found that ZIF-8 as a nanocarrier can induce autophagy to promote survival of cancer cells via the upstream Zn2+-stimulated mitochondrial reactive oxygen species (ROS) so that the anticancer effect is directly achieved by inhibiting this pro-survival autophagy using CQ released from mCG@ZIF under a tumor acidic microenvironment. Moreover, a cancer cell under starvation caused by GOx harnesses autophagy to maintain intracellular ATP levels and resist starvation therapy. The released CQ further inhibits the starvation-induced pro-survival autophagy and cuts off the protective pathway of cancer cells, enhancing the anticancer efficiency of GOx-based starvation therapy. Significantly, the cell membrane coating endows mCG@ZIF with excellent in vivo homotypic targeting ability. Both in vitro and in vivo results have confirmed the enhanced anticancer effect achieved by mCG@ZIF with a negligible side effect.
    Keywords:  ZIF-8; autophagy inhibition; nanocarrier; pro-survival autophagy; starvation therapy
    DOI:  https://doi.org/10.1021/acsami.2c00552
  28. Crit Rev Food Sci Nutr. 2022 May 02. 1-34
    Australian native fruits and vegetables: Chemical composition, nutritional profile, bioactivity and potential valorization by industries.
    Indeewarie Hemamali Dissanayake, Valeria Zak, Kirandeep Kaur, Kayla Jaye, Zahra Ayati, Dennis Chang, Chun Guang Li, Deep Jyoti Bhuyan.
      Australian native plants have adapted themselves to harsh climatic conditions enabling them to produce unique and high levels of secondary metabolites. Native fruits and vegetables have been an integral part of the Indigenous Australian diet and Bush medicine for centuries. They have recently gained popularity owing to their rich dietary fiber, minerals, polyphenolic and antioxidant contents. This review presents a comprehensive summary and critical assessment of the studies performed in the last few decades to understand the phytochemical and nutritional profiles and therapeutic properties of Australian native fruits and vegetables. Furthermore, the potential of these fruits and vegetables as functional food ingredients and in the prevention and treatment of different diseases is discussed. Research on the nutritional and phytochemical profiles and therapeutic activity of Australian vegetables is limited with most studies focused on native fruits. These fruits have demonstrated promising antioxidant, anticancer, anti-inflammatory and antimicrobial activities mostly in in vitro models. More research to a) identify novel bioactive compounds, b) define optimal post-harvest and extraction methods, and c) understand molecular mechanisms of pharmacological activity through preclinical and clinical studies is prudent for the prospective and wider use of Australian native fruits and vegetables by the food, pharmaceutical, and nutraceutical industries.
    Keywords:  Australian native fruits; Australian native vegetables; anti-inflammatory; anticancer; antimicrobial; antioxidants; bioactivity; industrial applications; nutritional profile; phytochemicals
    DOI:  https://doi.org/10.1080/10408398.2022.2057913
  29. Eur J Pharmacol. 2022 May 03. pii: S0014-2999(22)00256-4. [Epub ahead of print] 174995
    Natural products: Potential therapeutic agents to prevent skeletal muscle atrophy.
    Aarti Yadav, Surender Singh Yadav, Sandeep Singh, Rajesh Dabur.
      The skeletal muscle (SkM) is the largest organ, which plays a vital role in controlling musculature, locomotion, body heat regulation, physical strength, and metabolism of the body. A sedentary lifestyle, aging, cachexia, denervation, immobilization, etc. Can lead to an imbalance between protein synthesis and degradation, which is further responsible for SkM atrophy (SmA). To date, the understanding of the mechanism of SkM mass loss is limited which also restricted the number of drugs to treat SmA. Thus, there is an urgent need to develop novel approaches to regulate muscle homeostasis. Presently, some natural products attained immense attraction to regulate SkM homeostasis. The natural products, i.e., polyphenols (resveratrol, curcumin), terpenoids (ursolic acid, tanshinone IIA, celastrol), flavonoids, alkaloids (tomatidine, magnoflorine), vitamin D, etc. exhibit strong potential against SmA. Some of these natural products have been reported to have equivalent potential to standard treatments to prevent body lean mass loss. Indeed, owing to the large complexity, diversity, and slow absorption rate of bioactive compounds made their usage quite challenging. Moreover, the use of natural products is controversial due to their partially known or elusive mechanism of action. Therefore, the present review summarizes various experimental and clinical evidence of some important bioactive compounds that shall help in the development of novel strategies to counteract SmA elicited by various causes.
    Keywords:  Mitochondrial biogenesis; Muscle mass; Myogenesis; Natural products; Protein synthesis; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.ejphar.2022.174995
  30. RSC Adv. 2020 Aug 26. 10(53): 31961-31978
    Quercetin loaded folate targeted plasmonic silver nanoparticles for light activated chemo-photothermal therapy of DMBA induced breast cancer in Sprague Dawley rats.
    Pritha Bose, Amiya Priyam, Rajiv Kar, Shakti P Pattanayak.
      Currently, the paucity of free drugs in conventional chemotherapy for breast-cancer curbs the desired therapeutic efficiency, often aggravating systemic toxicity. Quercetin (QRC) is a potential chemotherapeutic bio-flavonoid that is associated with poor hydrophilicity. In contrast to spherical silver nanoparticles (AgNPs), anisotropic AgNPs exhibit prominent plasmonic tunability in the near infrared (NIR) region allowing deep tissue penetration and endowing them with the ability to act as photothermal transducers as well. In this study, we optimized a simple and novel method for synthesizing folate-receptor-targeted-plasmonic silver-nanoparticles (QRC-FA-AgNPs) to serve as an efficient nanoscopic carrier system for breast cancer-cell targeted delivery of QRC and to induce photothermal therapy. A one-pot chemical synthesis method was followed for synthesizing the QRC-FA-AgNPs by finely tailoring the hydrogen bond between the reductant and stabilizer. Detailed characterization through UV-visible, near infrared (UV-vis-NIR) spectroscopy, Fourier transform infrared (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), selected area electron diffraction (SAED), and energy-dispersive X-ray spectroscopy (EDX), along with particle-size, zeta-potential analysis, drug-loading and release capacity and stability studies were also performed. In vitro targeted cellular uptake, viability studies, chemo-photothermal efficacy, induction of apoptosis and the reactive oxygen species (ROS) generating potential were studied in the MDA-MB-231 cell-line and in vivo evaluation of the chemo-photothermal efficacy of QRC-FA-AgNPs was performed using a 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast-carcinogenesis model in Sprague Dawley rats. Unlike conventional AgNPs, these novel pentagonal QRC-FA-AgNPs (<50 nm) manifested a robust plasmon tunability in the NIR (>800 nm) region. Detailed in vitro and in vivo studies revealed their active role in improving breast-cancer conditions by allowing controlled and targeted discharge of QRC at the tumor site, along with evoking hyperthermia under NIR laser irradiation that induced selective ablation of cancer cells. Following successful cellular internalization, the photothermal efficacy of QRC-FA-AgNPs supplemented their chemotherapeutic potency, allowing apoptosis and restraining the tumor growth. This current study highlighted the augmented efficacy of plasmonic QRC-FA-AgNPs in comparison to free quercetin, thus the development of a potential nanocarrier based on the pleiotropic function of plasmonic AgNPs may provide an efficient combined chemo-photothermal based strategy for the assassination of breast-cancer cells.
    DOI:  https://doi.org/10.1039/d0ra05793b
  31. J Mater Chem B. 2022 May 04.
    An efficient photothermal-chemotherapy platform based on a polyacrylamide/phytic acid/polydopamine hydrogel.
    Zhen Zhao, Hua Zhang, Hongda Chen, Yuanhong Xu, Lina Ma, Zhenxin Wang.
      In this work, the polyacrylamide/phytic acid/polydopamine (termed as PAAM/PA/PDA) hydrogel is used as a drug loading matrix and photothermal conversion reagent, which is prepared by copolymerization of dopamine with acrylamide through a phytic acid crosslinker. Due to the porous structure of PAAM and strong near-infrared light (NIR)-absorption of PDA, the PAAM/PA/PDA hydrogel exhibits a high doxorubicin (DOX)-loading capacity (170 mg g-1) and efficient photothermal transduction efficiency (47.4%) even under low power density 808 nm NIR laser (0.75 W cm-2) irradiation, which is superior to those of most conventional photothermal conversion agents reported in the literature. With NIR laser irradiation, the PAAM/PA/PDA hydrogel loaded with DOX (termed as PAAM/PA/PDA/DOX) shows excellent synergistic interaction between photothermal therapy (PTT) and enhanced chemotherapy, resulting in the completely suppressed growth of mouse-bearing SW620 tumors. Furthermore, the PAAM/PA/PDA hydrogel shows good physicochemical stability, negligible cytotoxicity and low toxicity in vivo. All these characteristics render the as-prepared PAAM/PA/PDA hydrogel promising for biomedical applications.
    DOI:  https://doi.org/10.1039/d2tb00677d
  32. Front Pharmacol. 2022 ;13 809706
    Epigallocatechin-3-Gallate Delivery in Lipid-Based Nanoparticles: Potentiality and Perspectives for Future Applications in Cancer Chemoprevention and Therapy.
    Fulvia Farabegoli, Marina Pinheiro.
      Chemoprevention is a strategy aimed to not only reduce the risk but also delay the development or recurrence of cancer. An ideal chemopreventive agent is not dangerous and ought not to result in side effects or damage to human health. In this context, epigallocatechin-3-gallate (EGCG) is considered a suitable chemopreventive agent, but its clinical use is limited by many factors, namely, the difference in source, administration, individual metabolism, absorption, and distribution. Genetic and dietary differences greatly cause this variability, which has limited the rational use of EGCG in chemoprevention and, particularly, the definition of a safe and efficient concentration. In the present mini review, the main limitations to a complete understanding of the use of EGCG as a chemopreventive agent will be briefly illustrated. This review also indicates the introduction and trialing of lipid-based nanoparticles (NPs) as a proper strategy to deliver EGCG at a well-defined concentration for better investigation of the chemopreventive activity. Finally, some examples of cancers that might benefit from EGCG treatment in different stages of the disease are proposed.
    Keywords:  EGCG; cancer; catechins; medicinal chemistry; nanomedicine; nutraceutics
    DOI:  https://doi.org/10.3389/fphar.2022.809706
  33. J Control Release. 2022 May 02. pii: S0168-3659(22)00240-1. [Epub ahead of print]
    Nanomaterials in cancer: Reviewing the combination of hyperthermia and triggered chemotherapy.
    Tiago P Ribeiro, J Agostinho Moreira, Fernando J Monterio, Marta S Laranjeira.
      Nanoparticle mediated hyperthermia has been explored as a method to increase cancer treatment efficacy by heating tumours inside-out. With that purpose, nanoparticles have been designed and their properties tailored to respond to external stimuli and convert the supplied energy into heat, therefore inducing damage to tumour cells. Moreover, the combination of hyperthermia with chemotherapy has been described as a more effective strategy due to the synergy between the high temperature and the drug's effects, also associated with a remote controlled and on-demand drug release. In this review, the methods behind nanoparticle mediated hyperthermia, namely material design, external stimuli response and energy conversion will be discussed and critically analysed. We will address the most relevant studies on hyperthermia and temperature triggered drug release for cancer treatment. Finally, the advantages, difficulties and challenges of this therapeutic strategy will be discussed, while giving insight for future developments.
    Keywords:  Cancer; Chemotherapy; Drug Release; Hyperthermia; Nanoparticles
    DOI:  https://doi.org/10.1016/j.jconrel.2022.04.045
  34. RSC Adv. 2020 May 14. 10(32): 19089-19105
    Dual or multiple drug loaded nanoparticles to target breast cancer stem cells.
    Yu Gao, Mingtan Tang, Euphemia Leung, Darren Svirskis, Andrew Shelling, Zimei Wu.
      Breast cancer stem(-like) cells (BCSCs) have been found to be responsible for therapeutic resistance and disease relapse. BCSCs are difficult to eradicate due to their high resistance to conventional treatments and high plasticity. Functionalised nanoparticles have been investigated as smart vehicles to transport across various barriers and increase the interaction of therapeutic agents with cancer cells, as well as BCSCs. In this review, we discuss the different characteristics of BCSCs, and challenges to tackle BCSCs at cellular and molecular levels. The mechanisms of action and physicochemical properties of the current BCSC targeting agents are also covered. We will focus on the rational design and recent advances of "Nano + Nano" or single tumour targeting nanoparticle systems loaded with dual or multiple agents to kill all cancer cells including BCSCs. These cocktail therapies include the combination of a chemotherapy agent with a BCSC-specific inhibitor, a phytochemical agent or RNA based therapy. Given the heterogeneity of breast tumour tissue, targeting both BCSCs and bulk breast cancer cells simultaneously with multiple agents holds great promise in eliminating breast cancer. The future research needs to focus on overcoming various barriers in the 'clinical translation' of BCSC-targeting nanomedicines to cure breast cancer, which requires a significant multidisciplinary effort.
    DOI:  https://doi.org/10.1039/d0ra02801k
  35. Nanoscale. 2022 May 03.
    Enhanced delivery of theranostic liposomes through NO-mediated tumor microenvironment remodeling.
    Tao Tang, Biao Huang, Feng Liu, Ran Cui, Mingxi Zhang, Taolei Sun.
      Highly efficient delivery of nanoagents to the tumor region remains the primary challenge for cancer nanomedicine. Herein, we propose a NO-mediated tumor microenvironment (TME) remodeling strategy for the high-efficient delivery of nanoagents into tumor. Quantum dots (QDs) with bright fluorescence in the near-infrared IIb (NIR-IIb, 1500-1700 nm) window and high photothermal conversion efficiency were encapsulated into liposomes for the imaging-guided photothermal therapy (PTT) of tumor. The fabrication of PEG and arginine-glycine-aspartate (RGD) peptide on liposomes ensured the prolonged circulation in vivo and active targeting to tumor. Moreover, the loading of a natural NO generator L-arginine in liposomes realized the continuous generation of NO in the acidic TME. By co-localization fluorescence imaging and western blot of tumor tissue, we confirmed that the release of NO activated the expression of metalloproteinases in TME and further degraded Collagen I in the peripheral region of the tumor, thus removing the barrier for the permeation of liposomes. Attributed to the enhanced accumulation of liposomes inside the tumor, NIR IIb imaging-guided PTT was achieved with remarkable therapeutic efficacy.
    DOI:  https://doi.org/10.1039/d2nr01175a
  36. Chem Sci. 2022 Apr 13. 13(15): 4239-4269
    Stimulus-responsive self-assembled prodrugs in cancer therapy.
    Xiao Dong, Rajeev K Brahma, Chao Fang, Shao Q Yao.
      Small-molecule prodrugs have become the main toolbox to improve the unfavorable physicochemical properties of potential therapeutic compounds in contemporary anti-cancer drug development. Many approved small-molecule prodrugs, however, still face key challenges in their pharmacokinetic (PK) and pharmacodynamic (PD) properties, thus severely restricting their further clinical applications. Self-assembled prodrugs thus emerged as they could take advantage of key benefits in both prodrug design and nanomedicine, so as to maximize drug loading, reduce premature leakage, and improve PK/PD parameters and targeting ability. Notably, temporally and spatially controlled release of drugs at cancerous sites could be achieved by encoding various activable linkers that are sensitive to chemical or biological stimuli in the tumor microenvironment (TME). In this review, we have comprehensively summarized the recent progress made in the development of single/multiple-stimulus-responsive self-assembled prodrugs for mono- and combinatorial therapy. A special focus was placed on various prodrug conjugation strategies (polymer-drug conjugates, drug-drug conjugates, etc.) that facilitated the engineering of self-assembled prodrugs, and various linker chemistries that enabled selective controlled release of active drugs at tumor sites. Furthermore, some polymeric nano-prodrugs that entered clinical trials have also been elaborated here. Finally, we have discussed the bottlenecks in the field of prodrug nanoassembly and offered potential solutions to overcome them. We believe that this review will provide a comprehensive reference for the rational design of effective prodrug nanoassemblies that have clinic translation potential.
    DOI:  https://doi.org/10.1039/d2sc01003h
  37. Mater Today Bio. 2022 Jun;15 100264
    Architecting polyelectrolyte hydrogels with Cu-assisted polydopamine nanoparticles for photothermal antibacterial therapy.
    ZhangPing Li, Shengye You, Ruiting Mao, Yajing Xiang, Erya Cai, Hui Deng, Jianliang Shen, Xiaoliang Qi.
      Polydopamine nanoparticles (PDA NPs) are an appealing biomimetic photothermal agent for photothermal antibacterial treatment because of their long-term safety, excellent photostability, accessible manufacturing, and good biodegradability. However, the low photothermal conversion efficiency (PCE) of PDA NPs requires high-power and long-term near-infrared light irradiation, which severely restricts their practical application. In this work, PDA@Cu NPs were fabricated by growing Cu NPs in situ on the surface of PDA and then introduced into a polyelectrolyte hydrogel precursor (cationic polyethyleneimine/anionic pectin, named as CPAP). The formulated photothermal platform possessed a high PCE (55.4%), almost twice as much as pure PDA NPs (30.8%). Moreover, the designed CPAP/PDA@Cu captured and killed some bacteria by electrostatic adsorption, which helped enhance the antibacterial performance. As expected, the formed CPAP/PDA@Cu that combined the advantageous features of PDA@Cu NPs (high PCE) and CPAP matrix (inherent antibacterial activity and preventing NPs aggregation) can efficiently kill bacteria both in vitro and in vivo under the help of near-infrared laser irradiation. Taken together, this study offers a promising strategy for constructing a facile and safe PDA-based photothermal agent for photothermal antibacterial therapy.
    Keywords:  Cu nanoparticles; Photothermal antibacterial treatment; Polydopamine nanoparticles; Polyelectrolyte hydrogel; Wound healing
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100264
  38. Adv Pharm Bull. 2022 Jan;12(1): 45-57
    Dermal and Transdermal Drug Delivery through Vesicles and Particles: Preparation and Applications.
    Unnati Garg, Karuna Jain.
      Transdermal delivery over the past decade has become the field of interest for drug delivery due to its various advantages such as no first-pass metabolism, increased drug bioavailability, and easy administration. Different vesicle systems like ethosomes, liposomes, niosomes, and transferosomes along with particle systems like lipid nanoparticles, polymeric nanoparticles, carbon nanotubes, and fullerenes have been developed. These vesicles and particle systems have been developed using various easy and effective methods like cold injection method, rotary film evaporation, thin film hydration, high shear homogenization, solvent extraction method, and many more. These drug delivery systems are a very effective and feasible option for transdermal drug delivery and further developments can be made to increase their use. This article explains in detail the preparation methods and applications for these drug delivery systems.
    Keywords:  Dermal; Drug delivery; Ethosomes; Nanoparticles; Niosomes; Particle systems; Transdermal; Transferosomes; Vesicle systems
    DOI:  https://doi.org/10.34172/apb.2022.006
  39. Adv Sci (Weinh). 2022 May 04. e2200608
    A Space-Time Conversion Vehicle for Programmed Multi-Drugs Delivery into Pancreatic Tumor to Overcome Matrix and Reflux Barriers.
    Taotao Huo, Xiaoyi Zhang, Min Qian, Huifang Nie, Dong Liang, Chenteng Lin, Yafeng Yang, Wei Guo, Ulrich Lächelt, Rongqin Huang.
      The numerous biological barriers, which limit pharmacotherapy of pancreatic carcinoma, including inadequate drug accumulation in the tumor environment, a dense extracellular matrix (ECM) and efficient drug-efflux mechanisms, illustrate the requirement of multifunctional delivery systems to overcome the individual barriers at the right place at the right time. Herein, a space-time conversion vehicle based on covalent organic framework (COF)-coated mesoporous silica nanospheres (MSN) with a sandwiched polyethyleneimine (PEI) layer (MPCP), is designed. The space-specific drugs-loaded vehicle (MG PP CL P) is obtained by separately incorporating a chemotherapeutic agent (gemcitabine, G) into the MSN core, a P glycoprotein inhibitor (LY 335979, P) into the PEI layer, and an extracellular matrix disruptor (losartan, L) into the COF shell. Thereafter, a programmed drug delivery is achieved via the ordered degradation from COF shell to MSN core. Sequential release of the individual drugs, synergized with a change of nanoparticle surface charge, contribute to an obvious extracellular matrix distraction, distinct drug efflux inhibition, and consequently enhance chemotherapeutic outcomes in pancreatic carcinoma. This MPCP-based vehicle design suggests a robust space-time conversion strategy to achieve programmed multi-drugs delivery and represents a new avenue to the treatment of pancreatic carcinoma by overcoming extracellular matrix and drug reflux barriers.
    Keywords:  covalent organic framework; multi-drugs delivery; pancreatic carcinoma; programmed drug delivery
    DOI:  https://doi.org/10.1002/advs.202200608
  40. Crit Rev Food Sci Nutr. 2022 May 06. 1-21
    An updated and comprehensive review on the potential health effects of curcumin-encapsulated micro/nanoparticles.
    Ahmed K Rashwan, Naymul Karim, Yang Xu, Nemany A N Hanafy, Bin Li, Abul-Hamd E Mehanni, Eman M Taha, Wei Chen.
