bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–06–26
117 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Aggregation-Induced Emission Photosensitizer Synergizes Photodynamic Therapy and the Inhibition of the NF-κB Signaling Pathway to Overcome Hypoxia in Breast Cancer.
  2. Nano-Liposomes Double Loaded with Curcumin and Tetrandrine: Preparation, Characterization, Hepatotoxicity and Anti-Tumor Effects.
  3. Engineered Red Blood Cell Membrane-coating Salidroside/indocyanine Green Nanovesicles for High-efficiency Hypoxic Targeting Phototherapy of Triple Negative Breast Cancer.
  4. A photochemical-responsive nanoparticle boosts doxorubicin uptake to suppress breast cancer cell proliferation by apoptosis.
  5. The Role and Mechanisms of Action of Natural Compounds in the Prevention and Treatment of Cancer and Cancer Metastasis.
  6. Manipulating Metabolic Alterations and Its Consequence to Unleash the Potential of Antitumor Immunotherapy.
  7. Poly-l-lysine derivative-coated black phosphorus as a nanoplatform for photothermal chemotherapy to enhance anti-tumor efficiency.
  8. Fucoxanthin Is a Potential Therapeutic Agent for the Treatment of Breast Cancer.
  9. A targeted nanomodulator capable of manipulating tumor microenvironment against metastasis.
  10. Nanomedicine Penetration to Tumor: Challenges, and Advanced Strategies to Tackle This Issue.
  11. Cascade nanozymes based on the "butterfly effect" for enhanced starvation therapy through the regulation of autophagy.
  12. Cu2+-Chelating Mesoporous Silica Nanoparticles for Synergistic Chemotherapy/Chemodynamic Therapy.
  13. Targeting mitochondrial metabolism for metastatic cancer therapy.
  14. Royal Jelly as a Nutraceutical Natural Product with a Focus on Its Antibacterial Activity.
  15. Upconversion Luminescence-Boosted Escape of DNAzyme from Endosomes for Enhanced Gene-Silencing Efficacy.
  16. Interactions Between Natural Products and Tamoxifen in Breast Cancer: A Comprehensive Literature Review.
  17. The Effect and Related Mechanism of Action of Astragalus Compatible with Curcumin against Colon Cancer Metastasis in Mice.
  18. Cellular metabolism in pancreatic cancer as a tool for prognosis and treatment (Review).
  19. Construction Of High Loading Natural Active Substances Nanoplatform and Application in Synergistic Tumor Therapy.
  20. Natural Nanoparticles: A Safe Bullet for Treatment and Detection of Solid Tumors.
  21. Curcumin and resveratrol inhibit chemoresistance in cisplatin-resistant epithelial ovarian cancer cells via targeting P13K pathway.
  22. pH/Thermal-Sensitive Nanoplatform Capable of On-Demand Specific Release to Potentiate Drug Delivery and Combinational Hyperthermia/Chemo/Chemodynamic Therapy.
  23. Anti-Cancer Effects of Dietary Polyphenols via ROS-Mediated Pathway with Their Modulation of MicroRNAs.
  24. Ultrasound and Nanomedicine for Cancer-Targeted Drug Delivery: Screening, Cellular Mechanisms and Therapeutic Opportunities.
  25. PEGylated Magnetite/Hydroxyapatite: A Green Nanocomposite for T2-Weighted MRI and Curcumin Carrying.
  26. Free-Radical Cascade Generated by AIPH/Fe3O4-Coloaded Nanoparticles Enhances MRI-Guided Chemo/Thermodynamic Hypoxic Tumor Therapy.
  27. Synthetic Vulnerabilities in the KRAS Pathway.
  28. Sodium alginate based drug delivery in management of breast cancer.
  29. Pharmacological effects of D-Pinitol - A comprehensive review.
  30. Beneath the Skin: A Review of Current Trends and Future Prospects of Transdermal Drug Delivery Systems.
  31. Revisiting the therapeutic potential of tocotrienol.
  32. Glucose Metabolism Intervention-Facilitated Nanomedicine Therapy.
  33. Phytochemical and Potential Properties of Seaweeds and Their Recent Applications: A Review.
  34. Co-encapsulation of flavonoids with anti-cancer drugs: a challenge ahead.
  35. Applications of resveratrol in the treatment of gastrointestinal cancer.
  36. Silybin suppresses ovarian cancer cell proliferation by inhibiting isocitrate dehydrogenase 1 activity.
  37. Profiling the Effect of Targeting Wild Isocitrate Dehydrogenase 1 (IDH1) on the Cellular Metabolome of Leukemic Cells.
  38. Carbon Graphitization: Towards Greener Alternatives to Develop Nanomaterials for Targeted Drug Delivery.
  39. Long circulation and tumor-targeting biomimetic nanoparticles for efficient chemo/photothermal synergistic therapy.
  40. Stimuli-responsive prodrug of non-steroidal anti-inflammatory drug diclofenac: self-immolative drug release with turn-on near-infrared fluorescence.
  41. Synthesis of a versatile mitochondria-targeting small molecule for cancer near-infrared fluorescent imaging and radio/photodynamic/photothermal synergistic therapies.
  42. A plasmon-enhanced fluorescent gold coated novel lipo-polymeric hybrid nanosystem: synthesis, characterization and application for imaging and photothermal therapy of breast cancer.
  43. Polymeric micelles and cancer therapy: an ingenious multimodal tumor-targeted drug delivery system.
  44. The Potential Application of Natural Photosensitizers Used in Antimicrobial Photodynamic Therapy against Oral Infections.
  45. Shea Butter Potentiates the Anti-Bacterial Activity of Fusidic Acid Incorporated into Solid Lipid Nanoparticle.
  46. Phosphodiesterase 5 inhibitor sildenafil potentiates the antitumor activity of cisplatin by ROS-mediated apoptosis: a role of deregulated glucose metabolism.
  47. Effects of particle size and release property of paclitaxel-loaded nanoparticles on their peritoneal retention and therapeutic efficacy against mouse malignant ascites.
  48. High-Dose Vitamin C for Cancer Therapy.
  49. Multifunctional Magnetic Nanoparticles for MRI-guided Co-delivery of Erlotinib and L-Asparaginase to Ovarian Cancer.
  50. Biodegradable Carbonate Apatite Nanoparticle as a Delivery System to Promote Afatinib Delivery for Non-Small Cell Lung Cancer Treatment.
  51. Natural Marine Products: Anti-Colorectal Cancer In Vitro and In Vivo.
  52. Hollow microneedle assisted intradermal delivery of hypericin lipid nanocapsules with light enabled photodynamic therapy against skin cancer.
  53. Cell membrane-camouflaged inorganic nanoparticles for cancer therapy.
  54. Advances on Delivery of Cytotoxic Enzymes as Anticancer Agents.
  55. Essential role of aerobic glycolysis in epithelial-to-mesenchymal transition during carcinogenesis.
  56. Phytochemicals, Nutrition, Metabolism, Bioavailability, and Health Benefits in Lettuce-A Comprehensive Review.
  57. Rediscovery of Traditional Plant Medicine: An Underestimated Anticancer Drug of Chelerythrine.
  58. Editorial: Drug Delivery System Based on Nanoparticles for Inflammation and Cancer Therapy.
  59. Evaluation of anticancer effects of carboplatin-gelatin nanoparticles in different sizes synthesized with newly self-assembly method by exposure to IR light.
  60. Amino acid coordination complex mediates cisplatin entrapment within PEGylated liposome: an implication in colorectal cancer therapy.
  61. Shuanghua decoction exerts anticancer activity by activating NLRP3 inflammasome via ROS and inhibiting NF-κB signaling in hepatocellular carcinoma cells.
  62. Potential role of melatonin in prevention and treatment of lung cancer.
  63. Solid Dispersions Incorporated into PVP Films for the Controlled Release of Trans-Resveratrol: Development, Physicochemical and In Vitro Characterizations and In Vivo Cutaneous Anti-Inflammatory Evaluation.
  64. Ascorbate as a Bioactive Compound in Cancer Therapy: The Old Classic Strikes Back.
  65. Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia.
  66. Rethinking nanoparticulate polymer-drug conjugates for cancer theranostics.
  67. Antitumor Potential of Immunomodulatory Natural Products.
  68. Albumin-Stabilized Manganese Oxide/Semiconducting Polymer Nanocomposites for Photothermal-Chemodynamic Therapy of Hepatic Carcinoma.
  69. Efficient Delivery of Curcumin by Alginate Oligosaccharide Coated Aminated Mesoporous Silica Nanoparticles and In Vitro Anticancer Activity against Colon Cancer Cells.
  70. Biofunctionalized graphene oxide nanosheet for amplifying antitumor therapy: Multimodal high drug encapsulation, prolonged hyperthermal window, and deep-site burst drug release.
  71. Solid lipid nanoformulation of berberine attenuates Doxorubicin triggered in vitro inflammation in H9c2 rat cardiomyocytes.
  72. Anti-lung cancer effect of paclitaxel solid lipid nanoparticles delivery system with curcumin as co-loading partner in vitro and in vivo.