      Curcumin (CUR) is a natural hydrophobic compound, which is available in turmeric rhizome. It has several bioactivities including antioxidant, anti-obesity, anti-diabetic, cardioprotective, anti-inflammatory, antimicrobial, anticancer, and other activities. Despite its medical and biological benefits, it is using in limitations because of its hydrophobicity and sensitivity. These unfavorable conditions further reduced the bioavailability (BA) and biological efficacy of CUR. This review summarizes the stability and BA of free- and encapsulated-CUR, as well as comprehensively discusses the potential biological activity of CUR-loaded various micro-/nano-encapsulation systems. The stability and BA of CUR can be improved via loading in different encapsulation systems, including nanoemulsions, liposomes, niosomes, biopolymer-based nanoparticles, nano-hydrogel, and others. Biopolymer-based nanoparticles (especially poly lactic-co-glycolic acid (PLGA), zein, and chitosan) and nano-gels are the best carriers for encapsulating and delivering CUR. Both delivery systems are suitable because of their excellent functional properties such as high encapsulation efficiency, well-stability against unfavorable conditions, and can be coated using other encapsulation systems. Based on available evidences, encapsulated-CUR exerted greater biological activities especially anticancer (breast cancer), antioxidant, antidiabetic, and neuroprotective effects.
    Keywords:  Curcumin; bioavailability; biological activity; clinical studies; encapsulation systems; stability
    DOI:  https://doi.org/10.1080/10408398.2022.2070906
  41. Int J Nanomedicine. 2022 ;17 1803-1827
    How Advancing are Mesoporous Silica Nanoparticles? A Comprehensive Review of the Literature.
    Sahar Porrang, Soodabeh Davaran, Nader Rahemi, Somaiyeh Allahyari, Ebrahim Mostafavi.
      The application of mesoporous silica nanoparticles (MSNs) is ubiquitous in various sciences. MSNs possess unique features, including the diversity in manufacturing by different synthesis methods and from different sources, structure controllability, pore design capabilities, pore size tunability, nanoparticle size distribution adjustment, and the ability to create diverse functional groups on their surface. These characteristics have led to various types of MSNs as a unique system for drug delivery. In this review, first, the synthesis of MSNs by different methods via using different sources were studied. Then, the parameters affecting their physicochemical properties and functionalization have been discussed. Finally, the last decade's novel strategies, including surface functionalization, drug delivery, and cancer treatment, based on the MSNs in drug delivery and cancer therapy have been addressed.
    Keywords:  controlled release; drug delivery; mesoporous silica nanoparticles; natural sources; synthesis method; synthetic sources
    DOI:  https://doi.org/10.2147/IJN.S353349
  42. Recent Adv Drug Deliv Formul. 2022 May 06.
    ROS Modulating Inorganic Nanoparticles: A Novel Cancer Therapeutic Tool.
    Maria John Newton Amaldoss.
      The term "reactive oxygen species" (ROS) refers to a family of extremely reactive molecules. They are crucial as secondary messengers in both physiological functioning and the development of cancer. Tumors have developed the ability to survive at elevated ROS levels with their significantly higher H2O2 levels than normal tissues. Chemodynamic therapy is a novel approach to cancer treatment that generates highly toxic hydroxyl radicals via a Fenton/Fenton-like reaction between metals and peroxides. Inorganic nanoparticles cause cytotoxicity by releasing ROS. Inorganic nanoparticles can alter redox homoeostasis by generating ROS or diminishing scavenging mechanisms. Internalized nanoparticles generate ROS in biological systems independent of the route of internalisation. This method of producing ROS could be employed to kill cancer cells as a therapeutic strategy. ROS also play a role in regulating the development of normal stem cells, as excessive ROS disturb the stem cells' regular biological cycles. ROS treatment has a significant effect on normal cellular function. Mitochondrial ROS are at the centre of metabolic changes and control a variety of other cellular processes, which can lead to medication resistance in cancer patients. As a result, utilising ROS in therapeutic applications can be a double-edged sword that requires better understanding.
    Keywords:  Cancer ROS therapy; Chemodynamic therapy; Inorganic Nanoparticles; Prooxidant ; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.2174/2667387816666220506203123
  43. RSC Adv. 2021 Nov 23. 11(60): 37988-37994
    Disulfur-bridged polyethyleneglycol/DOX nanoparticles for the encapsulation of photosensitive drugs: a case of computational simulations on the redox-responsive chemo-photodynamic drug delivery system.
    Zhenchao Ma, Juanping Wu, Mengchi Sun, Bingyu Li, Xiang Yu.
      Tumor redox stimulus-responsive nanoparticulate drug delivery systems (nano-DDSs) have attracted considerable attention due to their thermodynamically stable microstructures and well-controlled drug release properties. However, drug-loading nanoparticle conformation and redox-triggered drug release mechanisms at the molecular level remain unclear. Herein, doxorubicin-conjugated polymers were constructed using disulfide bonds as linkages (PEG-SS-DOX), which loaded photosensitizer chlorin e6 (Ce6). We integrated multiple scale dynamic simulations (density functional theory (DFT) calculation, atomistic molecular dynamics (MD) simulation and dissipative particle dynamics (DPD) simulations) to elucidate the assembly/drug release dynamic processing. First, it was revealed that the emergence of the calculated bond flexible angle of disulfide bonds facilitated the assembly behavior and improved the stability of conformation. Sorted by the binding model, hydrogen bonding accounted for the major interactions between polymers and photosensitive drugs. DPD simulations were further delved into to acquire knowledge regarding the drug-free self-aggregation and Ce6-loaded assembly mechanism. The results show that nano-assembly conformation not only depended on the concentration of polymers, but also were associated with the polymer-drug ratio. Different from dicarbon bond-bridging polymers, disulfide bonds would contribute to the breakage of the polymer and the rapid release of DOX and Ce6. Our findings provide deep insights into the influence of redox-responsive chemical linkages and offer theoretical guidance to the rational design of specific stimulus-responsive nano-DDSs for cancer therapy.
    DOI:  https://doi.org/10.1039/d1ra05645j
  44. J Control Release. 2022 May 02. pii: S0168-3659(22)00243-7. [Epub ahead of print]
    Oxidative stress-amplified nanomedicine for intensified ferroptosis-apoptosis combined tumor therapy.
    Mian Yu, Jiayin Yu, Yunfei Yi, Ting Chen, Liu Yu, Weiwei Zeng, Xiao-Kun Ouyang, Chenyi Huang, Shengjie Sun, Yang Wang, Yuanqi Liu, Chuchu Lin, Meiying Wu, Lin Mei.
      Ferroptosis, as an effective sensitizer for apoptosis-based cancer treatments, has been elucidated to rely on high levels of intracellular oxidative stress mediated by the accumulation of reactive oxygen species (ROS). However, ferroptosis-related oxidation effect is largely counteracted by the endogenous reductive glutathione (GSH). Here, we constructed a self-assembled metal-organic nanomedicine p53/Ce6@ZF-T, which was composed of p53 plasmid-complexed chlorin e6 (Ce6)-poly(amidoamine), Fe2+-containing mesoporous zeolitic imidazolate framework-8 and naturally derived tannic acid (TA). The highly cytotoxic ROS was continuously produced via Fe2+-mediated and TA-assisted enhanced Fenton reaction as well as Ce6-induced photosensitive reaction, and meanwhile, the intratumoral upregulated p53 expression inactivated glutathione peroxidase 4 (GPX4) to suppress lipid peroxidation (LPO) resistance, thus resulting in amplified oxidative stress and intensified ferroptosis-apoptosis therapy. The notable anticancer efficacy of p53/Ce6@ZF-T both in vitro and in vivo substantially evidenced the high feasibility of oxidative stress-amplified therapeutic modality for enhanced ferroptosis-apoptosis combined therapy, which would be a promising approach in the field of cancer treatment in the future.
    Keywords:  Fenton reaction; Ferroptosis; Gene delivery; Oxidative stress; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.jconrel.2022.04.047
  45. J Nanobiotechnology. 2022 May 06. 20(1): 212
    Synergistic photothermal-photodynamic-chemotherapy toward breast cancer based on a liposome-coated core-shell AuNS@NMOFs nanocomposite encapsulated with gambogic acid.
    Rong-Tian Li, Yi-Dan Zhu, Wen-Ya Li, Ying-Ke Hou, Yi-Ming Zou, Ying-Hua Zhao, Quan Zou, Wen-Hua Zhang, Jin-Xiang Chen.
      A multifunctional nanoplatform with core-shell structure was constructed in one-pot for the synergistic photothermal, photodynamic, and chemotherapy against breast cancer. In the presence of gambogic acid (GA) as the heat-shock protein 90 (HSP90) inhibitor and the gold nanostars (AuNS) as the photothermal reagent, the assembly of Zr4+ with tetrakis (4-carboxyphenyl) porphyrin (TCPP) gave rise to the nanocomposite AuNS@ZrTCPP-GA (AZG), which in turn, further coated with PEGylated liposome (LP) to enhance the stability and biocompatibility, and consequently the antitumor effect of the particle. Upon cellular uptake, the nanoscale metal - organic framework (NMOF) of ZrTCPP in the resulted AuNS@ZrTCPP-GA@LP (AZGL) could be slowly degraded in the weak acidic tumor microenvironment to release AuNS, Zr4+, TCPP, and GA to exert the synergistic treatment of tumors via the combination of AuNS-mediated mild photothermal therapy (PTT) and TCPP-mediated photodynamic therapy (PDT). The introduction of GA serves to reduce the thermal resistance of the cell to re-sensitize PTT and the constructed nanoplatform demonstrated remarkable anti-tumor activity in vitro and in vivo. Our work highlights a facile strategy to prepare a pH-dissociable nanoplatform for the effective synergistic treatment of breast cancer.
    Keywords:  Chemotherapy; Gambogic acid; Gold nanostar; Nanoscale metal−organic framework; Photodynamic therapy; Photothermal therapy
    DOI:  https://doi.org/10.1186/s12951-022-01427-4
  46. Chem Pharm Bull (Tokyo). 2022 ;70(5): 334-340
    Biomimetic Nanoparticle Drug Delivery Systems to Overcome Biological Barriers for Therapeutic Applications.
    Tatsuya Fukuta, Kentaro Kogure.
      Targeted drug delivery using nanoparticles has been applied for the treatment of diverse diseases, including cancer and inflammatory diseases. Nanoparticle-mediated delivery of therapeutic agents via the enhanced permeability and retention effect generally augments their therapeutic efficiency; however, limitations with passive entry of nanoparticles into diseased sites, due to the presence of biological barriers represented by the endothelial layer, remain to be addressed. To this end, development of nanoparticles with intrinsic characteristics similar to circulatory cells (e.g., leukocytes, platelets) for use as biomimetic drug delivery systems (DDS) has been focused as a means to overcome the issues of conventional DDS. In particular, synthetic biomimetic nanoparticles coated with cellular membranes were recently prepared and shown to actively overcome the inflamed vessels and tumor microenvironment as a result of the functionality of membrane proteins, which allowed secure drug delivery into diseased sites. We recently developed liposomes modified with leukocyte membrane proteins via intermembrane protein transfer, a simple method to reconstitute cellular membrane proteins onto lipid bilayers. The resultant liposomes demonstrated the ability to cross the inflamed endothelial layer and permeate into tumor tissue by mimicking the properties of leukocytes. Thus, biomimetic DDS offer promise as new therapeutic approaches for various diseases by overcoming biological barriers that typically inhibit drug delivery. Herein, we review recent approaches to develop biomimetic DDS using the cell membrane coating method, and highlight our recent findings on leukocyte-mimetic liposomes prepared via intermembrane protein transfer.
    Keywords:  biomimetic nanoparticle; drug delivery system; intermembrane protein transfer; leukocyte; liposome
    DOI:  https://doi.org/10.1248/cpb.c21-00961
  47. ACS Appl Mater Interfaces. 2022 May 04.
    Engineering Chemotherapeutic-Augmented Calcium Phosphate Nanoparticles for Treatment of Intraperitoneal Disseminated Ovarian Cancer.
    Miaojuan Qiu, Junzong Chen, Xiuyu Huang, Binbin Li, Shiqiang Zhang, Peng Liu, Qiang Wang, Zhi Rong Qian, Yihang Pan, Yu Chen, Jing Zhao.
      Ovarian cancer is a common gynecologic malignancy with a high fatality rate. Intraperitoneal chemotherapy has been proved as an efficient clinical treatment for disseminated ovarian cancer. However, there are limitations for conventional small molecule drugs to achieve an ideal therapeutic effect. Herein, a synergistic treatment for intraperitoneally disseminated ovarian cancer was achieved by Arg-Gly-Asp (RGD)-modified amorphous calcium phosphate loading with doxorubicin (designated as RGD-CaPO/DOX). The engineered calcium-involved nanomedicine augmented the therapeutic effect of DOX by aggravating endoplasmic reticulum stress, calcium overload, and mitochondrial dysfunction, ultimately triggering mitochondrial apoptosis in the SKOV3 (human ovarian cancer) cell line. In an intraperitoneally disseminated tumor model, RGD modification and the weak negative surface potential of the NPs were beneficial for intraperitoneal retention and tumor targeting. Moreover, intraperitoneal injection of RGD-CaPO/DOX NPs resulted in a favorable antitumor effect. The mean survival time of SKOV3-bearing mice was significantly extended from 29 to 59 days with negligible toxicity. Therefore, this study has been designed to provide an effective chemotherapeutic-augmented treatment for intraperitoneally disseminated ovarian cancer.
    Keywords:  calcium overload; chemotherapy; nanomedicine; ovarian cancer; synergistic therapy
    DOI:  https://doi.org/10.1021/acsami.2c02552
  48. Int J Biol Macromol. 2022 May 02. pii: S0141-8130(22)00930-8. [Epub ahead of print]
    Hybrid PEGylated chitosan/PLGA nanoparticles designed as pH-responsive vehicles to promote intracellular drug delivery and cancer chemotherapy.
    Sheng-Jyun Huang, Tzu-Hao Wang, Ya-Hsuan Chou, Hui-Min David Wang, Tsai-Ching Hsu, Jia-Le Yow, Bor-Show Tzang, Wen-Hsuan Chiang.
      To achieve effective intracellular anticancer drug release for boosted antitumor efficacy, the acidity-responsive nanovehicles for doxorubicin (DOX) delivery were fabricated by tailor-made co-assembly of amphiphilic PEGylated chitosan20k and hydrophobic poly(lactic-co-glycolic acid) (PLGA) segments at pH 8.5. The attained DOX-loaded PEGylated chitosan20k/PLGA nanoparticles (DOX-PC20kPNs) were characterized to have a spherical shape composed of drug-encapsulated chitosan20k/PLGA-constituted solid core surrounded by hydrophilic PEG shells. Compared to non-pH-sensitive DOX-loaded PLGA nanoparticles (DOX-PNs), the DOX-PC20kPNs displayed outstanding colloidal stability under serum-containing condition and tended to swell in weak acidic milieu upon increased protonation of chitosan20k within hybrid cores, thus accelerating drug release. The in vitro cellular uptake and cytotoxicity studies revealed that the DOX-PC20kPNs after being endocytosed by prostate TRAMP-C1 cancer cells rapidly liberated drug, thus promoting drug accumulation in nuclei to enhance anticancer potency. Moreover, the hydrated PEG shells of DOX-PC20kPNs remarkably reduced their uptake by macrophage-like RAW264.7 cells. Importantly, in vivo animal findings showed that the DOX-PC20kPNs exhibited the capability of inhibiting TRAMP-C1 tumor growth superior to free hydrophobic DOX molecules and DOX-PNs, demonstrating the great potential in cancer chemotherapy.
    Keywords:  Acidity-responsive nanovehicles; PEGylated chitosan; cancer chemotherapy
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.04.209
  49. Colloids Surf B Biointerfaces. 2022 Apr 27. pii: S0927-7765(22)00207-7. [Epub ahead of print]215 112524
    Self-assembled bilosomes with stimuli-responsive properties as bioinspired dual-tunable nanoplatform for pH/temperature-triggered release of hybrid cargo.
    Ewelina Waglewska, Agata Pucek-Kaczmarek, Urszula Bazylińska.
      The rapid development of colloid chemistry has raised the possibility of using nanocarriers for the targeted delivery and the controlled drug release at predictable locations to reduce side effects and enhance therapeutic efficacy. In the present work, we focused on the influence of temperature and pH upon in vitro controlled phytochemical/dye-release from a modified bilosome. Drug molecules can affect the properties of nanocarriers, so the effect of encapsulated bioactive compounds on nanoparticle structure has been investigated. The self-assembly process of bioinspired components (i.e., phospholipids, bile salts, and cholesterol), and biocompatible polymeric triblock materials, made it possible to receive structures with a size below 100 nm, demonstrated good capacity for active cargo encapsulation. Differential scanning calorimetry studies showed the possibility of the payloads' interaction with the bilosomes structure. A highly lipophilic compound, such as curcumin, can weaken hydrophobic interactions between the acyl chains of phospholipids, leading to a more flexible membrane. The in vitro release profiles have proved that both solubilities of the therapeutic substances and various environmental conditions affect the release rate of the hybrid cargo. Overall, the obtained double-loaded bilosomes represent a promising bioinspired nanoplatform for oral, intravenous, and topical drug delivery in future biomedical applications.
    Keywords:  Biological stability; Colloidal stability; Elastic vesicular nanostructures; Sustainable nano-drug release system; Triggered-release soft colloidal system
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112524
  50. ACS Appl Mater Interfaces. 2022 May 02.
    Open-Source and Reduced-Expenditure Nanosystem with ROS Self-Amplification and Glutathione Depletion for Simultaneous Augmented Chemodynamic/Photodynamic Therapy.
    Miaomiao Chen, Shuju Zhao, Jialong Zhu, Erting Feng, Fangyuan Lv, Wenlong Chen, Shibo Lv, Yingnan Wu, Xiaojun Peng, Fengling Song.
      Reactive oxygen species (ROS)-induced cell apoptosis has emerged as an efficient strategy for cancer therapy. However, tumor hypoxia and insufficient amounts of endogenous hydrogen peroxide (H2O2) in the tumor microenvironment are currently the main limitations of photodynamic therapy (PDT) and chemodynamic therapy (CDT). Moreover, the glutathione (GSH) scavenging effect on ROS further hinders the efficiency of ROS-mediated therapy. Here, a CaO2-based nanosystem (named as CF@CO@HC) with ROS self-amplification and GSH-depletion abilities was developed by a bottom-up approach. This hybrid nanoparticle consisted of a photosensitizer-doped calcium peroxide (CaO2) core (CaO2-FM), a hybrid organosilica framework (Cu-ONS) incorporated with Fenton reagents (Cu2+) and tetrasulfide groups, and a local hydrophobic cage (HC) shell. The photosensitizer was fluorescein derivative 4-FM with a thermally activated delayed fluorescence (TADF) property. The HC shell was built to protect the CaO2 and the photosensitizer from being attacked by water. Upon being internalized into cancer cells, the nanosystem was decomposed through the reduction reactions of Cu2+ and the tetrasulfide bond-doped silica shell by GSH, thus releasing Cu+ for Cu+-mediated CDT. Meanwhile, the exposed CaO2-FM can react with H2O to liberate photosensitizer 4-FM and generate H2O2 and O2 to overcome barriers in CDT and PDT. Thus, our study provided an open-source and reduced-expenditure strategy via GSH depletion and ROS self-amplification behaviors for ROS generation and significantly achieved an improved synergistic PDT/CDT for cancers.
    Keywords:  calcium peroxide; chemodynamic therapy; reactive oxygen species photodynamic therapy; synergistic therapy
    DOI:  https://doi.org/10.1021/acsami.2c01782
  51. RSC Adv. 2020 Aug 17. 10(51): 30785-30795
    Curcumin loaded zinc oxide nanoparticles for activity-enhanced antibacterial and anticancer applications.
    W P T D Perera, Ranga K Dissanayake, U I Ranatunga, N M Hettiarachchi, K D C Perera, Janitha M Unagolla, R T De Silva, L R Pahalagedara.
      Zinc oxide nanoparticles and curcumin have been shown to be excellent antimicrobial agents and promising anticancer agents, both on their own as well as in combination. Together, they have potential as alternatives/supplements to antibiotics and traditional anticancer drugs. In this study, different morphologies of zinc oxide-grafted curcumin nanocomposites (ZNP-Cs) were synthesized and characterized using SEM, TGA, FTIR, XRD and UV-vis spectrophotometry. Antimicrobial assays were conducted against both Gram negative and Gram-positive bacterial stains. Spherical ZnO-curcumin nanoparticles (SZNP-Cs) and rod-shaped ZnO-curcumin nanoparticles showed the most promising activity against tested bacterial strains. The inhibition zones for these curcumin-loaded ZnO nanocomposites were consistently larger than their bare counterparts or pure curcumin, revealing an additve effect between the ZnO and curcumin components. The potential anticancer activity of the synthesized nanocomposites was studied on the rhabdomyosarcoma RD cell line via MTT assay, while their cytotoxic effects were tested against human embryonic kidney cells using the resazurin assay. SZNP-Cs exhibited the best balance between the two, showing the lowest toxicity against healthy cells and good anticancer activity. The results of this investigation demonstrate that the nanomatrix synthesized can act as an effective, additively-enhanced combination delivery/therapeutic agent, holding promise for anticancer therapy and other biomedical applications.