  73. Trident Molecule with Nanobrush-Nanoparticle-Nanofiber Transition Property Spatially Suppresses Tumor Metastasis.
  74. Current Researches on Nanodrug Delivery Systems in Bladder Cancer Intravesical Chemotherapy.
  75. Poly(curcumin β-amino ester)-Based Tablet Formulation for a Sustained Release of Curcumin.
  76. Preparation of NIR-Responsive Gold Nanocages as Efficient Carrier for Controlling Release of EGCG in Anticancer Application.
  77. Fabrication of injectable hydrogels from an anticancer peptide for local therapeutic delivery and synergistic photothermal-chemotherapy.
  78. Use of Self-Assembled Colloidal Prodrug Nanoparticles for Controlled Drug Delivery of Anticancer, Antifibrotic and Antibacterial Mitomycin.
  79. Liver Metastatic Breast Cancer: Epidemiology, Dietary Interventions, and Related Metabolism.
  80. Novel multifunctional bionanoparticles modified with sialic acid for stroke treatment.
  81. Emerging Prospects of Nanozymes for Antibacterial and Anticancer Applications.
  82. Iron Oxide Nanoparticles Functionalized with Fucoidan: a Potential Theranostic Nanotool for Hepatocellular Carcinoma.
  83. Recent advances in hyaluronic acid-based nanomedicines: Preparation and application in cancer therapy.
  84. Polymethoxylated flavone sudachitin is a safe anticancer adjuvant that targets glycolysis in cancer-associated fibroblasts.
  85. PEGylated Protamine Letrozole Nanoparticles: A Promising Strategy to Combat Human Breast Cancer via MCF-7 Cell Lines.
  86. Diselenide-crosslinked carboxymethyl chitosan nanoparticles for doxorubicin delivery: Preparation and in vivo evaluation.
  87. Bio-Assisted Synthesis and Characterization of Zinc Oxide Nanoparticles from Lepidium sativum and Their Potent Antioxidant, Antibacterial and Anticancer Activities.
  88. In Vitro Evaluation of Curcumin Encapsulation in Gum Arabic Dispersions under Different Environments.
  89. Evaluation of Different Surface Coating Agents for Selenium Nanoparticles: Enhanced Anti-Inflammatory Activity and Drug Loading Capacity.
  90. Radiotherapy-induced metabolic hallmarks in the tumor microenvironment.
  91. Liposomal Co-delivery of PD-L1 siRNA/Anemoside B4 for Enhanced Combinational Immunotherapeutic Effect.
  92. A review on anticancer, antibacterial and photo catalytic activity of various nanoparticles synthesized by probiotics.
  93. Functional Nanomaterials in Biomedicine: Current Uses and Potential Applications.
  94. Chemical Conjugation in Drug Delivery Systems.
  95. Biological Evaluation of Avocado Residues as a Potential Source of Bioactive Compounds.
  96. Boosting the Anticancer Activity of Sunitinib Malate in Breast Cancer through Lipid Polymer Hybrid Nanoparticles Approach.
  97. Tumor-Targeted Injectable Double-Network Hydrogel for Prevention of Breast Cancer Recurrence and Wound Infection via Synergistic Photothermal and Brachytherapy.
  98. Phage in cancer treatment - Biology of therapeutic phage and screening of tumor targeting peptide.
  99. Stem cell membrane, stem cell-derived exosomes and hybrid stem cell camouflaged nanoparticles: A promising biomimetic nanoplatforms for cancer theranostics.
  100. CD73 downregulation by EGFR-targeted liposomal CD73 siRNA potentiates antitumor effect of liposomal doxorubicin in 4T1 tumor-bearing mice.
  101. Design and Development of Neomycin Sulfate Gel Loaded with Solid Lipid Nanoparticles for Buccal Mucosal Wound Healing.
  102. Antagonistic Pharmacological Interaction between Sirtuin Inhibitor Cambinol and Paclitaxel in Triple-Negative Breast Cancer Cell Lines: An Isobolographic Analysis.
  103. Extracellular Vesicle-Based Drug Delivery Systems for Enhanced Anti-Tumor Therapies through Modulating Cancer-Immunity Cycle.
  104. Targeting Breast Cancer-Derived Stem Cells by Dietary Phytochemicals: A Strategy for Cancer Prevention and Treatment.
  105. Co-loaded lapatinib/PAB by ferritin nanoparticles eliminated ECM-detached cluster cells via modulating EGFR in triple-negative breast cancer.