    DOI:  https://doi.org/10.1039/d0ra05755j
  52. RSC Adv. 2021 Nov 17. 11(59): 37504-37513
    H2O2-independent chemodynamic therapy initiated from magnetic iron carbide nanoparticle-assisted artemisinin synergy.
    Fan Zhao, Jing Yu, Weiliang Gao, Xue Yang, Liying Liang, Xiaolian Sun, Dan Su, Yao Ying, Wangchang Li, Juan Li, Jingwu Zheng, Liang Qiao, Wei Cai, Shenglei Che, Xiaozhou Mou.
      Chemodynamic therapy (CDT) is a booming technology that utilizes Fenton reagents to kill tumor cells by transforming intracellular H2O2 into reactive oxygen species (ROS), but insufficient endogenous H2O2 makes it difficult to attain satisfactory antitumor results. In this article, a H2O2-free CDT technique with tumor-specificity is developed by using pH-sensitive magnetic iron carbide nanoparticles (PEG/Fe2C@Fe3O4 NPs) to trigger artemisinin (ART) to in situ form ROS. ART-loaded PEG/Fe2C@Fe3O4 NPs are fabricated for the enormous release of Fe2+ ions induced by the acidic conditions of the tumor microenvironment after magnetic-assisted tumor enrichment, which results in the rapid degradation of the PEG/Fe2C@Fe3O4 NPs and release of ART once endocytosed into tumor cells. In situ catalysis reaction between the co-released Fe2+ ions and ART generates toxic ROS and then induces apoptosis of tumor cells. Both in vitro and in vivo experiments demonstrate that the efficient Fe-enhanced and tumor-specific CDT efficacy for effective tumor inhibition based on ROS generation. This work provides a new direction to improve CDT efficacy based on H2O2-independent ROS generation.
    DOI:  https://doi.org/10.1039/d1ra04975e
  53. Adv Sci (Weinh). 2022 May 04. e2105451
    Synchronous Disintegration of Ferroptosis Defense Axis via Engineered Exosome-Conjugated Magnetic Nanoparticles for Glioblastoma Therapy.
    Boyan Li, Xin Chen, Wei Qiu, Rongrong Zhao, Jiazhi Duan, Shouji Zhang, Ziwen Pan, Shulin Zhao, Qindong Guo, Yanhua Qi, Wenhan Wang, Lin Deng, Shilei Ni, Yuanhua Sang, Hao Xue, Hong Liu, Gang Li.
      Glioblastoma (GBM) is one of the most fatal central nervous system tumors and lacks effective or sufficient therapies. Ferroptosis is a newly discovered method of programmed cell death and opens a new direction for GBM treatment. However, poor blood-brain barrier (BBB) penetration, reduced tumor targeting ability, and potential compensatory mechanisms hinder the effectiveness of ferroptosis agents during GBM treatment. Here, a novel composite therapeutic platform combining the magnetic targeting features and drug delivery properties of magnetic nanoparticles with the BBB penetration abilities and siRNA encapsulation properties of engineered exosomes for GBM therapy is presented. This platform can be enriched in the brain under local magnetic localization and angiopep-2 peptide-modified engineered exosomes can trigger transcytosis, allowing the particles to cross the BBB and target GBM cells by recognizing the LRP-1 receptor. Synergistic ferroptosis therapy of GBM is achieved by the combined triple actions of the disintegration of dihydroorotate dehydrogenase and the glutathione peroxidase 4 ferroptosis defense axis with Fe3 O4 nanoparticle-mediated Fe2+ release. Thus, the present findings show that this system can serve as a promising platform for the treatment of glioblastoma.
    Keywords:  blood-brain barrier; exosomes; ferroptosis; glioblastoma; magnetic nanoparticles
    DOI:  https://doi.org/10.1002/advs.202105451
  54. Front Pharmacol. 2022 ;13 875330
    Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives.
    Jia-Xin Li, Run-Ze Li, Lin-Rui Ma, Peng Wang, Dong-Han Xu, Jie Huang, Li-Qi Li, Ling Tang, Ying Xie, Elaine Lai-Han Leung, Pei-Yu Yan.
      In the past few decades, several gene mutations, including the anaplastic lymphoma kinase, epidermal growth factor receptor, ROS proto-oncogene 1 and rat sarcoma viral oncogene homolog (RAS), have been discovered in non-small cell lung cancer (NSCLC). Kirsten rat sarcoma viral oncogene homolog (KRAS) is the isoform most frequently altered in RAS-mutated NSCLC cases. Due to the structural and biochemical characteristics of the KRAS protein, effective approaches to treating KRAS-mutant NSCLC still remain elusive. Extensive recent research on KRAS-mutant inhibitors has made a breakthrough in identifying the covalent KRASG12C inhibitor as an effective agent for the treatment of NSCLC. This review mainly concentrated on introducing new covalent KRASG12C inhibitors like sotorasib (AMG 510) and adagrasib (MRTX 849); summarizing inhibitors targeting the KRAS-related upstream and downstream effectors in RAF/MEK/ERK pathway and PI3K/AKT/mTOR pathway; exploring the efficacy of immunotherapy and certain emerging immune-related therapeutics such as adoptive cell therapy and cancer vaccines. These inhibitors are being investigated in clinical trials and have exhibited promising effects. On the other hand, naturally extracted compounds, which have exhibited safe and effective properties in treating KRAS-mutant NSCLC through suppressing the MAPK and PI3K/AKT/mTOR signaling pathways, as well as through decreasing PD-L1 expression in preclinical studies, could be expected to enter into clinical studies. Finally, in order to confront the matter of drug resistance, the ongoing clinical trials in combination treatment strategies were summarized herein.
    Keywords:  KRAS; combination treatment; covalent KRASG12C inhibitor; immunotherapy; natural compound; non-small cell lung cancer
    DOI:  https://doi.org/10.3389/fphar.2022.875330
  55. Eur J Pharmacol. 2022 May 02. pii: S0014-2999(22)00252-7. [Epub ahead of print] 174991
    Exploring the role of senescence inducers and senotherapeutics as targets for anticancer natural products.
    Abdullah Al Mamun, Mohammad Abu Sufian, Md Sahab Uddin, Dewan Md Sumsuzzman, Philippe Jeandet, Mohammad Safiqul Islam, Hong-Jie Zhang, Ah-Ng Kong, Md Shahid Sarwar.
      During the last few decades, cancer has remained one of the deadliest diseases that endanger human health, emphasizing urgent drug discovery. Cellular senescence has gained a great deal of attention in recent years because of its link to the development of cancer therapy. Senescent cells are incapable of proliferating due to irreversibly inhibited the initiation of the cell cycle pathways. However, senescent cells aggregate in tissues and produce a pro-inflammatory secretome called senescence-associated secretory phenotype (SASP) that can cause serious harmful effects if not managed properly. There is mounting evidence that senescent cells lead to various phases of tumorigenesis in various anatomical sites, owing mostly to the paracrine activities of the SASP. Therefore, a new treatment field called senotherapeutics has been established. Senotherapeutics are newly developed anticancer agents that have been demonstrated to inhibit cancer effectively. In light of recent findings, several promising natural products have been identified as senescence inducers and senotherapeutics, including, miliusanes, epigallocatechin gallate, phloretin, silybin, resveratrol, genistein, sulforaphane, quercetin, allicin, fisetin, piperlongumine, berberine, triptolide, tocotrienols and curcumin analogs. Several of them have already been validated through preclinical trials and exert an enormous potential for clinical trials. This review article focuses on and summarises the latest advances on cellular senescence and its potential as a target for cancer treatment and highlights the well-known natural products as senotherapeutics for cancer treatment.
    Keywords:  Cancer; Cellular senescence; Natural products; Senolytic agents; Senotherapeutics
    DOI:  https://doi.org/10.1016/j.ejphar.2022.174991
  56. RSC Adv. 2020 Jul 21. 10(46): 27676-27687
    Simple weak-acid derivatives of paclitaxel for remote loading into liposomes and improved therapeutic effects.
    Jiang Yu, Shuang Zhou, Jinbo Li, Yingli Wang, Yujiao Su, Dongxu Chi, Jiamei Wang, Xue Wang, Zhonggui He, Guimei Lin, Dan Liu, Yongjun Wang.
      Liposomes are among the most successful nanocarriers; several products have been marketed, all of which were prepared by active loading methods. However, poorly water-soluble drugs without ionizable groups are usually incorporated into the lipid bi-layer of liposomes by passive loading methods, with serious drug leakage during blood circulation. Furthermore, there have been few improvements in their anti-cancer activity and safety. Herein, we designed and synthesized three weak-acid modified paclitaxel (PTX) derivatives with a one-step reaction for the remote loading of liposomal formulations. By comparison, PTX-succinic acid liposomes (PTX-SA LPs) exhibited the highest encapsulation efficiency (97.2 ± 1.8%) and drug loading (8.84 ± 0.16%); meanwhile, there was almost no change in their particle size or zeta potential within one month. Furthermore, compared with Taxol®, the PTX-SA LPs showed a 4.35-fold prolonged half-time, enhanced tumor accumulation, and an increased maximum tolerated dose (MTD) of more than 30 mg kg-1. As a result, the PTX-SA LPs displayed significantly improved in vivo anti-cancer efficacy in comparison with Taxol®. Therefore, weak-acid modification is proved to be a simple and effective method to achieve remote loading and high encapsulation efficiency of poorly soluble drugs, showing great potential for clinical application.
    DOI:  https://doi.org/10.1039/d0ra03190a
  57. APL Bioeng. 2022 Jun;6(2): 026101
    Use of mesoporous polydopamine nanoparticles as a stable drug-release system alleviates inflammation in knee osteoarthritis.
    Yun Wang, Weiwen Ge, Zhigui Ma, Guangyu Ji, Mingsong Wang, Guangdong Zhou, Xiansong Wang.
      Osteoarthritis drugs are often short-acting; therefore, to enhance their efficacy, long-term, stable-release, drug-delivery systems are urgently needed. Mesoporous polydopamine (MPDA), a natural nanoparticle with excellent biocompatibility and a high loading capacity, synthesized via a self-aggregation-based method, is frequently used in tumor photothermal therapy. Here, we evaluated its efficiency as a sustained and controlled-release drug carrier and investigated its effectiveness in retarding drug clearance. To this end, we used MPDA as a controlled-release vector to design a drug-loaded microsphere system (RCGD423@MPDA) for osteoarthritis treatment, and thereafter, tested the efficacy of the system in a rat model of osteoarthritis. The results indicated that at an intermediate drug-loading dose, MPDA showed high drug retention. Furthermore, the microsphere system maintained controlled drug release for over 28 days. Our in vitro experiments also showed that drug delivery using this microsphere system inhibited apoptosis-related cartilage degeneration, whereas MPDA-only administration did not show obvious cartilage degradation improvement effect. Results from an in vivo osteoarthritis model also confirmed that drug delivery via this microsphere system inhibited cartilage damage and proteoglycan loss more effectively than the non-vectored drug treatment. These findings suggest that MPDA may be effective as a controlled-release carrier for inhibiting the overall progression of osteoarthritis. Moreover, they provide insights into the selection of drug-clearance retarding vectors, highlighting the applicability of MPDA in this regard.
    DOI:  https://doi.org/10.1063/5.0088447
  58. J Photochem Photobiol B. 2022 Apr 25. pii: S1011-1344(22)00063-X. [Epub ahead of print]231 112449
    Photosensitization of pancreatic cancer cells by cationic alkyl-porphyrins in free form or engrafted into POPC liposomes: The relationship between delivery mode and mechanism of cell death.
    Eros Di Giorgio, Annalisa Ferino, Himanshi Choudhary, Phillip M G Löffler, Francesca D'Este, Valentina Rapozzi, Alexander Tikhomirov, Andrey Shchekotikhin, Stefan Vogel, Luigi E Xodo.
      Cationic porphyrins bearing an alkyl side chain of 14 (2b) or 18 (2d) carbons dramatically inhibit proliferation of pancreatic cancer cells following treatment with light. We have compared two different ways of delivering porphyrin 2d: either in free form or engrafted into palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes (L-2d). Cell cytometry shows that while free 2d is taken up by pancreatic cancer cells by active (endocytosis) and passive (membrane fusion) transports, L-2d is internalized solely by endocytosis. Confocal microscopy showed that free 2d co-localizes with the cell membrane and lysosomes, whereas L-2d partly co-localizes with lysosomes and ER. It is found that free 2d inhibits the KRAS-Nrf2-GPX4 axis and strongly triggers lipid peroxidation, resulting in cell death by ferroptosis. By contrast, L-2d does not affect the KRAS-Nrf2-GPX4 axis and activates cell death mainly through apoptosis. Overall, our study demonstrates for the first time that cationic alkyl porphyrins, which have a IC50 ~ 23 nM, activate a dual mechanism of cell death, ferroptosis and apoptosis, where the predominant form depends on the delivery mode.
    Keywords:  Alkyl-porphyrins; Apoptosis; Ferroptosis; GXP4; KRAS; POPC liposomes; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.jphotobiol.2022.112449
  59. RSC Adv. 2020 Oct 21. 10(64): 39348-39358
    Ultrasound-mediated delivery of RGD-conjugated nanobubbles loaded with fingolimod and superparamagnetic iron oxide nanoparticles: targeting hepatocellular carcinoma and enhancing magnetic resonance imaging.
    Xin-Min Guo, Jia-Lin Chen, Bao-Hui Zeng, Ji-Chuang Lai, Cui-Yan Lin, Mei-Yan Lai.
      Nanobubbles (NBs) are considered to be a new generation of ultrasound-responsive nanocarriers that can effectively target tumors, accurately release multi-drugs at desired locations, as well as simultaneously perform diagnosis and treatment. In this study, we designed theranostic NBs (FTY720@SPION/PFP/RGD-NBs) composed of RGD-modified liposomes as the shell, and perflenapent (PFP), superparamagnetic iron oxide nanoparticles (SPION), and fingolimod (2-amino-2[2-(4-octylphenyl)ethyl]-1,3-propanediol, FTY720) encapsulated as the core. The prepared FTY720@SPION/PFP/RGD-NBs were black spheres with a diameter range of 160-220 nm, eligible for enhanced permeability and retention (EPR) effects. The calculated average drug loading efficiency (LE) and encapsulation efficiency (EE) of the FTY720@SPION/PFP/RGD-NBs were 9.18 ± 0.61% and 88.26 ± 2.31%, respectively. With the promotion of low-intensity focused ultrasound (LIFU), the amount and the rate of FTY720 released from the prepared NB complex were enhanced when compared to the samples without LIFU treatment. In vitro magnetic resonance imaging (MRI) trials showed that the prepared FTY720@SPION/PFP/RGD-NBs had a high relaxation rate and MRI T2-weighted imaging (T2WI) scanning sensitivity conditions. The cell viability studies demonstrated that both HepG2 and Huh7 cells co-cultured with FTY720@SPION/PFP/RGD-NB (100 μg mL-1) + LIFU treatment had the lowest survival rate compared with the other groups at 24 h and 48 h, showing that FTY720@SPION/PFP/RGD-NB had the strongest anti-tumor efficiency among the prepared NBs. The cytotoxicity study also demonstrated that the prepared NBs had low toxicity to normal fibroblast 3T3 cells. Cellular uptake studies further indicated that both LIFU treatment and RGD modification could effectively improve the tumor-targeted effects, thereby enhancing the antitumor efficacy. The qRT-PCR results indicated that LIFU-mediated FTY720@SPION/PFP/RGD-NB could significantly cause the activation of Caspase3, Caspase9 and p53 compared to the control group, inducing HepG2 apoptosis. These results together indicated that FTY720@SPION/PFP/RGD-NBs combined with LIFU may serve as a multifunctional drug delivery platform for hepatocellular carcinoma treatment and provide a new strategy for tumor visualization by MRI.
    DOI:  https://doi.org/10.1039/d0ra06415g
  60. Curr Pharm Des. 2022 May 06.
    Functionalized PAMAM-Based Nanoformulation for Targeted Delivery of 5-Fluorouracil in Hepatocellular Carcinoma.
    Siwei Chen, Hu Ouyang, Dongxiu He, Daquan Liu, Xiao Wang, Hongyuan Chen, Wei Pan, Qi Li, Weiquan Xie, Cuiyun Yu.
      BACKGROUND: Efficacy of a traditional anticancer drug is challenged by adverse effects of the drug including its nonspecific bio-distribution, short half-life and side effects. Dendrimer-based targeted drug delivery sysytem has been considered as a promising strategy to increase targeting ability and reduce adverse effects of anti-cancer drugs.OBJECTIVE: This study analyzed the feasibility whether the anticancer drug 5-fluorouracil (5-FU) could be delivered by functionalized fifth-poly(amidoamine) (PAMAM) with the peptide WP05 and the acetic anhydride to the liver cancer cells, reducing toxicity of the PAMAM and improving the targeting property of 5-FU during delivery.
    METHODS: The functionalized PAMAM-based nanoformulation (WP05-G5.0NHAC-FUA) was fabricated through an amide condensation reaction to improve therapeutic efficacy of 5-Fluorouracil (5-FU) in hepatocellular carcinoma (HCC). The physicochemical structure, particle size, zeta potential, stability and in vitro release characteristics of WP05-G5.0NHAC-FUA were evaluated. In addition, the targeting, biocompatibility, anti-proliferation and anti-migration of WP05-G5.0NHAC-FUA were investigated. The anti-tumor effect of WP05-G5.0NHAC-FUA in vivo was evaluated by constructing xenograft tumor models of hunman hepatoma cells (Bel-7402) implanted in nude mice.
    RESULTS: The resultant WP05-G5.0NHAC-FUA displayed spherical-like nanoparticles with the size of 174.20 ± 3.59 nm. Zeta potential and the drug loading of WP05-G5.0NHAC-FUA were 5.62 ± 0.41mV and 28.67 ± 1.25 %, respectively. Notably, the optimized 5-FU-loaded formulation showed greater cytotoxicity with an IC50 of 30.80 ±4.04 μg/mL than free 5-FU (114.93 ±1.43 μg/mL) in Bel-7402 cancer liver cells, but a significantly reduced side effect relative to free 5-FU in L02 normal liver cells. In vivo animal study further confirmed efficient tumor accumulation and enhanced therapeutic efficiency.
    CONCLUSION: The developed nanoformulation is a promising platform for the targeting delivery of 5-FU and provides a promising solution for improving the efficacy of hepatocellular carcinoma chemotherapy.
    Keywords:  5-Fluorouracil; WP05; drug delivery system; functionalized PAMAM; hepatocellular carcinoma
    DOI:  https://doi.org/10.2174/1381612828666220506111918
  61. Curr Top Med Chem. 2022 May 04.
    Natural antioxidants as additional weapons in fight against malarial parasite.
    Sharma Arvind Virendra, Chandrakant Sahu, Ankur Kumar, Pooja A Chawla.
      BACKGROUND: All currently available antimalarial drugs are developed from natural product lineages that may be traced back to herbal medicines including quinine, lapachol, and artemisinin. Natural products, which primarily target free radicals or reactive oxygen species, play an important role in the treatment of malaria.OBJECTIVE: To review role of antioxidative therapy in treatment of malaria by scavenging or counter free radical and also review importance of natural plant extracts as antioxidants in oxidative therapy of malaria treatment.
    METHODS: The search for natural antioxidants was conducted using the following databases of Researchgate, science direct, google scholar, Bentham science using following keywords malaria, reactive oxygen species, natural antioxidants and antiplasmodial.
    CONCLUSION: This study reviewed various literature sources related to natural products employed in antimalarial therapy directly or indirectly by countering/scavenging reactive oxygen species that were published between 2016 to till date. The literature survey made it possible to summarize the natural products used in the treatment of malaria, with emphasis on botanical extracts, as a single component, as well as in association with other botanical extracts. Natural antioxidants like polyphenols, flavonoids, alkaloids, having a broad range of biological effects against malaria. This review is pivoted around natural antioxidants obtained from the food and medicinal plants and to explore their application in restraining reactive oxygen species (ROS). We anticipate this article will provide information on future research on the role of antioxidant therapy in malaria infection.
    Keywords:  Malaria; Reactive oxygen species; oxidative stress; plant extracts
    DOI:  https://doi.org/10.2174/1568026622666220504172655
  62. Appl Biochem Biotechnol. 2022 May 04.
    Bromelain Loaded Lipid-Polymer Hybrid Nanoparticles for Oral Delivery: Formulation and Characterization.
    Mahboubeh Ebrahimian, Fatemeh Mahvelati, Bizhan Malaekeh-Nikouei, Ezzat Hashemi, Fatemeh Oroojalian, Maryam Hashemi.
      Bromelain (Br), a mixture of proteolytic enzymes from pineapple (Ananas comosus), has various therapeutic potentials; however, its low bioavailability has limited the clinical applications specifically in oral delivery as the most common convenient used route of administration. In the present study, a lipopolymeric nanoparticle (NP) containing Br was developed to enhance its stability and oral delivery efficiency. Firstly, Br was loaded into poly (D, L-lactide-co-glycolide acid) (PLGA) and PLGA-phosphatidylcholine (PLGA-PC) NPs using double emulsion solvent evaporation technique. Then, Br integrity and activity were investigated using SDS-PAGE and gelatin test. The stability and release profile of Br from synthetized NPs were evaluated at different pH values of the digestive system. Furthermore, cytotoxicity, cellular uptake, and the amount of Br passage from Caco-2 cells were explored. The results showed PLGA-PC-Br NPs had higher encapsulation efficiency (83%) compared to PLGA-Br NPs (50%). In addition, this NP showed more Br released in neutral (20.36%) and acidic (34%) environments compared to PLGA-Br NPs after 5 days. The delay in the release of Br from PLGA-PC-Br NPs versus the faster release of Br from PLGA-Br formulation could assure that an appropriate concentration of Br has reached the intestine. Intestinal absorption study demonstrated that lipid polymer NPs were able to pass through Caco-2 cells about 1.5 times more (98.4%) than polymeric NPs (70%). In conclusion, PLGA-PC NPs would be considered as a promising lipid-polymer nanocarrier for effective intestinal absorption of Br.