  106. Tumor Microenvironment: Lactic Acid Promotes Tumor Development.
  107. Flexion of Nrf2 by tea phytochemicals: A review on the chemopreventive and chemotherapeutic implications.
  108. Lymphatic targeting for therapeutic application using nanoparticulate systems.
  109. A Historical Review of Brain Drug Delivery.
  110. Multifunctional PLA/Gelatin Bionanocomposites for Tailored Drug Delivery Systems.
  111. Signaling Pathways and Natural Compounds in Triple-Negative Breast Cancer Cell Line.
  112. A Fe(III)-porphyrin-oxaliplatin(IV) nanoplatform for enhanced ferroptosis and combined therapy.
  113. Nutraceuticals, a Bridge Between Past and Future: Focus on Mushrooms Biological Activities and Myco-Chemistry.
  114. [Preparation and effect against cervical cancer invasion in vitro of harmine-loaded photosensitive liposomes].
  115. Antioxidant Therapy in Cancer: Rationale and Progress.
  116. Active Compounds in Fruits and Inflammation in the Body.
  117. A glutathione-responsive sulfur dioxide polymer prodrug selectively induces ferroptosis in gastric cancer therapy.
  1. ACS Appl Mater Interfaces. 2022 Jun 21.
    Aggregation-Induced Emission Photosensitizer Synergizes Photodynamic Therapy and the Inhibition of the NF-κB Signaling Pathway to Overcome Hypoxia in Breast Cancer.
    Jia Wang, Haisi Wu, Qianqian Zhao, Yifan Zou, Dan Ding, Haitao Yin, Huae Xu.
      Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, and TNBC patients often develop resistance to endocrine or molecular targeted therapy. Thus, a search for effective treatments is urgently required. Photodynamic therapy (PDT) has been verified to be a successful therapy for cancer. However, this treatment is oxygen-consuming, thus considerably limiting the PDT outcomes. The present study introduced a multistage drug delivery system to alleviate hypoxia and enhance PDT efficiency. Specifically, aggregation-induced emission luminogen (AIEgen) TPE-Py was first introduced to achieve PDT properties, and natural naphthohydroquinone dimer Rubioncolin C (RC), a blocker of mitochondria-associated oxidative phosphorylation (OXPHOS) and an NF-κB inhibitor, was applied to suppress the O2 consumption of OXPHOS and mitigate hypoxia thereafter. Enhanced PDT efficiency was validated by in vitro and in vivo TNBC models. In terms of the mechanism, AIEgen-based PDT synergized with RC could induce a fatal burst of reactive oxygen species (ROS) and ROS-mediated apoptosis. Moreover, this combination promoted the effectiveness of PDT by inhibiting the NF-κB signaling pathway. All of these results demonstrated that the administration system not only achieved a synergistic anti-TNBC effect but also expanded the clinical application of AIEgen-based PDT by overcoming hypoxia and inhibiting the NF-κB signaling pathway.
    Keywords:  AIEgens; NF-κB signaling pathway; Rubioncolin C; hypoxia; photodynamic therapy
    DOI:  https://doi.org/10.1021/acsami.2c06063
  2. Int J Mol Sci. 2022 Jun 20. pii: 6858. [Epub ahead of print]23(12):
    Nano-Liposomes Double Loaded with Curcumin and Tetrandrine: Preparation, Characterization, Hepatotoxicity and Anti-Tumor Effects.
    Jia-Wen Song, Yu-Shi Liu, Yu-Rou Guo, Wen-Xiao Zhong, Yi-Ping Guo, Li Guo.
      (1) Background: Curcumin (CUR) and tetrandrine (TET) are natural compounds with various bioactivities, but have problems with low solubility, stability, and absorption rate, resulting in low bioavailability, and limited applications in food, medicine, and other fields. It is very important to improve the solubility while maintaining the high activity of drugs. Liposomes are micro-vesicles synthesized from cholesterol and lecithin. With high biocompatibility and biodegradability, liposomes can significantly improve drug solubility, efficacy, and bioavailability. (2) Methods: In this work, CUR and TET were encapsulated with nano-liposomes and g DSPE-MPEG 2000 (DP)was added as a stabilizer to achieve better physicochemical properties, biosafety, and anti-tumor effects. (3) Results: The nano-liposome (CT-DP-Lip) showed stable particle size (under 100 nm) under different conditions, high solubility, drug encapsulation efficiency (EE), loading capacity (LC), release rate in vitro, and stability. In addition, in vivo studies demonstrated CT-DP-Lip had no significant toxicity on zebrafish. Tumor cytotoxicity test showed that CT-DP-Lip had a strong inhibitory effect on a variety of cancer cells. (4) Conclusions: This work showed that nano-liposomes can significantly improve the physical and chemical properties of CUR and TET and make them safer and more efficient.