    Keywords:  Bromelain; Lipid-polymer nanoparticles; Oral administration; PLGA
    DOI:  https://doi.org/10.1007/s12010-022-03812-z
  63. Front Med (Lausanne). 2022 ;9 866343
    Combination of Vitamin C and Curcumin Safeguards Against Methotrexate-Induced Acute Liver Injury in Mice by Synergistic Antioxidant Effects.
    Dhekra Hasan Khudhair, Ali I Al-Gareeb, Hayder M Al-Kuraishy, Aya H El-Kadem, Engy Elekhnawy, Walaa A Negm, Sameh Saber, Simona Cavalu, Adrian Tirla, Saqer S Alotaibi, Gaber El-Saber Batiha.
      Methotrexate (MTX), an antineoplastic and immunosuppressive drug, widely used in the treatment of different types of cancers and the management of chronic inflammatory diseases. However, its use is associated with hepatotoxicity. Vitamin C (VC) and curcumin (CUR) exhibit anti-inflammatory and antioxidant effects. Thus, we aimed to investigate the potential hepatoprotective effects of VC and CUR pretreatment alone and in combination against MTX-induced hepatotoxicity. Albino mice were randomly divided into 7 groups: the control group, which received only normal saline; MTX group; VC group, pretreated with VC (100 or 200 mg/kg/day orally) for 10 days; CUR group, pretreated with CUR (10 or 20 mg/kg/day orally); and combination group, which received VC (100 mg/kg) and CUR (10 mg/kg). MTX was administered (20 mg/kg, intraperitoneally) to all the groups on the tenth day to induce hepatotoxicity. Forty eight hours after MTX administration, the mice were anesthetized. Blood samples were collected, the liver was removed for biochemical analysis, and a part of the tissue was preserved in formalin for histopathological analysis. The results indicated that pretreatment with a combination of VC and CUR induced a more significant decrease in the serum levels of alanine transaminase, aspartate transaminase, alkaline phosphatase, and lactic dehydrogenase and a significant increase in the tissue level of superoxide dismutase and glutathione; furthermore, it induced a significant decrease in malondialdehyde levels and improvement in histopathological changes in the liver tissues, confirming the potential hepatoprotective effects of the combination therapy on MTX-induced liver injury. To conclude, MTX-induced hepatotoxicity is mediated by induction of oxidative stress as evident by increased lipid peroxidation and reduction of antioxidant enzyme activity. Pretreatment with VC, CUR or their combination reduces the MTX-induced hepatotoxicity by antioxidant and anti-inflammatory effects. However, the combined effect of VC and CUR provided a synergistic hepatoprotective effect that surpasses pretreatment with CUR alone but seems to be similar to that of VC 200 mg/kg/day. Therefore, VC and CUR combination or a large dose of VC could be effective against MTX-induced hepatotoxicity. In this regard, further studies are warranted to confirm the combined hepatoprotective effect of VC and CUR against MTX-induced hepatotoxicity.
    Keywords:  Methotrexate; antioxidants; curcumin; liver; oxidative stress; vitamin C
    DOI:  https://doi.org/10.3389/fmed.2022.866343
  64. Biochemistry (Mosc). 2022 Feb;87(2): 141-149
    Investigation of the Antioxidant Properties of the Quaternized Chitosan Modified with a Gallic Acid Residue Using Peroxidase that Produces Reactive Oxygen Species.
    Dmitry B Kiselevsky, Alla V Il'ina, Alexey P Lunkov, Valery P Varlamov, Vitaly D Samuilov.
      Chitosan modified with a (2-hydroxy-3-trimethylammonium) propyl group and gallic acid residue, or quaternized chitosan with gallic acid (QCG), was synthesized. Antioxidant properties of the produced QCG have been investigated. Peroxidase in combination with NADH and salicyl hydroxamate (SHAM) caused consumption of oxygen and production of H2O2 in aqueous solution as a result of O2 reduction in the peroxidase-oxidase reactions. The rates of O2 consumption and H2O2 generation were reduced in the presence of QCG. The antioxidant propyl gallate (PG) and superoxide dismutase (SOD) had the same effect, but not the quaternized chitosan (QC) without gallic acid. The effect of chitosan derivatives on the production of reactive oxygen species (ROS) in the cells of pea leaf epidermis and on the cell death detected by the destruction of cell nuclei, was investigated. QCG, QC, and SOD had no effect, while PG decreased the rate of ROS generation in the cells of the epidermis, which was induced by NADH with SHAM or by menadione. QCG and QC prevented destruction of the guard cell nuclei in the pea leaf epidermis that was caused by NADH with SHAM or by KCN. SOD had no effect on the destruction of nuclei, while the effect of PG depended on the inducer of the cell death. Suppression of the destruction of guard cell nuclei by chitosan derivatives was associated not with their antioxidant effect, but with the disruption of the plasma membrane of the cells. The results obtained have shown that QCG exhibits antioxidant properties in solutions, but does not prevent generation of ROS in the plant cells. The mechanism of antioxidant effect of QCG is similar to that of PG and SOD.
    Keywords:  chitosan; peroxidase; propyl gallate; quaternized chitosan; reactive oxygen species; superoxide dismutase
    DOI:  https://doi.org/10.1134/S0006297922020067
  65. Curr Treat Options Psychiatry. 2022 Apr 23. 1-12
    A Possible Antidepressive Effect of Dietary Interventions: Emergent Findings and Research Challenges.
    Gilciane Ceolin, Vitor Breda, Elena Koning, Arun Chinna Meyyappan, Fabiano A Gomes, Júlia Dubois Moreira, Fernando Gerchman, Elisa Brietzke.
      Purpose: Despite recent advancements in the treatment of depression, the prevalence of affected individuals continues to grow. The development of new strategies has been required and emerging evidence has linked a possible antidepressant effect with dietary interventions. In this review, we discuss recent findings about the possible antidepressant effect of dietary interventions with an emphasis on the results of randomized controlled trials.Recent findings: A high consumption of refined sugars and saturated fat and a low dietary content of fruits and vegetables has been associated with the development of depression. There is evidence supporting a small to moderate beneficial effect of a Mediterranean-type diet in depression. In addition, new dietary protocols are being studied for their use as possible interventions, such as the ketogenic diet, Nordic diet, and plant-based diet.
    Summary: Lifestyle interventions surrounding diet and nutrition are a relatively affordable way to enhance response to treatment and to be employed as an adjunct in mental health care. Most studies, however, are limited by the difficulty in controlling for the placebo effect. Mediterranean-style diets seem to be the most promising as an adjunctive treatment for mood disorders. Larger randomized controlled trials that could assess predictors of response to dietary interventions are needed to establish a clear positive effect of diet and guide clinical care and nutritional recommendations concerning mental health care.
    Keywords:  Antidepressant; Bipolar disorder; Depression; Major depressive disorders; Mood disorders; Nutrition
    DOI:  https://doi.org/10.1007/s40501-022-00259-1
  66. RSC Adv. 2020 Jun 02. 10(36): 21413-21419
    Magnetic mesoporous bioactive glass for synergetic use in bone regeneration, hyperthermia treatment, and controlled drug delivery.
    Muhammad Saif Ur Rahman, Muhammad Asif Tahir, Saima Noreen, Muhammad Yasir, Ijaz Ahmad, Muhammad Bilal Khan, Khawajah Waqar Ali, Muhammad Shoaib, Ali Bahadur, Shahid Iqbal.
      A combination of chemotherapy with hyperthermia can produce remarkable success in treating advanced cancers. For this purpose, magnetite (Fe3O4)-doped mesoporous bioactive glass nanoparticles (Fe3O4-MBG NPs) were synthesized by the sol-gel method. Fe3O4-MBG NPs were found to possess spherical morphology with a size of approximately 50 ± 10 nm and a uniform pore size of 9 nm. The surface area (309 m2 g-1) was sufficient for high drug loading capacity and mitomycin C (Mc), an anticancer drug, was entrapped in the Fe3O4-MBG NPs. A variable rate of drug release was observed at different pH values (6.4, 7.4 & 8.4) of the release media. No significant death of normal human fibroblast (NHFB) cells was observed during in vitro analysis and for Mc-Fe3O4-MBG NPs considerable inhibitory effects on the viability of cancer cells (MG-63) were observed. When Fe3O4-MBG NPs were immersed in simulated body fluid (SBF), hydroxycarbonate apatite (HCA) was formed, as confirmed by XRD and FTIR spectra. A negligible value of coercivity and zero remanence confirms that Fe3O4-MBG NPs are superparamagnetic. Fe3O4-MBG NPs showed a hyperthermia effect in an alternating magnetic field (AMF), and a rise of 11.5 °C in temperature during the first 6 min, making it suitable for hyperthermia applications. Fe3O4-MBG NPs expressed excellent biocompatibility and low cytotoxicity, therefore, they are a safe biomaterial for bone tissue regeneration, drug delivery, and hyperthermia treatment.
    DOI:  https://doi.org/10.1039/c9ra09349d
  67. J Colloid Interface Sci. 2022 Apr 20. pii: S0021-9797(22)00652-X. [Epub ahead of print]622 298-308
    Carrier free nanomedicine for synergistic cancer therapy by initiating apoptosis and paraptosis.
    Rongrong Zheng, Yibin Liu, Baixue Yu, Linping Zhao, Ni Yang, Ali Chen, Lin Xu, Hong Cheng, Xueyan Jiang, Shiying Li.
      Although photodynamic therapy (PDT) has been well-known as a promising anti-tumor treatment, its limited therapeutic efficiency remains to be a large challenge. In this study, a carrier free nanomedicine (designated as PyroMor) is developed to greatly initiate cell apoptosis and paraptosis for synergistic cancer therapy. Pyropheophorbide-a (Pyro) and morusin (Mor) are capable of self-assembling into PyroMor, which has been testified to have superiority of improved stability, cellular internalization, and biocompatibility. Because of efficient cellular uptake behavior, PyroMor could induce cellular paraptosis by Mor-caused vacuolation in mitochondria, ER and cytoplasm, contributing to improving the PDT efficacy of Pyro. Therefore, self-delivery PyroMor is able to accomplish synergistic anti-tumor effect via stimulation of cell apoptosis as well as paraptosis. In addition, in vivo studies also clarify that PyroMor presents passive tumor targeting delivery, leading to robust repressive effect on tumor proliferation with negligible systemic toxicity. This strategy of combined cancer therapy by initiating both cell apoptosis and paraptosis extremely benefits to the development of precise and effective cancer therapy in clinic.
    Keywords:  Carrier free nanomedicine; Cell apoptosis; Paraptosis; Photodynamic therapy; Vacuolation
    DOI:  https://doi.org/10.1016/j.jcis.2022.04.090
  68. J Nanobiotechnology. 2022 May 06. 20(1): 216
    Simultaneous glutamine metabolism and PD-L1 inhibition to enhance suppression of triple-negative breast cancer.
    Yuxia Tang, Siqi Wang, Yang Li, Chen Yuan, Jie Zhang, Ziqing Xu, Yongzhi Hu, Haibin Shi, Shouju Wang.
      Blockade of programmed cell death 1 ligand (PD-L1) has been used to treat triple-negative breast cancer (TNBC), and various strategies are under investigation to improve the treatment response rate. Inhibition of glutamine metabolism can reduce the massive consumption of glutamine by tumor cells and meet the demand for glutamine by lymphocytes in tumors, thereby improving the anti-tumor effect on the PD-L1 blockade therapy. Here, molybdenum disulfide (MoS2) was employed to simultaneously deliver anti-PDL1 antibody (aPDL1) and V9302 to boost the anti-tumor immune response in TNBC cells. The characterization results show that MoS2 has a dispersed lamellar structure with a size of about 181 nm and a size of 232 nm after poly (L-lysine) (PLL) modification, with high stability and biocompatibility. The loading capacity of aPDL1 and V9302 are 3.84% and 24.76%, respectively. V9302 loaded MoS2 (MoS2-V9302) can effectively kill 4T1 cells and significantly reduce glutamine uptake of tumor cells. It slightly increases CD8+ cells in the tumor and promotes CD8+ cells from the tumor edge into the tumor core. In vivo studies demonstrate that the combination of aPDL1 and V9302 (MoS2-aPDL1-V9302) can strongly inhibit the growth of TNBC 4T1 tumors. Interestingly, after the treatment of MoS2-aPDL1-V9302, glutamine levels in tumor interstitial fluid increased. Subsequently, subtypes of cytotoxic T cells (CD8+) in the tumors were analyzed according to two markers of T cell activation, CD69, and CD25, and the results reveal a marked increase in the proportion of activated T cells. The levels of cytokines in the corresponding tumor interstitial fluid are also significantly increased. Additionally, during the treatment, the body weights of the mice remain stable, the main indicators of liver and kidney function in the blood do not increase significantly, and there are no obvious lesions in the main organs, indicating low systemic toxicity. In conclusion, our study provides new insights into glutamine metabolism in the tumor microenvironment affects immune checkpoint blockade therapy in TNBC, and highlights the potential clinical implications of combining glutamine metabolism inhibition with immune checkpoint blockade in the treatment of TNBC.
    Keywords:  Anti-PDL1; Glutamine metabolism inhibitor; MoS2 nanosheets; Triple-negative breast cancer; V9302
    DOI:  https://doi.org/10.1186/s12951-022-01424-7
  69. Cancer Lett. 2022 May 02. pii: S0304-3835(22)00197-5. [Epub ahead of print] 215713
    Metabolism in the progression and metastasis of brain tumors.
    Abhishek Tyagi, Shih-Ying Wu, Kounosuke Watabe.
      Malignant brain tumors and metastases pose significant health problems and cause substantial morbidity and mortality in children and adults. Based on epidemiological evidence, gliomas comprise 30% and 80% of primary brain tumors and malignant tumors, respectively. Brain metastases affect 15-30% of cancer patients, particularly primary tumors of the lung, breast, colon, and kidney, and melanoma. Despite advancements in multimodal molecular targeted therapy and immunotherapy that do not ensure long-term treatment, malignant brain tumors and metastases contribute significantly to cancer related mortality. Recent studies have shown that metastatic cancer cells possess distinct metabolic traits to adapt and survive in new environment that differs significantly from the primary site in both nutrient composition and availability. As metabolic regulation lies at the intersection of many research areas, concerted efforts to understand the metabolic mechanism(s) driving malignant brain tumors and metastases may reveal novel therapeutic targets to prevent or reduce metastasis and predict biomarkers for the treatment of this aggressive disease. This review focuses on various aspects of metabolic signaling, interface between metabolic regulators and cellular processes, and implications of their dysregulation in the context of brain tumors and metastases.
    Keywords:  Brain metastasis; Brain tumor; Cancer; Immune cell metabolism; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.canlet.2022.215713
  70. Chempluschem. 2022 Apr 20. e202200086
    Rational Molecular Design of Efficient Heavy-Atom-Free Photosensitizers for Cancer Photodynamic Therapy.
    Van-Nghia Nguyen, Jeongsun Ha, Hyunsun Jeong, Moonyeon Cho, Gyongmi Kim, Juyoung Yoon.
      Photodynamic therapy has emerged as a promising modality for treatment of cancer due to its minimal invasiveness and high selectivity. However, development of advanced photosensitizers (PSs) for clinical translation of photodynamic therapy remains challenging. To overcome the limitations of common photosensitizers containing heavy atoms, we herein developed highly effective heavy-atom-free photosensitizers based on strong donor-π-acceptor-type structures (PTZ-CN and PXZ-CN) for bioimaging and photodynamic ablation of cancer. These PSs exhibited bright fluorescence emission with a large Stokes shift as well as considerable reactive oxygen generation capability under specific conditions. Notably, PTZ-CN could produce reactive oxygen species more efficiently than Ru(bpy)3 2+ (commercial PS) with an approximately 2.2-fold via type I and type II photochemical mechanisms. In addition, their stable nanoparticles were easily formed by self-assembly in an aqueous solution without employing a polymer. More importantly, PTZ-CN/PXZ-CN exhibited bright fluorescence and excellent photodynamic performance with negligible dark cytotoxicity toward HeLa cells. This study demonstrates the promising potential of donor-π-acceptor-type molecule-based PSs in fluorescence image-guided photodynamic therapy.
    Keywords:  donor-acceptor structure; intersystem crossing; photodynamic therapy; photosensitizer; reactive oxygen species
    DOI:  https://doi.org/10.1002/cplu.202200086
  71. RSC Adv. 2020 Jul 15. 10(45): 27161-27172
    Understanding the relevance of protein corona in nanoparticle-based therapeutics and diagnostics.
    Debolina Chakraborty, K R Ethiraj, Amitava Mukherjee.
      Over the past few decades, nanoparticle-based therapeutic and diagnostic systems have gained immense recognition. A relative improvement in the status of the global cancer burden has been successful due to the advent of nanoparticle-based formulations. However, exposure of nanoparticles (NPs) to a real-time biological media alters its native identity due to the formation of the biomolecular corona. Such biological interactions hinder the efficiency of the NPs system. The parameters that govern such intricate interaction are generally overlooked while designing nano drugs and delivery systems (nano-DDS). Fabricating nano-DDS with prolonged circulation time, enhanced drug-loading, and release capacity along with efficient clearance, remain the primary concerns associated with cancer therapeutics. This present review firstly aims to summarize the critical aspects that influence protein coronation on therapeutic nanoparticles designed for anti-cancer therapy. The role of protein corona in modifying the overall pharmacodynamics of the nanoparticle-based DDS has been discussed. Further, the studies and patents that extend the concept of protein corona into diagnostics have been elaborated. An understanding of the pros and cons associated with protein coronation would not only help us gain better insights into the fabrication of effective anti-cancer drug-delivery systems but also improve the shortcomings related to the clinical translation of these nanotherapeutics.
    DOI:  https://doi.org/10.1039/d0ra05241h
  72. Adv Mater. 2022 May 06. e2203246
    Activatable cancer sono-immunotherapy using semiconducting polymer nanobodies.
    Ziling Zeng, Chi Zhang, Shasha He, Jingchao Li, Kanyi Pu.
      Despite the great promises of sonodynamic therapy (SDT) in combination cancer therapy, its clinical applications are hindered by the lack of efficient sonosensitizers and "always-on" pharmacological activities of therapeutic agents. Herein, we report the development of semiconducting polymers as efficient sonosensitizers and further development of sono-immunotherapeutic nanobodies (SPNAb ) for activatable cancer sono-immunotherapy. Conjugation of anti-CTLA-4 antibodies onto the polymer nanoparticles through 1 O2 -cleavable linker affords SPNAb with relatively low CTLA-4 binding affinity. Upon sono-irradiation, SPNAb generates 1 O2 not only to elicit sonodynamic effect to induce the immunogenic cell death, but also to release anti-CTLA-4 antibodies and trigger in situ checkpoint blockade. Such a synergistic therapeutic action mediated by SPNAb modulates the tumoricidal function of T-cell immunity by promoting the proliferation of cytotoxic T lymphocytes and depleting immunosuppressive regulatory T cells, resulting in effective tumor regression, metastasis inhibition, durable immunological memory, and prevention of relapse. Therefore, this study represents a proof-of-concept sonodynamic strategy using semiconducting polymers for precise spatiotemporal control over immunotherapy. This article is protected by copyright. All rights reserved.
    Keywords:  Organic nanoparticles; cancer therapy; immunotherapy; sonodynamic therapy
    DOI:  https://doi.org/10.1002/adma.202203246
  73. RSC Adv. 2020 Aug 10. 10(50): 30094-30109
    Rational design of yolk-shell nanostructures for drug delivery.
    Ghodsi Mohammadi Ziarani, Parisa Mofatehnia, Fatemeh Mohajer, Alireza Badiei.
      Yolk-shell nanoparticles (YSNPs) are a new class of hollow nanostructures, and their unique properties can be utilized in drug delivery systems. The recent progress in YSNPs-based carriers is highlighted in drug delivery systems. Doxorubicin hydrochloride, ceftriaxone sodium, and methotrexate are three of the most common drugs that are used in this field. According to the reported studies, the materials used most often as yolk-shells are magnetic nanoparticles and polymers. The used methods for synthesizing a diverse array of YSNPs are classified based on their core structures. Various properties of YSNPs include their high drug-loading capacity, and their ability to decrease drug toxicity and satisfactorily and efficiently release drugs.
    DOI:  https://doi.org/10.1039/d0ra03611k
  74. RSC Adv. 2020 Jun 08. 10(37): 22091-22101
    A tumor-microenvironment-responsive nanomaterial for cancer chemo-photothermal therapy.
    Kaiyu Wang, Zhiyuan Cai, Rong Fan, Qian Yang, Tao Zhu, Zhongying Jiang, Yuqiang Ma.