    Keywords:  anti–tumor effects; curcumin; nano–liposome; physicochemical properties; tetrandrine; zebrafish
    DOI:  https://doi.org/10.3390/ijms23126858
  3. Adv Healthc Mater. 2022 Jun 23. e2200962
    Engineered Red Blood Cell Membrane-coating Salidroside/indocyanine Green Nanovesicles for High-efficiency Hypoxic Targeting Phototherapy of Triple Negative Breast Cancer.
    Yi Pan, Yichen He, Xin Zhao, Yue Pan, Xuli Meng, Zhenye Lv, Zhiming Hu, Xiaozhou Mou, Yu Cai.
      Triple negative breast cancer (TNBC) presents special biological behavior and clinicopathological characteristics, and leads to a worse prognosis than other types of breast cancer. The development of an effective therapeutic method is significant to improve the survival rate of TNBC cancer patients. In this work, an engineered red blood cell membrane (RBCm)-coating salidroside/indocyanine green nanovesicle (ARISP) was successfully prepared for hypoxic targeting phototherapy of TNBC. Salidroside in ARISP effectively ameliorates hypoxia-induced tumorigenesis by downregulating the expression of hypoxia-inducible factor 1α (HIF-1α), which increased the killing effect of reactive oxygen species on tumor cells during photodynamic therapy (PDT) using the photosensitizer indocyanine green. Besides, ARISP has an anti-LDLR modified RBCm-coating that extends its circulation time in the blood and escapes from immune surveillance, and enhances hypoxia-targeted cellular uptake via the overexpressed LDLR receptor in hypoxic tumor sites. Moreover, guided by near-infrared fluorescence imaging and photoacoustic imaging, ARISP can eliminate tumors via high-efficiency phototherapy and inhibit lung and liver metastasis in TNBC models. Cytotoxicity assay of ARISP indicates the excellent biocompatibility to normal cells and tissues. This study provided fulfilling insights into the anticancer mechanism of reducing HIF-1α for enhanced PDT, and has a promising therapeutic potential for TNBC treatment. This article is protected by copyright. All rights reserved.
    Keywords:  Engineered red blood cell membrane; Hypoxic targeted drug delivery; Photoacoustic imaging; Phototherapy; Triple negative breast cancer
    DOI:  https://doi.org/10.1002/adhm.202200962
  4. Sci Rep. 2022 Jun 20. 12(1): 10354
    A photochemical-responsive nanoparticle boosts doxorubicin uptake to suppress breast cancer cell proliferation by apoptosis.
    Ying Zhang, Kaiting Li, Xiaoyu Han, Qing Chen, Lan Shao, Dingqun Bai.
      In the course of chemotherapy for breast cancer, doxorubicin (DOX) is one of the most commonly prescribed agents. However, it has been recognized as clinically circumscribed on account of its poor selectivity and toxic reactions to normal tissues. Fortunately, the distinct merit of photochemical-responsive nanoparticle delivery systems to enhance cellular drugs uptake through localized concentration, adequate selective and minimizing systemic toxicity has aroused substantial interest recently. In this study, we synthesized photochemical-responsive nanoparticle by incorporating DOX, curcumin (CUR), and perfluorooctyl bromide (PFOB) into poly(lactic-co-glycolic acid) (PLGA) via double emulsification (DOX-CUR-PFOB-PLGA). The synthesized composite nanoparticles, which featured good ultrasound imaging, engendered photochemical activation for drug release when given laser irradiation. Cumulative release rates for DOX were 76.34%, and for CUR were 83.64%, respectively. Also, MCF-7 cells displayed significant intracellular DOX uptake and reactive oxygen species (ROS) levels, degraded cytoskeleton, and decreased cell growth and migration capacity. At the molecular level, cellular pAKT levels decreased, which resulted in downregulated HIF-1α and BAX/BCl-2 levels, leading to Caspase-3 activation and thus induction of apoptosis. Therefore, the photochemical-responsive nanoparticles possess the potential to elicit apoptosis in MCF-7 cells via enhanced DOX uptake.
    DOI:  https://doi.org/10.1038/s41598-022-14518-x
  5. Front Biosci (Landmark Ed). 2022 Jun 15. 27(6): 192
    The Role and Mechanisms of Action of Natural Compounds in the Prevention and Treatment of Cancer and Cancer Metastasis.
    Yunqiao Wang, Mingtai Chen, Hao Yu, Gang Yuan, Li Luo, Xiongfei Xu, Yanneng Xu, Xinbing Sui, Elaine Lai-Han Leung, Qibiao Wu.