      Taxol (TAX) is a typical anticancer drug that is widely used in clinical treatment of cancer, while gold nanorods (AuNRs) are a kind of well-known material applied for photothermal therapy (PTT). The therapeutic outcome of TAX in chemotherapy is however limited by drug resistance, while AuNRs often show poor accuracy in PTT. To optimize the functions of TAX and AuNRs, we developed a hydrogen peroxide (H2O2)-triggered nanomaterial (LV-TAX/Au@Ag) for combined chemo-photothermal therapy. In normal tissues, TAX is protected in the lipid bilayer and isolated from the surrounding normal cells, while AuNRs are coated with silver shells and show low photothermal capacity. However, after reaching the tumor tissues, the silver shells can be etched by endogenous H2O2 in the tumor microenvironment, and the photothermal properties of AuNRs are then recovered. Meanwhile, the generated oxygen destabilizes the LV, which makes the 100 nm sized nanosystems disassemble into the smaller sized TAX and AuNRs, leading to the deep penetration and direct interaction with tumor tissues. The related in vitro experiments proved the validity of this "turn off/on" effect. Extensive necrosis and apoptosis were observed in the tumor tissues and the proliferation of solid tumor was greatly suppressed due to this combined chemo-photothermal therapy. In addition, no significant damage was found in normal tissues after the treatment of LV-TAX/Au@Ag. Therefore, the strategy to achieve environmental response by modifying the photothermal agents enhanced the efficiency and safety of nanomedicine, which may help improve cancer treatment.
    DOI:  https://doi.org/10.1039/d0ra04171h
  75. RSC Adv. 2020 Jun 19. 10(40): 24095-24107
    Effective in vitro delivery of paclitaxel by nanocargo of mesoporous polycaprolactone against triple negative breast cancer cells by minimalizing drug dose.
    Himadri Medhi, Saratchandra Singh Khumukcham, Bramanandam Manavathi, Pradip Paik.
      Among the breast cancers, triple negative breast cancer (TNBC) has relatively poor outcomes with a lower survival rate and personalised chemotherapy is the only option available for treatment. Currently in the biomedical domain, nanomaterials with porous morphology have revealed their tremendous possibilities to be used as a nanocarrier in treating cancer by offering void space to encapsulate/entrap biological agents. However, the development of nanocarrier-based targeted therapy with high therapeutic efficacy and fewer side effects to normal cells is always a challenge. Here, we have developed nanocargos based on biodegradable mesoporous PCL (polycaprolactone) of approx. diameter of 75 nm by template removal synthesis techniques. Succeeding the comparative analysis of the nanocarriers, the efficiencies of core shell PCL-mZnO (PZ) and mesoporous PCL (HPZ) to deliver paclitaxel (Taxol/T) into breast cancer cells, is investigated. We found that HPZ nanocapsules have less cytotoxicity and drug loading efficiency of about 600 μg mg-1. The Taxol-loaded nanoparticles (T-HPZ) have exhibited more cytotoxicity than Taxol alone treated cancer cells. Furthermore, T-HPZ treated MDA-MB231 cells are accumulated at G2/M phase of the cell cycle and eventually undergo apoptosis. In support of this, anchorage independent growth of MDA-MB231 cells are significantly inhibited by T-HPZ treatment. Together, our findings suggest that T-HPZ-based paclitaxel (Taxol/T) loaded nanoparticles provide a novel therapeutic option in the treatment of TNBC.
    DOI:  https://doi.org/10.1039/d0ra04505e
  76. Nanoscale. 2022 May 05.
    Doxorubicin delivery performance of superparamagnetic carbon multi-core shell nanoparticles: pH dependence, stability and kinetic insight.
    Adriano Santos Silva, Jose Luis Diaz de Tuesta, Thais Sayuri Berberich, Simone Delezuk Inglez, Ana Raquel Bertão, Ihsan Çaha, Francis Leonard Deepak, Manuel Bañobre-López, Helder Teixeira Gomes.
      In the past decade, magnetic nanoparticles (MNPs) have been among the most attractive nanomaterials used in different fields, such as environmental and biomedical applications. The possibility of designing nanoparticles with different functionalities allows for advancing the biomedical applications of these materials. Additionally, the magnetic characteristics of the nanoparticles enable the use of magnetic fields to drive the nanoparticles to the desired sites of delivery. In this context, the development of new MNPs in new approaches for drug delivery systems (DDSs) for cancer treatment has increased. However, the synthesis of nanoparticles with high colloidal stability triggered drug delivery, and good biocompatibility remains a challenge. Herein, multi-core shell MNPs functionalized with Pluronic ® F-127 were prepared and thoroughly characterized as drug carriers for doxorubicin delivery. The functionalized nanoparticles have an average size of 17.71 ± 4.2 nm, high water colloidal stability, and superparamagnetic behavior. In addition, the nanoparticles were able to load 936 μg of DOX per mg of functionalized nanomaterial. Drug release studies at different pH values evidenced a pH-triggered DOX release effect. An increase of 62% in cumulative drug release was observed at pH simulating tumor endosome/lysosome microenvironments (pH 4.5) compared to physiological conditions (pH 7.4). In addition, an innovative dynamic drug delivery study was performed as a function of pH. The results from this test confirmed the pH-induced doxorubicin release capability of carbon multi-core shell MNPs. The validity of traditional kinetic models to fit dynamic pH-dependent drug release was also studied for predictive purposes.
    DOI:  https://doi.org/10.1039/d1nr08550f
  77. Curr Drug Deliv. 2022 Apr 27.
    Computational Design of Molecularly Imprinted Polymers in Drug Delivery Systems: A Comprehensive Review.
    Gurpreet Singh, Pooja A Chawla, Abdul Faruk, Viney Chawla, Anmoldeep Kaur.
      BACKGROUND: Nowadays, biomedical research has been focusing on the design and development of new drug delivery systems that provide efficient drug targeting. The molecularly imprinted polymers (MIPs) have attracted wide interest and play an indispensable role as a drug carrier. Drug delivery systems based on MIPs have been frequently cited in the literature. They are cross-linked polymers that contain binding sites according to the complementary structure of the template molecules. They possess distinctive features of structure predictability and site recognition specificity. Versatile applications of MIPs include purification, biosensing, bioseparation, artificial antibodies, and drug delivery. An ideal MIPs should include features such as biocompatibility, biodegradability, and stability.OBJECTIVE: In this article, we elaborate the historic growth, synthesis, and preparation of different MIPs and present an updated summary of recent advances in the development of new drug delivery system which are based on this technique. Their potential to deliver drugs in a controlled and targeted manner will also be discussed.
    CONCLUSION: MIPs possess unique advantages, such as lower toxicity, and fewer side effects, and good therapeutic potential. They offer administration of drugs by different routes, i.e., oral, ocular or transdermal. Despite several advantages, biomedical companies are hesitant to invest in MIPs based drug delivery system due to the limited availability of chemical compounds.
    Keywords:  Methacrylic acid; Molecular imprinted polymer; density functional theory; polymerization process.
    DOI:  https://doi.org/10.2174/1567201819666220427134549
  78. Front Bioeng Biotechnol. 2022 ;10 845821
    Fucoidan-Mediated Anisotropic Calcium Carbonate Nanorods of pH-Responsive Drug Release for Antitumor Therapy.
    Pei Wang, Fei Tong, Jun Luo, Zhihua Li, Junchao Wei, Yuangang Liu.
      The shape of nanoparticles can determine their physical properties and then greatly impact the physiological reactions on cells or tissues during treatment. Traditionally spherical nanoparticles are more widely applied in biomedicine but are not necessarily the best. The superiority of anisotropic nanoparticles has been realized in recent years. The synthesis of the distinct-shaped metal/metal oxide nanoparticles is easily controlled. However, their biotoxicity is still up for debate. Hence, we designed CaCO3 nanorods for drug delivery prepared at mild condition by polysaccharide-regulated biomineralization in the presence of fucoidan with sulfate groups. The CaCO3 nanorods with a pH sensitivity-loaded antitumor drug mitoxantrone hydrochloride (MTO) showed excellent antitumor efficacy for the HeLa cells and MCF-7 cells in vitro. We believe that anisotropic nanoparticles will bring forth an emblematic shift in nanotechnology for application in biomedicine.
    Keywords:  anisotropic nanorods; biocompatibility; chemotherapy; control release; polysaccharide
    DOI:  https://doi.org/10.3389/fbioe.2022.845821
  79. Front Chem. 2022 ;10 899321
    Recent Advances in Transition-Metal Based Nanomaterials for Noninvasive Oncology Thermal Ablation and Imaging Diagnosis.
    Qiuxia Peng, Zhangbo Qian, Huali Gao, Kun Zhang.
      With the developments of nanobiotechnology and nanomedicine, non-invasive thermal ablation with fewer side effects than traditional tumor treatment methods has received extensive attention in tumor treatment. Non-invasive thermal ablation has the advantages of non-invasiveness and fewer side effects compared with traditional treatment methods. However, the clinical efficiency and biological safety are low, which limits their clinical application. Transition-metal based nanomaterials as contrast agents have aroused increasing interest due to its unique optical properties, low toxicity, and high potentials in tumor diagnosis. Transition-metal based nanomaterials have high conversion efficiency of converting light energy into heat energy, good near-infrared absorption characteristics, which also can targetedly deliver those loaded drugs to tumor tissue, thereby improving the therapeutic effect and reducing the damage to the surrounding normal tissues and organs. This article mainly reviews the synthesis of transition-metal based nanomaterials in recent years, and discussed their applications in tumor thermal ablation and diagnosis, hopefully guiding the development of new transition metal-based nanomaterials in enhancing thermal ablation.
    Keywords:  cancer; imaging diagnosis; nanomedicine; non-invasive thermal ablation; transition-metal based nanomaterials
    DOI:  https://doi.org/10.3389/fchem.2022.899321
  80. Food Chem X. 2022 Mar 30. 13 100217
    Terpenes and terpenoids as main bioactive compounds of essential oils, their roles in human health and potential application as natural food preservatives.
    Ayu Masyita, Reka Mustika Sari, Ayun Dwi Astuti, Budiman Yasir, Nur Rahma Rumata, Talha Bin Emran, Firzan Nainu, Jesus Simal-Gandara.
      Essential oils (EOs) are volatile and concentrated liquids extracted from different parts of plants. Bioactive compounds found in EOs, especially terpenes and terpenoids possess a wide range of biological activities including anticancer, antimicrobial, anti-inflammatory, antioxidant, and antiallergic. Available literature confirms that EOs exhibit antimicrobial and food preservative properties that are considered as a real potential application in food industry. Hence, the purpose of this review is to present an overview of current knowledge of EOs for application in pharmaceutical and medical industries as well as their potential as food preservatives in food industry.
    Keywords:  Anti-inflammatory; Anticancer; Antimicrobial; Atractylone (PubChem CID: 3080635); Bakuchiol (PubChem CID: 5468522); Carvacrol (PubChem CID: 10364); Carvone (PubChem CID: 7439); Essential oil; Eugenol (PubChem CID: 3314); Food preservatives; Hinokitiol (PubChem CID: 3611); Limonene (PubChem CID: 22311); Linalool (PubChem CID: 6549); Myrcene (PubChem CID: 31253); Terpenes; α-Terpineol (PubChem CID: 17100)
    DOI:  https://doi.org/10.1016/j.fochx.2022.100217
  81. Drug Deliv Transl Res. 2022 Apr 30.
    Natural polysaccharide-based biodegradable polymeric platforms for transdermal drug delivery system: a critical analysis.
    Sobia Noreen, Jin-Xiang Ma, Muhammad Saeed, Fahad Pervaiz, Muhammad Farhan Hanif, Bilal Ahmed, Muhammad Irshad Farooq, Faizan Akram, Muhammad Safdar, Asadullah Madni, Muhammad Naveed, Li Chang-Xing.
      Natural biodegradable polymers generally include polysaccharides (starch, alginate, chitin/chitosan, hyaluronic acid derivatives, etc.) and proteins (collagen, gelatin, fibrin, etc.). In transdermal drug delivery systems (TDDS), these polymers play a vital role in controlling the device's drug release. It is possible that natural polymers can be used for TDDS to attain predetermined drug delivery rates due to their physicochemical properties. These polymers can be employed to market products and scale production because they are readily available and inexpensive. As a result of these polymers, new pharmaceutical delivery systems can be developed that is both regulated and targeted. The focus of this article is the application of a biodegradable polymeric platform based on natural polymers for TDDS. Due to their biocompatibility and biodegradability, natural biodegradable polymers are frequently used in biomedical applications. Additionally, these natural biodegradable polymers are being studied for their characteristics and behaviors.
    Keywords:  Biodegradable; Carrageenan; Chitosan; Hyaluronic acid; Natural polymers; Polysaccharides; Protein-based polymer; Transdermal drug delivery system
    DOI:  https://doi.org/10.1007/s13346-022-01152-3
  82. Colloids Surf B Biointerfaces. 2022 Apr 26. pii: S0927-7765(22)00204-1. [Epub ahead of print]215 112521
    Surfactin effectively improves bioavailability of curcumin by formation of nano-capsulation.
    Mengyuan Shan, Fanqiang Meng, Chao Tang, Libang Zhou, Zhaoxin Lu, Yingjian Lu.
      To improve the bioavailability of curcumin, surfactin was used to prepare curcumin-loaded nanoemulsions (Cur-NEs). Moreover, the physicochemical properties, digestive characteristics, as well as inhibition activity to Caco-2 cells of Cur-NEs were measured. Furthermore, the morphological analysis revealed that Cur-NEs with 320 mg/L surfactin appeared spherical nanoparticale (23.23 ± 2.86 nm) and uniform distribution. The encapsulation efficiency of Cur-NEs with 320 mg/L surfactin was 97.25 ± 1.28%. Simulated gastrointestinal digestion results indicated that surfactin elevated the sustained-release characteristics and higher bioaccessibility (40.92 ± 2.84%) of curcumin. Besides, Cur-NEs with 320 mg/L surfactin exhibited excellent stability in different temperature, pH and light irradiation. In addition, the inhibition of Cur-NEs with 320 mg/L surfactin to Caco-2 cells was 71.29%. Biochemical analysis showed that Cur-NEs enhanced the activity of lactate dehydrogenase, superoxide dismutase, catalase and glutathione peroxidase, as well as the reactive oxygen species content. RT-PCR and ELISA results also revealed that Cur-NEs inhibited Caco-2 cells through the activated mitochondria-mediated pathway. This study provided a strategy to encapsulate curcumin in nanoparticles with surfactin for improving bioavailability.
    Keywords:  Caco-2 cells; Curcumin; Nanoemulsion; Physiochemical property; Surfactin
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112521
  83. RSC Adv. 2020 Jul 03. 10(43): 25958-25965
    Near-infrared and metal-free tetra(butylamino)phthalocyanine nanoparticles for dual modal cancer phototherapy.
    Ying-Jie Wu, Fan-Hong Lv, Jing-Lan Kan, Qun Guan, Anqi Xue, Quanbo Wang, Yan-An Li, Yu-Bin Dong.
      Synergistic phototherapy combining photodynamic therapy (PDT) and photothermal therapy (PTT) based on near-infrared (NIR) dyes using a single light source offers the opportunity to treat diseases at deep locations. In this study, we reported human serum albumin (HSA)-involving tetra(butylamino)phthalocyanine (Pc)-based nanomaterials of HSA-α-Pc and HSA-β-Pc as highly efficient dual-phototherapy agents, namely 1(4),8(11),15(18),22(25)-tetra(butylamino)phthalocyanine (α-Pc) and 2(3),9(10),16(17),23(24)-tetra(butylamino)phthalocyanine (β-Pc). Both HSA-α-Pc and HSA-β-Pc showed excellent photothermal effects under a single NIR (808 nm) laser irradiation due to the S 1 fluorescence emission quenching of Pcs. Compared to HSA-β-Pc, HSA-α-Pc exhibited better singlet oxygen generation ability and its highly efficient PDT/PTT dual-phototherapy was also well evidenced via in vitro and vivo experiments under a single 808 nm laser irradiation. Overall, this approach would be viable for the fabrication of more new Pc-based metal-free nano agents for PDT/PTT synergistic phototherapy upon a single NIR light source.
    DOI:  https://doi.org/10.1039/d0ra03898a
  84. Front Pharmacol. 2022 ;13 851242
    Folic Acid-Decorated pH-Responsive Nanoniosomes With Enhanced Endocytosis for Breast Cancer Therapy: In Vitro Studies.
    Tahereh Rezaei, Mehdi Rezaei, Sara Karimifard, Farzaneh Mahmoudi Beram, Mohammad Sedigh Dakkali, Maryam Heydari, Soheil Afshari-Behbahanizadeh, Ebrahim Mostafavi, Dmitry Olegovich Bokov, Mohammad Javed Ansari, Bahareh Farasati Far, Iman Akbarzadeh, Chaiyavat Chaiyasut.
      Breast cancer is the most common invasive cancer in women and the second leading cause of cancer death in women after lung cancer. The purpose of this study is a targeted delivery toward in vitro (on MCF7 and 4T1 breast cancer cell lines) through niosomes-based nanocarriers. To this end, different bioactive molecules, including hyaluronic acid (HA), folic acid (FA), and polyethylene glycol (PEG), were used and compared for surface modification of niosomes to enhance endocytosis. FA-functionalized niosomes (Nio/5-FU/FA) were able to increase cell cytotoxicity and reduce cell migration and invasion compared to PEG-functionalized niosomes (Nio/5-FU/PEG), and HA-functionalized niosomes (Nio/5-FU/HA) groups in MCF-7 and 4T1 cell lines. Although the Nio/5-FU/PEG and Nio/5-FU/HA demonstrated MCF7 cell uptake, the Nio/5-FU/FA exhibited the most preponderant endocytosis in pH 5.4. Remarkably, in this study 5-FU loaded niosomes (nonionic surfactant-based vesicles) were decorated with various bioactive molecules (FA, PEG, or HA) to compare their ability for breast cancer therapy. The fabricated nanoformulations were readily taken up by breast cancer cells (in vitro) and demonstrated sustained drug release characteristics, inducing cell apoptosis. Overall, the comprehensive comparison between different bioactive molecules-decorated nanoniosomes exhibited promising results in finding the best nano formulated candidates for targeted delivery of drugs for breast cancer therapy.
    Keywords:  5-FU; breast cancer; endocytosis; folic acid; hyaluronic acid; niosome
    DOI:  https://doi.org/10.3389/fphar.2022.851242
  85. RSC Adv. 2020 Nov 11. 10(68): 41560-41576
    Photodynamic diagnosis and photodynamic therapy of colorectal cancer in vitro and in vivo.
    Nokuphila Winifred Nompumelelo Simelane, Cherie Ann Kruger, Heidi Abrahamse.
      Colorectal cancer (CRC) is a global challenge to eradicate. Early diagnosis and treatment strategies with ideal advantages, such as high tumor selectivity and negligible adverse effects, are significant, since they can result in precise diagnosis and treatment to reduce the overall incidence of CRC. The photodynamic approach for the detection and therapeutic treatment of cancer is a promising novel strategy in comparison to conventional treatments. Photodynamic diagnosis (PDD) is a diagnostic modality that involves the emission of light-induced excitation fluorescence to enhance early detection, without tumor destruction, after photosensitizer exposure to blue light. Photodynamic therapy (PDT) is a photochemistry-based approach that is rapidly progressing to solve the limitations of standard CRC treatments. PDT involves the interaction of a photosensitizer, tissue oxygen, and red light, which forms reactive oxygen species and radicals to elicit localized cancer cell death. This review discusses conventional CRC diagnostic and treatment methods, with their limitations, in comparison to the newly evolving in vitro and in vivo photo-diagnostic and treatment regimes, which have been investigated over the last several years. It also gives an overview of the integration of PDT with PDD, and utilization of specific photosensitizers for the possible early diagnosis and treatment of CRC.
    DOI:  https://doi.org/10.1039/d0ra08617g
  86. RSC Adv. 2021 Oct 25. 11(55): 34613-34630
    Microbial transglutaminase nanoflowers as an alternative nanomedicine for breast cancer theranostics.
    Syeda Warisul Fatima, Khalid Imtiyaz, Mohammad M Alam Rizvi, Sunil K Khare.
      Breast cancer is the most common malignancy among women. With the aim of decreasing the toxicity of conventional breast cancer treatments, an alternative that could provide appropriate and effective drug utilization was envisioned. Thus, we contemplated and compared the in vitro effects of microbial transglutaminase nanoflowers (MTGase NFs) on breast cancer cells (MCF-7). Transglutaminase is an important regulatory enzyme acting as a site-specific cross-linker for proteins. With the versatility of MTGase facilitating the nanoflower formation by acting as molecular glue, it was demonstrated to have anti-cancer properties. The rational drug design based on a transglutaminase enzyme-assisted approach led to the uniform shape of petals in these nanoflowers, which had the capacity to act directly as an anti-cancer drug. Herein, we report the anti-cancer characteristics portrayed by enzymatic MTGase NFs, which are biocompatible in nature. This study demonstrated the prognostic and therapeutic significance of MTGase NFs as a nano-drug in breast cancer treatment. The results on MCF-7 cells showed a significantly improved in vitro therapeutic efficacy. MTGase NFs were able to exhibit inhibitory effects on cell viability (IC50-8.23 μg ml-1) within 24 h of dosage. To further substantiate its superior anti-proliferative role, the clonogenic potential was measured to be 62.8%, along with migratory inhibition of cells (3.76-fold change). Drastic perturbations were induced (4.61-fold increase in G0/G1 phase arrest), pointed towards apoptotic induction with a 58.9% effect. These results validated the role of MTGase NFs possessing a cytotoxic nature in mitigating breast cancer. Thus, MTGase bestows distinct functionality towards therapeutic nano-modality, i.e., nanoflowers, which shows promise in cancer treatment.
    DOI:  https://doi.org/10.1039/d1ra04513j
  87. Methods Mol Biol. 2022 ;2451 711-720
    Detection of Paraptosis After Photodynamic Therapy.
    David Kessel.
      Photodynamic therapy (PDT) is a procedure for the selective photosensitization of neoplastic tissues. Subsequent irradiation with visible light can lead to cell death along with vascular shutdown and other responses that lead to selective eradication of malignant cells. Among the cellular responses to PDT are necrosis, apoptosis, and autophagy. These pathways have generally been associated with cell death, although autophagy can also be cytoprotective. A fourth effect that has hitherto been somewhat neglected is termed "paraptosis," a lethal response that can be identified by detecting an extensive collection of cytoplasmic vacuoles. Unlike autophagy, these vacuoles are bound by single membranes. Paraptosis has been characterized as a response to misfolded endoplasmic reticulum proteins that must be "cleared" if the affected cell is to survive. At present, there is no simple biochemical test for paraptosis. This chapter describes the procedure for detection of paraptosis using phase-contrast microscopy, along with some confirmatory approaches.
    Keywords:  Apoptosis; Autophagy; Cell death signaling; Endoplasmic reticulum stress; Photodamage; Vacuolization
    DOI:  https://doi.org/10.1007/978-1-0716-2099-1_38
  88. Methods Mol Biol. 2022 ;2451 261-283
    Photosensitized Oxidation of Intracellular Targets: Understanding the Mechanisms to Improve the Efficiency of Photodynamic Therapy.
    Thiago Teixeira Tasso, Maurício S Baptista.
      The development of improved photosensitizers is a key aspect in the establishment of photodynamic therapy (PDT) as a reliable treatment modality. In this chapter, we discuss how molecular design can lead to photosensitizers with higher selectivity and better efficiency, with focus on the importance of specific intracellular targeting in determining the cell death mechanism and, consequently, the PDT outcome.
    Keywords:  Activatable photosensitizers; Cell death; Drug delivery; Organelle targeting; Photobleaching; Photosensitizer
    DOI:  https://doi.org/10.1007/978-1-0716-2099-1_18
  89. Curr Opin Genet Dev. 2022 Apr 29. pii: S0959-437X(22)00023-5. [Epub ahead of print]74 101914
    The origins of cancer cell dormancy.
    Jorge Morales-Valencia, Gregory David.
      Cancer cell dormancy has emerged as an important nongenetic driver of drug resistance. Dormant cells are characterized by a reversible cell cycle exit. They represent a reservoir for eventual cancer relapse, and upon reactivation, can fuel metastatic disease. Although dormant cells were originally believed to emerge from a drug-resistant pre-existing cancer subpopulation, this notion has been recently challenged. Here, we review recent evidence indicating that dormancy represents an adaptive strategy employed by cancer cells to avoid the cytotoxic effects of antitumor therapy. Furthermore, we outline the molecular pathways engaged by cancer cells to enter dormancy upon drug exposure, with a focus on cellular senescence as a driver of dormancy.
    DOI:  https://doi.org/10.1016/j.gde.2022.101914
  90. Methods Mol Biol. 2022 ;2451 185-201
    Photodynamic Treatments for Disseminated Cancer Metastases Using Fiber-Optic Technologies.
    Eric M Kercher, Bryan Q Spring.
      Tumor-targeted and -activatable photosensitizer delivery platforms are creating new opportunities to develop photodynamic therapy (PDT) of metastatic disease. This is possible by confining the activity of the photosensitizing chemical (i.e., the PDT agent) to the tumor in combination with diffuse near-infrared light irradiation for wide-field treatment. This chapter outlines protocols and research tools for preclinical development of light-activated therapies of cancer metastases using advanced-stage ovarian cancer as a model system. We also describe an in vivo molecular imaging approach that uniquely enables tracking intraperitoneal micrometastatic burden and responses to treatment using fluorescence microendoscopy.
    Keywords:  Cancer metastases; Fluorescence microendoscopy; Molecular imaging; Mouse models; Ovarian cancer; Peritoneal carcinomatosis; Photodynamic therapy; Photoimmunotherapy; Targeted therapy
    DOI:  https://doi.org/10.1007/978-1-0716-2099-1_14
  91. ACS Biomater Sci Eng. 2022 May 05.
    Polysaccharide-Based Theranostic Systems for Combined Imaging and Cancer Therapy: Recent Advances and Challenges.
    Aastha Gupta, Ankur Sood, Erwin Fuhrer, Kristina Djanashvili, Garima Agrawal.
      Designing novel systems for efficient cancer treatment and improving the quality of life for patients is a prime requirement in the healthcare sector. In this regard, theranostics have recently emerged as a unique platform, which combines the benefits of both diagnosis and therapeutics delivery. Theranostics have the desired contrast agent and the drugs combined in a single carrier, thus providing the opportunity for real-time imaging to monitor the therapy results. This helps in reducing the hazards related to treatment overdose or underdose and gives the possibility of personalized therapy. Polysaccharides, as natural biomolecules, have been widely explored to develop theranostics, as they act as a matrix for simultaneously loading both contrast agents and drugs for their utility in drug delivery and imaging. Additionally, their remarkable physicochemical attributes (biodegradability, satisfactory safety profile, abundance, and diversity in functionality and charge) can be tuned via postmodification, which offers numerous possibilities to develop theranostics with desired characteristics. Hence, we provide an overview of recent advances in polysaccharide matrix-based theranostics for drug delivery combined with magnetic resonance imaging, computed tomography, positron emission tomography, single photon emission computed tomography, and ultrasound imaging. Herein, we also summarize the toxicity assessment of polysaccharides, associated contrast agents, and nanotoxicity along with the challenges and future research directions.
    Keywords:  Contrast agent; Drug delivery; Imaging; Polysaccharides; Theranostics; Toxicity
    DOI:  https://doi.org/10.1021/acsbiomaterials.1c01631
  92. Int J Nanomedicine. 2022 ;17 1881-1902
    Folic Acid and Chitosan-Functionalized Gold Nanorods and Triangular Silver Nanoplates for the Delivery of Anticancer Agents.
    You Jeong Lee, Yeon-Jeong Kim, Youmie Park.
      Background: Advances in the field of nanotechnology have shed light on the applications of nanoparticles for cancer treatment.Methods: Folic acid and chitosan-functionalized gold nanorods (FACS-R) and triangular silver nanoplates (FACS-T) were synthesized and their properties were elucidated by UV-visible spectrophotometry, Fourier-transform infrared spectroscopy, field emission transmission electron microscopy and high-resolution X-ray diffraction.
    Results: The average size of the FACS-R was determined to be a transverse length of 13.1 ± 1.8 nm and a longitudinal length of 47.2 ± 8.9 nm with an aspect ratio of 3.6. The average size of FACS-T was measured to be 31.8 ± 7.7 nm. Colloidal solutions of FACS-R and FACS-T were stable on the shelf at ambient temperature for 14 days in the dark. Anticancer agents were encapsulated in FACS-R and FACS-T. FACS-T showed a higher encapsulation efficiency with docetaxel, paclitaxel and diallyl disulfide than FACS-R. The cell viability on human gastric adenocarcinoma cells (AGS), human epithelial cervix adenocarcinoma cells (HeLa) and human colorectal adenocarcinoma cells (HT-29) after treatment with anticancer agent-encapsulated FACS-R and FACS-T was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Interestingly, paclitaxel-encapsulated FACS-R and FACS-T showed the highest percentages of early and late apoptosis on HeLa cells. A cell cycle analysis demonstrated increased G2/M arrest on HeLa cells with docetaxel and paclitaxel-encapsulated FACS-R and FACS-T. The FACS-T induced more G2/M arrest on HeLa cells than the FACS-R. To assess applications in near-infrared photothermal therapy (PTT), the cell viability on HeLa cells with the anticancer agent-encapsulated FACS-R and FACS-T was assessed in the presence or absence of 808 nm laser irradiation. The results showed that 808 nm laser irradiation significantly decreased cell viability.
    Conclusion: Collectively, the triangular silver nanoplates were more effective than the gold nanorods for PTT. We believe that as-prepared nanoparticles have remarkable features and will become promising future nanomedicine.
    Keywords:  HeLa cells; anticancer activity; chitosan; folic acid; gold nanorods; photothermal therapy; triangular silver nanoplates
    DOI:  https://doi.org/10.2147/IJN.S354866
  93. Int J Pharm. 2022 Apr 30. pii: S0378-5173(22)00343-X. [Epub ahead of print] 121788
    Sphingomyelin-based PEGylation Cu(DDC)2 Liposomes Prepared via the Dual Function of Cu2+ for Cancer Therapy: Facilitating DDC Loading and Exerting Synergistic Antitumor Effects.
    Hao Liu, Yihan Kong, Zixu Liu, Xueting Guo, Bing Yang, Tian Yin, Haibing He, Jingxin Gou, Yu Zhang, Xing Tang.
      The old alcohol-aversion drug disulfiram (DSF) has aroused wide attention as a drug repurposing strategy in terms of cancer therapy because of the high antitumor efficacy in combination with copper ion. However, numerous defects of DSF (e.g., the short half-life and acid instability) have limited the application in cancer treatment. Cu(DDC)2, the complex of diethyldithiocarbamate (DDC, DSF metabolite) and Cu2+, have been proven as the vital active component on cancer, which have aroused the attention of researchers from DSF to Cu(DDC)2. However, the poor water solubility of Cu(DDC)2 increase more difficulties to the treatment and in-depth investigations of Cu(DDC)2. In this study, sphingomyelin (SM)-based PEGylated liposomes (SM/Chol/DSPE-mPEG2000 (55:40:5, mole%)) were produced as the carriers for Cu(DDC)2 delivery to enhance the water solubility. DDC was added to Cu-containing liposomes with a higher encapsulation efficiency of more than 90%, and it reacted with Cu2+ to synthesize Cu(DDC)2. Due to the high phase transition temperature of SM and strong intermolecular hydrogen bonds with cholesterol, SM-based liposomes would be conducive to enhancing the stability of Cu(DDC)2 and preventing drug leakage during delivery. As proven by pharmacokinetic studies, loading Cu(DDC)2 into liposomes improve bioavailability, and the area under the curve (AUC0-t) and the mean elimination half-life (t1/2) increased 1.9-time and 1.3-time to those of free Cu(DDC)2, respectively. Furthermore, the anticancer effect of Cu(DDC)2 was enhanced by the liposomal encapsulation, thus resulting in remarkable cell apoptosis in vitro and a tumor-inhibiting rate of 77.88% in vivo. Thus, it was concluded that Cu(DDC)2 liposomes could be promising in cancer treatment.
    Keywords:  Cancer treatment; Copper diethyldithiocarbamate; Disulfiram; PEGylation Liposomes; Sphingomyelin
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121788
  94. Int J Pharm. 2022 Apr 27. pii: S0378-5173(22)00330-1. [Epub ahead of print] 121775
    Drug Self-delivery Nanorods Enhance Photodynamic Therapy of Triple-Negative Breast Cancer by inhibiting Oxidative Phosphorylation.
    Wenhao Gao, Jialiang Zhang, Weifeng Wang, Zhihong Liu, Mulan Chen, Xiaomu Hu, Lingjun Zeng, Changqing Zheng, Hongtao Song, Qian Zhang.
      Photodynamic therapy (PDT) shows very high potential for the clinical treatment of triple-negative breast cancer. However, the efficacy of PDT is significantly weakened by tumor hypoxia, the relatively high intracellular glutathione levels and the active proliferation of cancer cells. To address these issues, we developed a novel drug self-delivery nanorod (defined as AINRs) through the hydrophobic interaction among the mitochondrial complex III inhibitor (atovaquone, ATO), the photosensitizer (indocyanine green, ICG) and the dispersion stabilizer (distearoyl phosphoethanolamine-polyethylene glycol 2000, DSPE-PEG 2000). The AINRs showed a rod-like morphology with a mean diameter of 120.6 ± 5.4 nm, a zeta potential of -26.35 ± 1.63 mV and a significantly high drug loading rate of 93.48%. The results of in vitro cell experiments involving triple-negative breast cancer cell lines (4T1 cells and MDA-MB-231 cells) indicated that the AINRs could effectively block the oxidative phosphorylation of cancer cells through the inhibition of mitochondrial complex III, which results in the reduction of endogenous oxygen consumption and the decrease of the intracellular ATP level. The reduction of ATP content further inhibited the glutathione synthesis and arrested the cell cycle at the S-phase, which results in enhanced in vitro PDT efficacy of ICG. The results of in vivo antitumor activity in 4T1-bearing mice showed that the tumor growth inhibition rate of the AINRs with near-infrared laser irradiation (NIR) was 90%, whereas the tumor growth inhibition rates of the AINRs without NIR, ICG with NIR and doxorubicin (3 mg/kg) were only 31.68%, 61.15% and 24.59%, respectively. In addition, the results of safety studies, including body weights, biochemical indicators and H&E staining images of the main organs demonstrated the security of the AINRs. In summary, this study showed that the oxidative phosphorylation inhibition of triple-negative breast cancer was a safe and effective method to enhance its PDT efficacy.
    Keywords:  Atovaquone; Nanorod; Oxidative phosphorylation blocking; Photodynamic therapy; Self-assembly; Triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121775
  95. Front Immunol. 2022 ;13 855342
    The Antioxidant, Anti-Inflammatory and Immunomodulatory Effects of Camel Milk.
    Sepide Behrouz, Saeideh Saadat, Arghavan Memarzia, Hadi Sarir, Gert Folkerts, Mohammad Hossein Boskabady.
      Camel milk (CM) has been found to have several health benefits, including antiviral, antibacterial, anti-tumor, anti-fungal, antioxidant, hypoglycaemic and anti-cancer activities. In addition, CM can counter signs of aging and may be a useful naturopathic treatment for autoimmune diseases. The composition of CM varies with geographic origin, feeding conditions, seasonal and physiological changes, genetics and camel health status. In the present review, we collate the diverse scientific literature studying antioxidant, anti-inflammatory and immunomodulatory effects of CM and its bioactive compounds. The databases Scopus, PubMed, and Web of Science were searched until the end of September 2021 using the keywords: camel milk, antioxidant, anti-inflammatory, immunomodulatory. The anti-inflammatory mechanism of CM in various inflammatory disorders was consistently reported to be through modulating inflammatory cells and mediators. The common anti-inflammatory bioactive components of CM seem to be lactoferrin. The antioxidant effects of α-lactalbumin, β-caseins and vitamin C of CM work by reducing or inhibiting the production of reactive oxygen species (ROS), hydroxyl radicals, nitric oxide (NO), superoxide anions and peroxyl radicals, likely alleviating oxidative stress. Higher levels of protective proteins such as lysozyme, IgG and secretory IgA compared to cow's milk, and insulin-like protein activity of CM on ß cells appear to be responsible for the immunomodulatory properties of CM. The evidence indicates that CM and its bioactive components has the potential to be a therapeutic value for diseases that are caused by inflammation, oxidative stress and/or immune-dysregulation.
    Keywords:  anti-inflammatory; antioxidant; camel milk; immunomodulatory; treatment
    DOI:  https://doi.org/10.3389/fimmu.2022.855342
  96. RSC Adv. 2020 Oct 15. 10(63): 38621-38630
    Sulfobetaine methacrylate-functionalized graphene oxide-IR780 nanohybrids aimed at improving breast cancer phototherapy.
    Miguel M Leitão, Cátia G Alves, Duarte de Melo-Diogo, Rita Lima-Sousa, André F Moreira, Ilídio J Correia.
      The application of Graphene Oxide (GO) in cancer photothermal therapy is hindered by its lack of colloidal stability in biologically relevant media and modest Near Infrared (NIR) absorption. In this regard, the colloidal stability of GO has been improved by functionalizing its surface with poly(ethylene glycol) (PEG), which may not be optimal due to the recent reports on PEG immunogenicity. On the other hand, the chemical reduction of GO using hydrazine hydrate has been applied to enhance its photothermal capacity, despite decreasing its cytocompatibility. In this work GO was functionalized with an amphiphilic polymer containing [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA) brushes and was loaded with IR780, for the first time, aiming to improve its colloidal stability and phototherapeutic capacity. The attained results revealed that the SBMA-functionalized GO displays a suitable size distribution, neutral surface charge and adequate cytocompatibility. Furthermore, the SBMA-functionalized GO exhibited an improved colloidal stability in biologically relevant media, while its non-SBMA functionalized equivalent promptly precipitated under the same conditions. By loading IR780 into the SBMA-functionalized GO, its NIR absorption increased by 2.7-fold, leading to a 1.2 times higher photothermal heating. In in vitro cell studies, the combination of SBMA-functionalized GO with NIR light only reduced breast cancer cells' viability to 73%. In stark contrast, by combining IR780 loaded SBMA-functionalized GO and NIR radiation, the cancer cells' viability decreased to 20%, hence confirming the potential of this nanomaterial for cancer photothermal therapy.
    DOI:  https://doi.org/10.1039/d0ra07508f
  97. Inflammopharmacology. 2022 May 07.
    Promising role of polymeric nanoparticles in the treatment of rheumatoid arthritis.
    Rida Siddique, Malik Hassan Mehmood, Muhammad Haris, Ammara Saleem, Zunera Chaudhry.
      Rheumatoid arthritis (RA) is a chronic inflammatory illness caused by an autoimmune disorder of synovial membrane resulting in synovial membrane dysfunction. The available treatment particularly focuses on inhibiting macrophage proliferation and reducing the generation of pro-inflammatory cytokines. However, therapeutic success of current treatment options at targeted site is limited; therefore, development of promising therapeutic strategy is the need of time that may provide better targeted delivery of drug with added safety. In development of precision medicine to manage RA, nanotechnology is a viable option to be considered. Recent research using nanoparticles for the treatment of RA, particularly polymeric nanoparticles, has been discussed in this article. Using polymeric nanoparticles as a therapeutic method has shown considerable promise of enhancing treatment success over standard medications used in routine. It is exclusively evident that the viability of using nanoparticles is mainly owed due to their biocompatibility, chemical stability, controlled drug release, and selective drug delivery to inflamed tissues in RA model animals. The current analysis focuses on the critical design characteristics of RA-targeted nanotechnology-based strategies in quest of better therapeutic strategies for RA, and to identify leading polymer as the most effective medications in RA therapy.
    Keywords:  Arthritis; Inflammation; Nanoparticles; Polymers
    DOI:  https://doi.org/10.1007/s10787-022-00997-x
  98. RSC Adv. 2020 Jun 08. 10(37): 21736-21744
    SWCNT-porphyrin nano-hybrids selectively activated by ultrasound: an interesting model for sonodynamic applications.
    Federica Bosca, Ingrid Corazzari, Federica Foglietta, Roberto Canaparo, Gianni Durando, Linda Pastero, Silvia Arpicco, Franco Dosio, Daniele Zonari, Giancarlo Cravotto, Silvia Tagliapietra, Loredana Serpe, Francesco Turci, Alessandro Barge.
      Sonodynamic therapy (SDT) is an innovative anticancer approach, based on the excitation of a given molecule (usually a porphyrin) by inertial acoustic cavitation that leads to cell death via the production of reactive oxygen species (ROS). This study aims to prepare and characterize nanosystems based on porphyrin grafted carbon nanotubes (SWCNTs), to understand some aspects of the mechanisms behind the SDT phenomenon. Three different porphyrins have been covalently linked to SWCNTs using either Diels-Alder or 1,3-dipolar cycloadditions. ROS production and cell viability have been evaluated upon ultrasound irradiation. Despite the low porphyrin content linked on the SWCNT, these systems have shown high ROS production and high tumour-cell-killing ability. The existence of a PET (photoinduced electron transfer)-like process would appear to be able to explain these observations. Moreover, the demonstrated ability to absorb light limits the impact of side effects due to light-excitation.
    DOI:  https://doi.org/10.1039/d0ra03944f
  99. Adv Colloid Interface Sci. 2022 Apr 28. pii: S0001-8686(22)00087-2. [Epub ahead of print]304 102685
    Recent developments in industrial applications of nanoemulsions.
    Yesim Ozogul, Gokcem Tonyali Karsli, Mustafa Durmuş, Hatice Yazgan, Halil Mecit Oztop, David Julian McClements, Fatih Ozogul.