      Cancer has emerged as one of the world's most concerning health problems. The progression and metastasis mechanisms of cancer are complex, including metabolic disorders, oxidative stress, inflammation, apoptosis, and intestinal microflora disorders. These pose significant challenges to our efforts to prevent and treat cancer and its metastasis. Natural drugs have a long history of use in the prevention and treatment of cancer. Many effective anti-tumor drugs, such as Paclitaxel, Vincristine, and Camptothecin, have been widely prescribed for the prevention and treatment of cancer. In recent years, a trend in the field of antitumor drug development has been to screen the active antitumor ingredients from natural drugs and conduct in-depth studies on the mechanisms of their antitumor activity. In this review, high-frequency keywords included in the literature of several common Chinese and English databases were analyzed. The results showed that five Chinese herbal medicines (Radix Salviae, Panax Ginseng C. A. Mey, Hedysarum Multijugum Maxim, Ganoderma, and Curcumaelongae Rhizoma) and three natural compounds (quercetin, luteolin, and kaempferol) were most commonly used for the prevention and treatment of cancer and cancer metastasis. The main mechanisms of action of these active compounds in tumor-related research were summarized. Finally, we found that four natural compounds (dihydrotanshinone, sclareol, isoimperatorin, and girinimbin) have recently attracted the most attention in the field of anti-cancer research. Our findings provide some inspiration for future research on natural compounds against tumors and new insights into the role and mechanisms of natural compounds in the prevention and treatment of cancer and cancer metastasis.
    Keywords:  Chinese medicine; bioactive compounds; cancer; molecular mechanisms; tumor
    DOI:  https://doi.org/10.31083/j.fbl2706192
  6. Curr Protein Pept Sci. 2022 Jun 20.
    Manipulating Metabolic Alterations and Its Consequence to Unleash the Potential of Antitumor Immunotherapy.
    Xuanyu Zhu, Longfei Zhu, Yan Wu.
      Cellular metabolic reprogramming driven by oncogenic mutations is considered as a hallmark in the development of malignant cells, and has been a focus of increased investigation over the past decade. A common theme emerging from these metabolic alterations is that tumor cells can acquire necessary nutrients from a nutrient-limited microenvironment and utilize them to sustain growth and unrestrained cellular division. However, this significant metabolic flexibility and the hostile microenvironment caused by the insufficient vascular exchange, depletion of nutrients, hypoxia, and accumulation of waste products, can inhibit the metabolism and immune activity of tumor-infiltrating lymphocytes and impose barriers to effective antitumor immunotherapies. In this Perspective, we review the classical alterations in tumorigenesis-associated metabolic reprogramming and examine the functional contribution of these aberrant metabolisms to the establishment and maintenance of an immunosuppressive microenvironment. Furthermore, we explore the possible approaches to targeting these metabolic pathways to achieve anti-tumor immunotherapy, as well as some hypothetical or ongoing combination therapeutic strategies that could, to a certain extent, biologically rationalize and broaden the utility of immune checkpoint inhibitors. Ultimately, we elucidate some dietary modifications that can limit tumor-specific nutritional requirements and maximize the cytotoxicity of other antineoplastic drugs.
    Keywords:  Tumor metabolic reprogramming; antitumor immunotherapy; diet intervention.; immune response; nutrition; t cell
    DOI:  https://doi.org/10.2174/1389203723666220620161742
  7. J Mater Chem B. 2022 Jun 21.
    Poly-l-lysine derivative-coated black phosphorus as a nanoplatform for photothermal chemotherapy to enhance anti-tumor efficiency.
    Anning Li, Siqi Wang, Zhiqiang Zhang, Na Xu, Guixia Ling, Peng Zhang.
      Severe systemic toxicity and side effects are major obstacles to the success of chemotherapy for tumors. Regardless of the choice of chemotherapy drugs, the safety of drug delivery materials is crucial, and therefore, there have been various efforts to improve the therapeutic effect and the biological safety of drug delivery systems (DDSs). In this study, a dual stimulus-response DDS (PLL-SS@DOX-BP) was constructed based on the biomaterials of black phosphorus (BP) nanosheets and poly-l-lysine (PLL) to enhance the treatment of doxorubicin hydrochloride (DOX) for breast cancer. The PLL derivative was nano-coated on the surface of drug-loaded BP nanosheets, and it prevented premature leakage of the drug and maintained the stability of the DDS. The introduced disulfide bonds and photothermal agent BP enabled the redox and near-infrared responsive drug release of the DDS, and the coated PLL derivative on the nanocarrier decreased premature leakage of the drug before the DDS reached the tumor tissues. The in vitro and in vivo experiments showed that the combination of biomaterial (PLL) and photothermal material (BP nanosheets) exhibited excellent biological safety and remarkable drug delivery capacity. Moreover, the pharmacodynamic studies indicated that PLL-SS@DOX-BP is a powerful vehicle for photothermal therapy in combination with chemotherapy. Compared with chemotherapy alone, the developed DDS displayed enhanced anti-tumor efficiency with decreased systemic toxicity, and thus, it has the potential to be a promising anti-tumor treatment strategy.