      Nanotechnology is being utilized in various industries to increase the quality, safety, shelf-life, and functional performance of commercial products. Nanoemulsions are thermodynamically unstable colloidal dispersions that consist of at least two immiscible liquids (typically oil and water), as well as various stabilizers (including emulsifiers, texture modifiers, ripening inhibitors, and weighting agents). They have unique properties that make them particularly suitable for some applications, including their small droplet size, high surface area, good physical stability, rapid digestibility, and high bioavailability. This article reviews recent developments in the formulation, fabrication, functional performance, and gastrointestinal fate of nanoemulsions suitable for use in the pharmaceutical, cosmetic, nutraceutical, and food industries, as well as providing an overview of regulatory and health concerns. Nanoemulsion-based delivery systems can enhance the water-dispersibility, stability, and bioavailability of hydrophobic bioactive compounds. Nevertheless, they must be carefully formulated to obtain the required functional attributes. In particular, the concentration, size, charge, and physical properties of the nano-droplets must be taken into consideration for each specific application. Before launching a nanoscale product onto the market, determination of physicochemical characteristics of nanoparticles and their potential health and environmental risks should be evaluated. In addition, legal, consumer, and economic factors must also be considered when creating these systems.
    Keywords:  Foods; Gastrointestinal fate; Health; Nanoemulsion; Neutraticals
    DOI:  https://doi.org/10.1016/j.cis.2022.102685
  100. RSC Adv. 2020 Jul 15. 10(45): 27103-27136
    Xanthan gum derivatives: review of synthesis, properties and diverse applications.
    Jwala Patel, Biswajit Maji, N S Hari Narayana Moorthy, Sabyasachi Maiti.
      Natural polysaccharides are well known for their biocompatibility, non-toxicity and biodegradability. These properties are also inherent to xanthan gum (XG), a microbial polysaccharide. This biomaterial has been extensively investigated as matrices for tablets, nanoparticles, microparticles, hydrogels, buccal/transdermal patches, tissue engineering scaffolds with different degrees of success. However, the native XG has its own limitations with regards to its susceptibility to microbial contamination, unusable viscosity, poor thermal and mechanical stability, and inadequate water solubility. Chemical modification can circumvent these limitations and tailor the properties of virgin XG to fulfill the unmet needs of drug delivery, tissue engineering, oil drilling and other applications. This review illustrates the process of chemical modification and/crosslinking of XG via etherification, esterification, acetalation, amidation, and oxidation. This review further describes the tailor-made properties of novel XG derivatives and their potential application in diverse fields. The physicomechanical modification and its impact on the properties of XG are also discussed. Overall, the recent developments on XG derivatives are very promising to progress further with polysaccharide research.
    DOI:  https://doi.org/10.1039/d0ra04366d
  101. RSC Adv. 2020 Aug 21. 10(52): 31106-31114
    Development and evaluation of a pH-responsive and water-soluble drug delivery system based on smart polymer coating of graphene nanosheets: an in silico study.
    Abutaleb Alinejad, Heidar Raissi, Hassan Hashemzadeh.
      The objective of this study is to develop a controlled and water-soluble delivery system for doxorubicin (DOX) based on the coating of graphene (G) with a smart polymer. A combination of polyethyleneimine (PEI) and G-DOX is investigated by performing density functional theory (DFT) calculations and molecular dynamics (MD) simulations. Several parameters have been employed to evaluate the effect of PEI on the adsorption and release mechanisms of DOX. The obtained results indicated that the binding energy of the drug molecule on G in the presence of PEI is enhanced by about 20% under neutral conditions, whereas the drug absorption becomes weaker in an acidic environment so that DOX could be separated from the carrier surface using near-infrared radiation (NIR). Based on the atom in molecule (AIM) theory, two hydrogen bonds with strengths of about -12.59 and -39.99 kJ mol-1 have been established. Furthermore, evaluating the dynamic behavior of the designed systems in water solution shows that the polymer in physiological pH rapidly adsorbed on the drug-carrier complex. However, at acidic pH, it is quickly desorbed from the carrier surface and the G-DOX complex can be exposed to cancer cells. The obtained results of the present research may be used in future experimental work to design smart DDSs.
    DOI:  https://doi.org/10.1039/d0ra06705a
  102. Front Microbiol. 2022 ;13 866849
    Size and Shape Directed Novel Green Synthesis of Plasmonic Nanoparticles Using Bacterial Metabolites and Their Anticancer Effects.
    Snehal Patil, Murali Sastry, Atul Bharde.
      The growing need for developing new synthesis methods of plasmonic nanoparticles (PNPs) stems from their various applications in nanotechnology. As a result, a variety of protocols have been developed for the synthesis of PNPs of different shapes, sizes, and compositions. Though widely practiced, the chemical synthesis of PNPs demands stringent control over the experimental conditions, often employs environmentally hazardous chemicals for surface stabilization, and is frequently energy-intensive. Additionally, chemically obtained PNPs require subsequent surface engineering steps for various optoelectronic and biomedicine applications to minimize the toxic effects and render them useful for targeted drug delivery, sensing, and imaging. Considering the pressing need to develop environmentally-friendly technology solutions, "greener" methods of nanoparticle synthesis are gaining importance. Here, we report on the biological synthesis of plasmonic nanoparticles using bacterial metabolites. A peptide-based siderophore pyoverdine and a blue-green pigment pyocyanin obtained from a marine strain of Pseudomonas aeruginosa rapidly produced plasmonic nanoparticles of gold and silver in an aqueous environment. The morphology of plasmonic nanoparticles could be modulated by tuning the concentration of these metabolites and the reaction time. The exposure of pyoverdine to chloroauric acid resulted in anisotropic gold nanoparticles. On the other hand, pyocyanin produced a highly monodispersed population of gold nanoparticles and anisotropic silver nanoparticles. Biologically obtained gold and silver nanoparticles retained pyoverdine and pyocyanin on the nanoparticle surface and were stable for an extended period of time. The biologically obtained gold and silver plasmonic nanoparticles displayed potent anticancer activities against metastatic lung cancer cells. Biogenic nanoparticles were rapidly internalized by cancer cells in high quantity to affect the cellular organization, and karyoplasmic ratio, indicating the potential of these nanoparticles for cancer nanomedicine.
    Keywords:  anisotropic nanoparticles; cancer nanotechnology; nanomedicine; nanoparticle biosynthesis; plasmonic nanoparticles
    DOI:  https://doi.org/10.3389/fmicb.2022.866849
  103. Chem Pharm Bull (Tokyo). 2022 ;70(5): 351-358
    The Challenge to Deliver Oxaliplatin (l-OHP) to Solid Tumors: Development of Liposomal l-OHP Formulations.
    Nana Cristina Amorim Matsuo, Hidenori Ando, Yusuke Doi, Taro Shimizu, Yu Ishima, Tatsuhiro Ishida.
      Oxaliplatin (l-OHP) is a third-generation platinum (Pt) agent approved for the treatment of patients with advanced colorectal cancer. Despite the fact that l-OHP has shown clinical therapeutic efficacy and better tolerability compared with other Pt agents, the use of l-OHP has been limited to clinical settings because of dose-limiting side effects such as cumulative neurotoxicity and acute dysesthesias, which can be severe. In preclinical and clinical studies, our group and several others have attempted the delivery of l-OHP to solid tumors via encapsulation in PEGylated liposomes. Herein, we review these attempts.
    Keywords:  PEGylated liposome; cancer therapy; drug delivery system (DDS); oxaliplatin (l-OHP)
    DOI:  https://doi.org/10.1248/cpb.c22-00099
  104. RSC Adv. 2020 Jun 29. 10(42): 24951-24972
    Pharmacological and natural products diversity of the brown algae genus Sargassum.
    Mohammed I Rushdi, Iman A M Abdel-Rahman, Hani Saber, Eman Zekry Attia, Wedad M Abdelraheem, Hashem A Madkour, Hossam M Hassan, Abeer H Elmaidomy, Usama Ramadan Abdelmohsen.
      Sargassum (F. Sargassaceae) is an important seaweed excessively distributed in tropical and subtropical regions. Different species of Sargassum have folk applications in human nutrition and are considered a rich source of vitamins, carotenoids, proteins, and minerals. Many bioactive compounds chemically classified as terpenoids, sterols, sulfated polysaccharides, polyphenols, sargaquinoic acids, sargachromenol, and pheophytin were isolated from different Sargassum species. These isolated compounds and/or extracts exhibit diverse biological activities, including analgesic, anti-inflammatory, antioxidant, neuroprotective, anti-microbial, anti-tumor, fibrinolytic, immune-modulatory, anti-coagulant, hepatoprotective, and anti-viral activities. This review covers the literature from 1974 to 2020 on the genus Sargassum, and reveal the active components together with their biological activities according to their structure to create a base for additional studies on the clinical applications of Sargassum.
    DOI:  https://doi.org/10.1039/d0ra03576a
  105. Exp Mol Pathol. 2022 Apr 29. pii: S0014-4800(22)00037-5. [Epub ahead of print] 104777
    Effect of glycated HDL on oxidative stress and cholesterol homeostasis in a human bladder cancer cell line, J82.
    Md ObaidulIslam, Tiziana Bacchetti, Hicham Berrougui, AbdelouahedKhalil, Gianna Ferretti.
      Epidemiological studies suggest associations between diabetes mellitus (DM) andbladder cancer. Several potential mechanisms may explain the increased bladdercancer burden in DM patients. Hyperglycaemia is associated with dysregulation of cellintracellular metabolism and alterations of lipoprotein metabolism and oxidative stress. Dysfunctional HDL including glycated and oxidized HDL are described in DM. Weevaluated the effect of normal HDL (N-HDL) and glycated HDL (G-HDL) on cellproliferation and oxidative stress of J82 bladder cancer cells. We also studied the effectof HDL on cholesterol influx and efflux. In addition, the levels of proteins involvedin cholesterol transport (ABCA1, SRB1, ABCG1) by western blot analysis were studied.Our results demonstrate that N-HDL and G-HDL promote cell proliferation and increase intracellular reactive oxygen species (ROS) levels triggered by incubation of tert-butylhydroperoxide. The increase of intracellular ROS in cells preincubated with G-HDL was associated to higher levels of TBARS in cells compared to N-HDL. Cholesterol efflux wasincreased, on the contrary cholesterol influx was significantly decreased in cellsincubated with G-HDL with respect to cells incubated with N-HDL. Levels of SR-B1 and ABCG1 was increased in cells incubated with G-HDL, suggestingthat dysfunctional HDL could affect cholesterol homeostasis in J82 cells. These resultssuggest that HDL-based treatments should be considered for treatment of urinary bladder cancer.
    Keywords:  Bladder cancer; Cholesterol flux capacity; Cholesterol transport; High-density lipoprotein; Oxidative stress; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.yexmp.2022.104777
  106. RSC Adv. 2020 Dec 17. 10(73): 44654-44671
    The bioactive components as well as the nutritional and health effects of sea buckthorn.
    Ruru Ren, Nan Li, Chao Su, Yingli Wang, Xiaojun Zhao, Lingling Yang, Yanting Li, Bo Zhang, Jianyu Chen, Xueqin Ma.
      Sea buckthorn (SB), also named sea berry, Hippophae rhamnoides L. or Elaeagnus rhamnoides L., has been used in daily life for centuries with kinds of purposes ranging from a beverage with a pleasant taste and flavor, to an agent for treatment of many disorders and diseases. SB is well known more than just a fruit. So far, a unique mixture of bioactive components was elucidated in SB including flavonoids, phenolic acids, proanthocyanidins, carotenoids, fatty acids, triterpenoids, vitamins and phytosterols, which implied the great medicinal worth of this seaberry. Both in vitro and in vivo experiments, ranged from cell lines to animals as well as a few in patients and healthy volunteers, indicated that SB possessed various biological activities including anti-inflammatory and immunomodulatory effects, antioxidant properties, anti-cancer activities, hepato-protection, cardiovascular-protection, neuroprotection, radioprotection, skin protection effect as well as the protective effect against some eye and gastrointestinal sickness. Furthermore, the toxicological results revealed neither the fruits, nor the seeds of SB were toxic. The present review summarizes the unique profile of the chemical compounds, the nutritional and health effects as well as the toxicological properties of SB, which lay the foundation for practical applications of SB in treatment of human diseases.
    DOI:  https://doi.org/10.1039/d0ra06488b
  107. Cancer Res. 2022 May 03. 82(9): 1695-1697
    No Back-up Plan: Loss of Isozyme Diversity as a Promising Therapeutic Strategy for Cancer.
    Abisola Z Kehinde, Seth J Parker.
      Metabolic rewiring in cancer cells supports many aspects of tumor growth. Understanding the mechanisms that result in metabolic rewiring, such as altered enzyme expression, is key to identifying therapeutic vulnerabilities that selectively target cancer cells. In this issue of Cancer Research, Marczyk and colleagues analyze matched tumor-normal enzyme expression across 14 different cancer types and report that cancer cells exhibit a general loss of isozyme diversity (LID) relative to corresponding normal tissue. The authors hypothesized that the presence of a cancer dominant isozyme may reduce metabolic plasticity and uniquely sensitize cancer cells to isozyme-specific inhibitors. Several LID targets were identified, including acetyl-CoA carboxylase 1 (ACC1), which the authors validated using a clinically available inhibitor of ACC1/2. This study is the first to systematically evaluate isozymes affected by LID, which represents a promising strategy to target the unique metabolic demands of cancer. See related article by Marczyk et al., p. 1698.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0855
  108. Photodiagnosis Photodyn Ther. 2022 Apr 29. pii: S1572-1000(22)00179-X. [Epub ahead of print] 102893
    Acute acne flare following isotretinoin administration successfully treated by 5-aminolevulinic acid photodynamic therapy.
    Liu Jia, Shi Lei, Linglin Zhang, Xiaojin Liu, Haiyan Zhang, Yunfeng Zhang, Peiru Wang, Guolong Zhang, Zhongxia Zhou, Wang Xiuli.
      The acne flare occurs in a small proportion of patients at the initiation of oral isotretinoin. The traditional therapy is oral corticosteroids. But for particularly patients it's also accompany with side effects, such as metabolic disorder, inhibition of immune function and so on. Here, we report a young man with acute acne flare following isotretinoin administration was treated by 5-aminolevulinic acid photodynamic therapy (ALA-PDT). 5-ALA cream (5%) has been applied on all skin lesions and kept under a black plastic film for 2 h, and then the skin lesions were exposed under a LED PDT equipment, with a wavelength of 633 ± 6 mm, power density of 42 mW/cm2, irradiation duration of 30 min for each light spot and light dose of 75.6 J/cm2, for each treated area. A total of seven treatments were provided, with complete clearance and excellent cosmetic result. Here, ALA-PDT as a novel therapeutic option in acne flare.
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.102893
  109. J Pain Res. 2022 ;15 1203-1219
    Analgesic and Anti-Inflammatory Properties of Two Hydrogel Formulations Comprising Polyherbal Extract.
    Tayyba Saher, Rizwana Manzoor, Khizar Abbas, Jahanzeb Mudassir, M Asif Wazir, Ejaz Ali, Faheem Ahmad Siddique, Akhtar Rasul, Muhammad Imran Qadir, Ambreen Aleem, Naeem Qaiser, Adeel Usman, Muhammad Romman, Muhammad Sajid Ali.
      Background: Nature represents a basic source of medicinal scaffolds that can develop into potent drugs used in the treatment of many diseases.Aim: The present study was planned to evaluate the combined effects of polyherbal methanolic extract of the herbs (fruit of capsicum, bark of cinnamon, rhizome of turmeric and rhizome of ginger) that were individually well known for their analgesic and anti-inflammatory activities. Furthermore, we aimed to develop hydrogel formulation of this polyherbal extract and to characterize and evaluate its analgesic and anti-inflammatory potential.
    Materials and Methods: Zingiber officinale (R.), Capsicum annuum (L.), Curcuma longa (L.), and Cinnamomum verum (J.) polyherbal extract (GCTC) was prepared by maceration and evaluated for analgesic and anti-inflammatory potential. Then, two different types of hydrogel formulation were prepared. One is pH-based hydrogel in which carbopol-940 was used and the other is temperature-based gel in which methocel-K100 was used as gelling agent. Different concentrations of polyherbal extract (GCTC), at 1%, 3% and 5%, were used in hydrogel formulation. These prepared hydrogel formulations were characterized and evaluated for analgesic and anti-inflammatory potential.
    Results: Results show that polyherbal extract and all the developed formulations of polyherbal extract (GCTC), at concentrations of 1%, 3% and 5%, have significant analgesic and anti-inflammatory effects with good appearance, homogeneity, spreadability, extrudability and stability.
    Conclusion: It was concluded from this project that polyherbal extract (GCTC) and its hydrogel have significant analgesic and anti-inflammatory potential.
    Keywords:  carbopol; carrageenan; formulation; inflammation; methocel
    DOI:  https://doi.org/10.2147/JPR.S351921
  110. Methods Mol Biol. 2022 ;2451 405-480
    Strategies for Improving Photodynamic Therapy Through Pharmacological Modulation of the Immediate Early Stress Response.
    Photodynamic Therapy Study Group
      Photodynamic therapy (PDT) is a minimally to noninvasive treatment modality that has emerged as a promising alternative to conventional cancer treatments. PDT induces hyperoxidative stress and disrupts cellular homeostasis in photosensitized cancer cells, resulting in cell death and ultimately removal of the tumor. However, various survival pathways can be activated in sublethally afflicted cancer cells following PDT. The acute stress response is one of the known survival pathways in PDT, which is activated by reactive oxygen species and signals via ASK-1 (directly) or via TNFR (indirectly). The acute stress response can activate various other survival pathways that may entail antioxidant, pro-inflammatory, angiogenic, and proteotoxic stress responses that culminate in the cancer cell's ability to cope with redox stress and oxidative damage. This review provides an overview of the immediate early stress response in the context of PDT, mechanisms of activation by PDT, and molecular intervention strategies aimed at inhibiting survival signaling and improving PDT outcome.
    Keywords:  ASK-1; Cancer cell survival; Pharmacological intervention; Photosensitizer; Tumor recalcitrance; p38 and JNK, Therapy resistance
    DOI:  https://doi.org/10.1007/978-1-0716-2099-1_20
  111. Cureus. 2022 Mar;14(3): e23656
    KRAS Mutations in Colorectal Cancer: Relationship With Clinicopathological Characteristics and Impact on Clinical Outcomes in Saudi Arabia.
    Mohammed Alghamdi, Nujud Alabdullatif, Ajeed Al-Rashoud, Joud Alotaibi, Nouf Alhussaini, Sedra Elsirawani, Haneen Somily, Norah Alkhudair, Maram AlOtaiby, Shaik S Ahamed, Nashwa Abd El-Aziz.
      Background Few studies have addressed the prevalence and prognostic impacts of KRAS mutations in Saudi patients with colorectal cancer (CRC). The present study aimed to address the prevalence of KRAS mutations and evaluate their impact on clinical outcomes (if any) among Saudi patients. Methods This retrospective cohort study was conducted at King Saud University Medical Centre (KSUMC), Saudi Arabia. All medical records of biopsy-proven CRC patients between 2015 and 2021 were reviewed. Statistical analysis was carried out to address the associations between KRAS mutations and the clinicopathological patients' variables and survival. Results KRAS mutations were found in 97/194 (50%) CRC patients. In comparison to wild type KRAS tumors, KRAS- mutated ones had shown a trend toward right-sided tumors (30% and 4.3% vs 16% and 1.1%, p-value = 0.032, respectively) and peritoneal metastases (34% vs 19%, p-value = 0.014). Older age at diagnosis, gender, tumor grade, microsatellite instability (MSI), tumor stage (T), and the presence of distant metastasis were independent prognostic factors for poor overall survival (OS). There was no significant association between KRAS mutations and the hazard of mortality (HR: 0.653, 95% CI 0.873-1.134, p = 0.131). For progression-free survival (PFS), older age at presentation, MSI, tumor nodal stage (N), the presence of liver and lung metastasis, and recurrence were poor prognostic factors for PFS. There was no significant relation between KRAS mutations and PFS (HR ratio: 0.756, 95% CI 0.229-2.497, p = 0.646). Conclusions The prevalence of KRAS mutations in CRC patients was similar to that observed in previous studies of Saudi patients. KRAS mutations showed a trend toward right-sided tumors and peritoneal metastases. Survival was significantly related to different clinicopathologic variables of the study cohort but was not affected by the KRAS mutational status.
    Keywords:  clinical; colorectal cancer; kras; prognosis; saudi arabia; survival
    DOI:  https://doi.org/10.7759/cureus.23656
  112. J Cancer. 2022 ;13(7): 2362-2373
    Low Intensity Ultrasound as an Antidote to Taxane/Paclitaxel-induced Cytotoxicity.
    Celina Amaya, Elizabeth R Smith, Xiang-Xi Xu.