    DOI:  https://doi.org/10.1039/d1tb02456f
  8. Mar Drugs. 2022 May 30. pii: 370. [Epub ahead of print]20(6):
    Fucoxanthin Is a Potential Therapeutic Agent for the Treatment of Breast Cancer.
    Tsz-Ying Lau, Hiu-Yee Kwan.
      Breast cancer (BC) is one of the most common cancers diagnosed and the leading cause of cancer-related death in women. Although there are first-line treatments for BC, drug resistances and adverse events have been reported. Given the incidence of BC keeps increasing, seeking novel therapeutics is urgently needed. Fucoxanthin (Fx) is a dietary carotenoid commonly found in seaweeds and diatoms. Both in vitro and in vivo studies show that Fx and its deacetylated metabolite fucoxanthinol (Fxol) inhibit and prevent BC growth. The NF-κB signaling pathway is considered the major pathway contributing to the anti-proliferation, anti-angiogenesis and pro-apoptotic effects of Fx and Fxol. Other signaling molecules such as MAPK, MMP2/9, CYP and ROS are also involved in the anti-cancer effects by regulating the tumor microenvironment, cancer metastasis, carcinogen metabolism and oxidation. Besides, Fx also possesses anti-obesity effects by regulating UCP1 levels and lipid metabolism, which may help to reduce BC risk. More importantly, mounting evidence demonstrates that Fx overcomes drug resistance. This review aims to give an updated summary of the anti-cancer effects of Fx and summarize the underlying mechanisms of action, which will provide novel strategies for the development of Fx as an anti-cancer therapeutic agent.
    Keywords:  anti-cancer; breast cancer; cancer prevention; drug resistance; fucoxanthin; fucoxanthinol; marine drug
    DOI:  https://doi.org/10.3390/md20060370
  9. J Control Release. 2022 Jun 18. pii: S0168-3659(22)00351-0. [Epub ahead of print]348 590-600
    A targeted nanomodulator capable of manipulating tumor microenvironment against metastasis.
    Hailong Tian, Li Zhou, Yu Wang, Edouard C Nice, Canhua Huang, Haiyuan Zhang.
      Recently, lactate has been considered as an alternative direct energy substance to glucose for tumor proliferation and metastasis. Meanwhile, mitochondria, as important energy-supplying organelles, are also closely related to tumor progression. Consequently, a new research direction for lactate comprises lactate deprivation coupled with mitochondria-targeted phototherapy to achieve a safer and more effective strategy against tumor metastasis. Herein, linoleic acid-conjugated hyaluronic acid (HL), disulfide bond-rich nanovehicle (mesoporous silica, MOS), mitochondria-targeted IR780 (M780) and lactate oxidase (LOD) are rationally designed as a specific-targeting metabolism nanomodulator (HL/MOS@M780&LOD NPs), fulfilling the task of simultaneous depriving cells of lactate and damaging mitochondria to prevent tumor metastasis. Interestingly, M780-mediated photodynamic therapy (PDT) and LOD-mediated starvation therapy can effectively exacerbate the hypoxia state of tumor cells, thereby increasing the free iron levels to activate ferroptosis. On one hand, pyruvic acid and H2O2 generated by LOD-mediated lactate metabolism can provide powerful conditions for iron-catalyzed ferroptosis. On the other, the depleted GSH and increased reactive oxygen species (ROS) can oxidize linoleic acid into lipid peroxides (LPO) to further augment ferroptosis. The designed nanomodulator therefore shows great promise for fighting tumor metastasis by manipulating energy metabolism and the hypoxia microenvironment.
    Keywords:  Hypoxia; Lactate; Mitochondrial dysfunction; Starvation-phototherapy; Tumor metastasis
    DOI:  https://doi.org/10.1016/j.jconrel.2022.06.022
  10. Cancers (Basel). 2022 Jun 13. pii: 2904. [Epub ahead of print]14(12):
    Nanomedicine Penetration to Tumor: Challenges, and Advanced Strategies to Tackle This Issue.
    Muhammad Usman Munir.