      The taxane family of compounds, including Taxol/paclitaxel and Taxotere/docetaxel, are surprisingly successful drugs used in combination or alone for the treatment of most major solid tumors, especially metastatic cancer. The drugs are commonly used in regimen with other agents (often platinum drugs) as frontline treatment, or used as a single agent in a dose dense regimen for recurrent cancer. The major side effects of taxanes are peripheral neuropathy, alopecia, and neutropenia, which are grave burden for patients and limit the full potential of the taxane drugs. Especially in the current treatment protocol for peripheral neuropathy, taxane dosage is reduced once the symptoms present, resulting in the loss of full or optimal cancer killing activity. Substantial efforts have been made to address the problem of cytotoxic side effects of taxanes, though strategies remain very limited. Following administration of the taxane compound by infusion, taxane binds to cellular microtubules and is sequestered within the cells for several days. Taxane stabilizes and interferes with microtubule function, leading to ultimate death of cancer cells, but also damages hair follicles, peripheral neurons, and hemopoietic stem cells. Currently, cryo-treatment is practiced to limit exposure and side effects of the drug during infusion, though the effectiveness is uncertain or limited. A recent laboratory finding may provide a new strategy to counter taxane cytotoxicity, that a brief exposure to low density ultrasound waves was sufficient to eliminate paclitaxel cytotoxicity cells in culture by transiently breaking microtubule filaments, which were then relocated to lysosomes for disposal. Thus, ultrasonic force to break rigid microtubules is an effective solution to counter taxane cytotoxicity. The discovery and concept of low intensity ultrasound as an antidote may have the potential to provide a practical strategy to counter paclitaxel-induced peripheral neuropathy and alopecia that resulted from chemotherapy. Taxanes are a class of important drugs used in chemotherapy to treat several major cancers. This article reviews a new laboratory discovery that ultrasound can be used as an antidote for the peripheral cytotoxicity of taxane drugs and discusses the potential development and application of low intensity ultrasound to prevent side effects in chemotherapeutic treatment of cancer patients.
    Keywords:  Taxol/paclitaxel; Ultrasound; alopecia; cancer chemotherapy; cytotoxicity; microtubules; neutropenia; peripheral neuropathy; shock wave; side effects
    DOI:  https://doi.org/10.7150/jca.71263
  113. Evid Based Complement Alternat Med. 2022 ;2022 5359669
    A Comprehensive Insight into the Phytochemical, Pharmacological Potential, and Traditional Medicinal Uses of Albizia lebbeck (L.) Benth.
    Acharya Balkrishna, Sakshi, Mayur Chauhan, Anurag Dabas, Vedpriya Arya.
      Background: Albizialebbeck is a deciduous tree having tremendous medicinal utilities, for example, respiratory, skin, gastrointestinal, oral disorders, eye, urinary, genital, anorectal, inflammatory, and neurological disorders, and venereal diseases. Several studies have been undertaken on the medicinal and traditional values of A. lebbeck.Objective: The detailed information about its medicinal uses and pharmacological implications is highly scattered and distributed in different data sources. Hence, the study was conducted to supply an inclusive review of its ethnomedicinal uses, phytochemicals, and the available pharmacological attributes supporting its efficiency in traditional medicine.
    Method: Literature surveys were conducted on this medicinal plant via search engines like Google Scholar, PubMed, and Science Direct, and obtained information up to December 2020 has been assessed and analyzed for this study.
    Results: Systematic investigation revealed that A. lebbeck consists of various phytochemicals, including major alkaloids, flavonoids, saponins, and terpenoids. Its crude extract, fraction, and bioactive compounds exhibited potent adulticidal, antiallergic, anticancer, anticonvulsant, antidiabetic, antidiarrheal, anti-inflammatory, antimicrobial, antinociceptive, antioxidant, antiparasitic, antipyretic, antivenom, estrogenic, neuroprotective, nootropic, ovicidal, and wound healing activities.
    Conclusions: This study proposes that A. lebbeck remains a rich source of phytochemicals with various biological activities which possess outstanding therapeutic benefits to humanity across the world. However, studies are required to estimate the potential side effects. Moreover, mechanistic physiognomies of the isolated compounds with known bioactivities are quite limited; thus, forthcoming research needs to focus on the mechanisms of these active phytochemicals to facilitate their potential enrolling for drug discovery.
    DOI:  https://doi.org/10.1155/2022/5359669
  114. Oxid Med Cell Longev. 2022 ;2022 8615242
    Pharmacological Properties of Bergapten: Mechanistic and Therapeutic Aspects.
    Maria Magdalena Quetglas-Llabrés, Cristina Quispe, Jesús Herrera-Bravo, Marcelo D Catarino, Olívia R Pereira, Susana M Cardoso, Kamal Dua, Dinesh Kumar Chellappan, Kavita Pabreja, Saurabh Satija, Meenu Mehta, Antoni Sureda, Miquel Martorell, Dinara Satmbekova, Balakyz Yeskaliyeva, Javad Sharifi-Rad, Naeem Rasool, Monica Butnariu, Iulia Cristina Bagiu, Radu Vasile Bagiu, Daniela Calina, William C Cho.
      Bergapten (BP) or 5-methoxypsoralen (5-MOP) is a furocoumarin compound mainly found in bergamot essential oil but also in other citrus essential oils and grapefruit juice. This compound presents antibacterial, anti-inflammatory, hypolipemic, and anticancer effects and is successfully used as a photosensitizing agent. The present review focuses on the research evidence related to the therapeutic properties of bergapten collected in recent years. Many preclinical and in vitro studies have been evidenced the therapeutic action of BP; however, few clinical trials have been carried out to evaluate its efficacy. These clinical trials with BP are mainly focused on patients suffering from skin disorders such as psoriasis or vitiligo. In these trials, the administration of BP (oral or topical) combined with UV irradiation induces relevant lesion clearance rates. In addition, beneficial effects of bergamot extract were also observed in patients with altered serum lipid profiles and in people with nonalcoholic fatty liver. On the contrary, there are no clinical trials that investigate the possible effects on cancer. Although the bioavailability of BP is lower than that of its 8-methoxypsoralen (8-MOP) isomer, it has fewer side effects allowing higher concentrations to be administered. In conclusion, although the use of BP has therapeutic applications on skin disorders as a sensitizing agent and as components of bergamot extract as hypolipemic therapy, more trials are necessary to define the doses and treatment guidelines and its usefulness against other pathologies such as cancer or bacterial infections.
    DOI:  https://doi.org/10.1155/2022/8615242
  115. Evid Based Complement Alternat Med. 2022 ;2022 9302403
    Salvianolic Acid B Suppresses Non-Small-Cell Lung Cancer Metastasis through PKM2-Independent Metabolic Reprogramming.
    Hong Zhang, Jianming Tang, Yu Cao, Tianhu Wang.
      Objective: Salvianolic acid B (Sal B) has been demonstrated to be a potential chemoprevention agent for several cancers. Herein, we investigated the pharmacological function of Sal B on non-small-cell lung cancer (NSCLC) metastasis.Methods: Two NSCLC cell lines (NCI-H2030 and NCI-H1650) were disposed of by 200 μM Sal B or 10 μM PKM2 agonist TEPP-46. Wound healing and transwell experiments were implemented for analyzing migratory and invasive capacities. Epithelial-to-mesenchymal transition (EMT) markers β-catenin and E-cadherin were measured via western blotting. Cellular bioenergetics were evaluated with glucose uptake, lactate production, enolase activity, cellular ATP levels, as well as seahorse-based oxygen consumption rate (OCR), extracellular acidification rate (ECAR) analysis. Metabolic reprogramming markers PKM2, LDHA, and GLUT1 were detected via western blotting and immunofluorescence.
    Results: The results showed that Sal B disposal weakened the migration and invasion of NCI-H2030 and NCI-H1650 cells and inactivated the EMT process according to downregulation of β-catenin and upregulation of E-cadherin. Sal B-treated NSCLC cells displayed decreased glucose uptake, lactate production, enolase activity, cellular ATP levels, OCR, and ECAR, indicating a reduction in metabolic reprogramming. Additionally, Sal B downregulated the expression of PKM2, LDHA, and GLUT1. TEPP-46 may reverse the inhibitory effect of Sal B on metastasis as well as metabolic reprogramming.
    Conclusion: Our findings provide evidence that Sal B enables to weaken NSCLC metastasis through PKM2-independent metabolic reprogramming, which sheds light on the promising therapeutic usage of Sal B in treating NSCLC.
    DOI:  https://doi.org/10.1155/2022/9302403
  116. RSC Adv. 2020 Oct 07. 10(61): 36989-37004
    Natural deep eutectic solvent supported targeted solid-liquid polymer carrier for breast cancer therapy.
    Xianfu Sun, Periyakaruppan Pradeepkumar, Naresh Kumar Rajendran, Harshavardhan Shakila, Nicolette Nadene Houreld, Dunia A Al Farraj, Yousif M Elnahas, Nandhakumar Elumalai, Mariappan Rajan.
      Solid-liquid nanocarriers (SLNs) are at the front of the rapidly emerging field of medicinal applications with a potential role in the delivery of bioactive agents. Here, we report a new SLN of natural deep eutectic solvent (NADES) and biotin-conjugated lysine-polyethylene glycol copolymer. The SLN system was analyzed for its functional groups, thermal stability, crystalline nature, particle size, and surface morphology through the instrumental analysis of FT-IR, TGA, XRD, DLS, SEM, and TEM. Encapsulation of PTX (paclitaxel) and 7-HC (7-hydroxycoumarin) with the SLN was carried out by dialysis, and UV-visible spectra evidenced the drug loading capacity and higher encapsulation efficiency obtained. The enhanced anticancer potential of PTX- and 7-HC-loaded SLN was assessed in vitro, and the system reduces the cell viability of MDA-MB-231 cells. The PTX- and 7-HC-loaded SLN system was investigated in a breast cancer-induced rat model via in vivo studies. It shows decreased lysosomal enzymes and increased levels of caspase to cure breast tumors. It very well may be reasoned that the designed PTX- and 7-HC-loaded SLN system has strong anticancer properties and exhibits potential for delivery of drug molecules in cancer treatment.
    DOI:  https://doi.org/10.1039/d0ra03790g
  117. Bioorg Chem. 2022 Apr 25. pii: S0045-2068(22)00222-X. [Epub ahead of print]124 105817
    Natural terpenoids with anti-inflammatory activities: Potential leads for anti-inflammatory drug discovery.
    Jiamin Ge, Zhen Liu, Zhichao Zhong, Liwei Wang, Xiaotao Zhuo, Junjie Li, Xiaoying Jiang, Xiang-Yang Ye, Tian Xie, Renren Bai.
      Natural products are mainly secondary metabolites produced by plants, microorganisms, and animals, which are still abundant in modern drug discovery. Terpenoids are the most diverse group of natural products, attracting extensive attention owing to their various biological activities. This manuscript reviewed the chemical structures, anti-inflammatory activities, and mechanisms of action of 281 terpenoid natural products reported from 2010 to the present. Their biological targets and both in vitro and in vivo screening models were also surveyed and statistically summarized. This review will provide potential anti-inflammatory lead compounds and helpful information to researchers engaged in natural products and anti-inflammatory drug discovery.
    Keywords:  Anti-inflammatory activities; Drug discovery; Natural products; Targets; Terpenoids
    DOI:  https://doi.org/10.1016/j.bioorg.2022.105817
  118. Life Sci. 2022 Apr 29. pii: S0024-3205(22)00293-4. [Epub ahead of print]300 120593
    Recent progress in the early detection of cancer based on CD44 biomarker; nano-biosensing approaches.
    Youkabed Kazemi, Sadegh Dehghani, Rahim Nosrati, Seyed Mohammad Taghdisi, Khalil Abnous, Mona Alibolandi, Mohammad Ramezani.
      CD44 is a cell matrix adhesion molecule overexpressed on the cell surfaces of the major cancers. CD44 as a cancer-related biomarker has an essential role in the invasion and metastasis of cancer. The detection and quantification of CD44 can provide essential information useful for clinical cancer diagnosis. In this regard, biosensors with sensitive and specific properties, give prominence to the development of CD44 detection platforms. To date, various aptamer-based sensitive-enhancers together with nanoparticles (NPs) have been combined into the biosensors systems to provide an innovative biosensing method (aptasensors/nano-aptasensors) with substantially improved detection limit. This review article discusses the recent advances in the field of biosensors, nanobiosensors, and aptasensors for the quantitative determination of CD44 and the detection of CD44-expressing cancer cells.
    Keywords:  Aptasensor; Biosensor; CD44; Cancer biomarker; Nanosensor
    DOI:  https://doi.org/10.1016/j.lfs.2022.120593
  119. Colloids Surf B Biointerfaces. 2022 Apr 26. pii: S0927-7765(22)00203-X. [Epub ahead of print]215 112520
    Fabrication, physicochemical characterization and In vitro anticancer activity of nerolidol encapsulated solid lipid nanoparticles in human colorectal cell line.
    Shabi Parvez, Archana Karole, Shyam Lal Mudavath.
      Nerolidol is a sesquiterpene that occurs naturally and possesses a diverse set of biological characteristics including anticancer activity but has limited solubility, bioavailability, and fast hepatic metabolism. The goal of this study was to develop a nanocarrier system encapsulating a bioactive as well as to evaluate its efficacy in Human Colorectal Cell Line. Solid lipid nanoparticles were fabricated by the emulsion solvent evaporation method and determined the particle size, polydispersity index (PDI), zeta potential, % entrapment efficiency, scanning electron microscopy (SEM), transmission electron microscopy (TEM), drug-excipient interaction study of developed nanoparticles. MTT assay was used to assess the cytotoxicity of formulations in vitro. Nerolidol loaded solid lipid nanoparticles (NR-LNPs) have presented satisfactory properties: mean particles diameter of 159 ± 4.89 nm, PDI of 0.32 ± 0.01, the zeta potential value was found to be -10 ± 1.97 and % entrapment efficiency 71.3% ± 6.11. The formulations demonstrated enhanced biological activity due to enhanced solubility and stability of the bioactive after loading into a nanoformulation along with the better internalization inside the cells.
    Keywords:  Anti-cancer activity; Apoptosis; Caco-2 cells; Nerolidol; Solid lipid nanoparticles
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112520
  120. Methods Mol Biol. 2022 ;2451 245-258
    Cytotoxicity of Metal-Based Photoactivated Chemotherapy (PACT) Compounds.
    Vadde Ramu, Austin B Auyeung, Sylvestre Bonnet.
      Metal-based compounds have been used to treat cancer for decades, with cisplatin being the most common and widely used. Photodynamic therapy (PDT) is another clinical modality used to fight cancer, which uses a photosensitizer (PS) that localizes in cancer tissues. This PS is activated by the illumination of the tumor with visible light. Photoactivated chemotherapy (PACT) is a new concept that brings these two ideas together. Like PDT , PACT aims at sparing healthy tissues while maintaining toxicity against cancerous cells. Unlike PDT , which often stops working when the concentration of dioxygen in illuminated tissues is too low, light activation of PACT compounds remains efficient in hypoxic cancer cells. This chapter addresses the methodology to experimentally measure the phototoxicity of PACT compounds in cancer cell lines, under both normoxic and hypoxic conditions.
    Keywords:  Chemotherapy; Cytotoxicity; Hypoxia; Metal complexes; Metal-based; Normoxia; PACT; Photoactivation
    DOI:  https://doi.org/10.1007/978-1-0716-2099-1_17
  121. RSC Adv. 2020 Nov 27. 10(71): 43629-43639
    Formulation development, in vitro and in vivo evaluation of chitosan engineered nanoparticles for ocular delivery of insulin.
    Priyanka Rathore, Alok Mahor, Surendra Jain, Anzarul Haque, Prashant Kesharwani.
      Insulin-dependent diabetic patients have to count on the administration of painful and discomforting insulin injections. However, inadequate insulin absorption and the risk of insulin level escalation in the blood are some disadvantages associated with insulin therapy. Thus, the current study intends to formulate insulin-loaded chitosan nanoparticles for refining the systemic absorption of insulin via the ocular route. Insulin-loaded chitosan nanoparticles were prepared by the ionotropic gelation method and characterized for various parameters. Optimized insulin loaded nanoparticles (C4T4I4) were positively charged with a particle size of 215 ± 2.5 nm and showed 65.89 ± 4.3% entrapment efficiency. The in vitro drug release exhibited sustained release of insulin, where 77.2 ± 2.1% of release was observed after 12 h and leads to an assumption of the non-Fickian diffusion release mechanism. The permeation study discloses good mucoadhesive and better permeation properties of insulin loaded nanoparticles compared to free Insulin. No significant difference was observed in the size of particles after six months of storage, signifying their adequate stability. Nanoparticles were found to be non-irritant to ocular tissues and exhibited prominent blood glucose level reduction in vivo. The outcomes of this study suggested that the chitosan nanoparticulate system could act as a prominent carrier system for insulin with enhanced stability and efficacy.
    DOI:  https://doi.org/10.1039/d0ra07640f
  122. Nanomicro Lett. 2022 May 05. 14(1): 123
    Emerging Strategies in Enhancing Singlet Oxygen Generation of Nano-Photosensitizers Toward Advanced Phototherapy.
    Mohammad Tavakkoli Yaraki, Bin Liu, Yen Nee Tan.
      The great promise of photodynamic therapy (PDT) has thrusted the rapid progress of developing highly effective photosensitizers (PS) in killing cancerous cells and bacteria. To mitigate the intrinsic limitations of the classical molecular photosensitizers, researchers have been looking into designing new generation of nanomaterial-based photosensitizers (nano-photosensitizers) with better photostability and higher singlet oxygen generation (SOG) efficiency, and ways of enhancing the performance of existing photosensitizers. In this paper, we review the recent development of nano-photosensitizers and nanoplasmonic strategies to enhance the SOG efficiency for better PDT performance. Firstly, we explain the mechanism of reactive oxygen species generation by classical photosensitizers, followed by a brief discussion on the commercially available photosensitizers and their limitations in PDT. We then introduce three types of new generation nano-photosensitizers that can effectively produce singlet oxygen molecules under visible light illumination, i.e., aggregation-induced emission nanodots, metal nanoclusters (< 2 nm), and carbon dots. Different design approaches to synthesize these nano-photosensitizers were also discussed. To further enhance the SOG rate of nano-photosensitizers, plasmonic strategies on using different types of metal nanoparticles in both colloidal and planar metal-PS systems are reviewed. The key parameters that determine the metal-enhanced SOG (ME-SOG) efficiency and their underlined enhancement mechanism are discussed. Lastly, we highlight the future prospects of these nanoengineering strategies, and discuss how the future development in nanobiotechnology and theoretical simulation could accelerate the design of new photosensitizers and ME-SOG systems for highly effective image-guided photodynamic therapy.
    Keywords:  Aggregation-induced emission; Carbon dots; Metal nanocluster; Metal-enhanced singlet oxygen generation; Nano-photosensitizer; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s40820-022-00856-y
  123. J Nanobiotechnology. 2022 May 02. 20(1): 209
    Nanozyme-natural enzymes cascade catalyze cholesterol consumption and reverse cancer multidrug resistance.
    Bin Du, Mei Zheng, Huizhen Ma, Jingshu Huang, Qingqing Jiao, Yimeng Bai, Mengmeng Zhao, Jie Zhou.
      Multidrug resistance is still a major obstacle to cancer treatment. The most studies are to inhibit the activity of the drug transporter P-glycoprotein (P-gp), but the effect is not ideal. Herein, a nanosystem was built based on cascade catalytic consumption of cholesterol. Cholesterol oxidase (natural enzyme, COD) was immobilized on the carrier (NH2-MIL-88B, MOF) through amide reaction, COD catalyzed the consumption of cholesterol, the reaction product H2O2 was further produced by the MOF with its peroxidase-like activity to produce hydroxyl radicals (•OH) with killing effect. Due to the high expression of CD44 receptor on the surface of tumor cells, we encapsulated chondroitin sulfate gel shell (CS-shell) with CD44 targeting and apoptosis promoting effect on the surface of DOX@MOF-COD nanoparticles, which can accurately and efficiently deliver the drugs to the tumor site and improve the effect of reversing drug resistance. Taking drug-resistant cell membrane as "breakthrough", this paper will provide a new idea for reversing multidrug resistance of tumor.
    Keywords:  Apoptosis; Cholesterol; Cholesterol oxidase; Chondroitin sulfate; Fluidity; Lipid raft; Reverse drug resistance
    DOI:  https://doi.org/10.1186/s12951-022-01406-9
  124. Drug Res (Stuttg). 2022 May 03.
    Solid Lipid Nanoparticles of Lepidium Sativum L Seed Extract: Formulation, Optimization and In vitro Cytotoxicity Studies.
    Asad Ahmad, Heena Tabassum, Rabia Nabi, Anuradha Mishra, Iffat Zareen Ahmad.
      The current study focused on important bioactive compounds in plants that make them pharmacologically valuable. Therefore, this study was aimed to develop Lepidium sativum (L. sativum) seed extract loaded solid lipid nanoparticles and explore its cytotoxic effect on human liver cancer cells (HepG2 cells). The ethanolic extract of L. sativam used to develop L. sativum seed extract loaded solid lipid nanoparticles (SLNs) was analyzed by gas chromatography-mass spectrometry, thin-layer chromatography (TLC) and high-performance thin-layer chromatography (HPTLC) for phytochemical profiling. The L. sativum seed extract loaded SLNs were efficaciously prepared by the nanoprecipitation method and screened on the basis of physicochemical properties. The L. sativum seed extract loaded SLN-2 was characterized using various parameters like particle size (237.1±0.104), % entrapment efficiency (80±1.15), zeta potential (42.1±0.102) and % drug release (45% at the end 8 hours and release the entire amount in 12 h). The SLN-2 formulation was optimized based on the recipient factor, and SLN-2 was used to further evaluate the in vitro cytotoxicity of HepG2 cells in a dose-dependent manner by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay. The IC50 value of SLN2 was 52.37 ug/ml and sub IC50 26.1 ug/ml at 24 h and 48 h, respectively. Thus, we concluded that L. sativum extract loaded SLN-2 could act as an alternative therapy, possibly controlling therapeutic action by making a substantial reduction in side effects.
    DOI:  https://doi.org/10.1055/a-1800-5956
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