      Nanomedicine has been under investigation for several years to improve the efficiency of chemotherapeutics, having minimal pharmacological effects clinically. Ineffective tumor penetration is mediated by tumor environments, including limited vascular system, rising cancer cells, higher interstitial pressure, and extra-cellular matrix, among other things. Thus far, numerous methods to increase nanomedicine access to tumors have been described, including the manipulation of tumor micro-environments and the improvement of nanomedicine characteristics; however, such outdated approaches still have shortcomings. Multi-functional convertible nanocarriers have recently been developed as an innovative nanomedicine generation with excellent tumor infiltration abilities, such as tumor-penetrating peptide-mediated transcellular transport. The developments and limitations of nanomedicines, as well as expectations for better outcomes of tumor penetration, are discussed in this review.
    Keywords:  anticancer; cancer therapy; drug delivery; drug penetration; extra-cellular matrix; nanocarriers; nanomedicine; polymeric nanoparticle; siRNA; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers14122904
  11. Biomater Sci. 2022 Jun 21.
    Cascade nanozymes based on the "butterfly effect" for enhanced starvation therapy through the regulation of autophagy.
    Hanchun Yao, Xiaobao Gong, Meilin Geng, Songchao Duan, Pan Qiao, Fangfang Sun, Zhihui Zhu, Bin Du.
      Although tumor starvation therapy has been proven to be an excellent method for tumor therapy, its efficiency may be weakened by autophagy, a self-protection mechanism exerted by tumors under starvation stress. Interestingly, over-activated autophagy not only improves the efficacy of starvation therapy, but also induces autophagic death. Herein, we report cascade nanozymes for enhanced starvation therapy by inducing over-activated autophagy. First, glucose oxidase (GOx) modified metal-organic frameworks (NH2-MIL88, MOF) were constructed (MOF-GOx). After loading with curcumin (Cur), Cur@MOF-GOx was further decorated with tumor-targeting hyaluronic acid (HA) to obtain Cur@MOF-GOx/HA nanozymes. GOx can catalyze glucose into H2O2 and gluconic acid, which not only leads to tumor starvation, but also provides reactants for the Fenton reaction mediated by the MOF to generate hydroxyl radicals (˙OH) for chemo-dynamic therapy. Most importantly, protective autophagy caused by tumor starvation can be over-activated by Cur to convert autophagy from pro-survival to pro-death, realizing augmented anticancer therapy efficacy. With these cascade reactions, the synergistic action of starvation, autophagy and chemo-dynamic therapy was realized. Generally, the introduction of Cur@MOF-GOx/HA into tumor cells leads to a "butterfly effect", which induces enhanced starvation therapy through subsequent autophagic cell death to completely break the self-protective mechanism of cancer cells, and generate ˙OH for chemo-dynamic therapy. Precise design allows for the use of cascade nanozymes to realize efficient cancer treatment and restrain metastasis.
    DOI:  https://doi.org/10.1039/d2bm00595f
  12. Pharmaceutics. 2022 Jun 04. pii: 1200. [Epub ahead of print]14(6):
    Cu2+-Chelating Mesoporous Silica Nanoparticles for Synergistic Chemotherapy/Chemodynamic Therapy.
    Yanyan Zhang, Jiadong Lou, Gareth R Williams, Yuhan Ye, Dandan Ren, Anhua Shi, Junzi Wu, Wenling Chen, Li-Min Zhu.
      In this study, a pH-responsive controlled-release mesoporous silica nanoparticle (MSN) formulation was developed. The MSNs were functionalized with a histidine (His)-tagged targeting peptide (B3int) through an amide bond, and loaded with an anticancer drug (cisplatin (CP)) and a lysosomal destabilization mediator (chloroquine (CQ)). Cu2+ was then used to seal the pores of the MSNs via chelation with the His-tag. The resultant nanoparticles showed pH-responsive drug release, and could effectively target tumor cells via the targeting effect of B3int. The presence of CP and Cu2+ permits reactive oxygen species to be generated inside cells; thus, the chemotherapeutic effect of CP is augmented by chemodynamic therapy. In vitro and in vivo experiments showed that the nanoparticles are able to effectively kill tumor cells. An in vivo cancer model revealed that the nanoparticles increase apoptosis in tumor cells, and thereby diminish the tumor volume. No off-target toxicity was noted. It thus appears that the functionalized MSNs developed in this work have great potential for targeted, synergistic anticancer therapies.
    Keywords:  chelation; gatekeeper; mesoporous silica nanoparticles; synergistic treatment
    DOI:  https://doi.org/10.3390/pharmaceutics14061200
  13. Mol Carcinog. 2022 Jun 20.
    Targeting mitochondrial metabolism for metastatic cancer therapy.
    Antonino Passaniti, Myoung Sook Kim, Brian M Polster, Paul Shapiro.
      Primary tumors evolve metabolic mechanisms favoring glycolysis for adenosine triphosphate (ATP) generation and antioxidant defenses. In contrast, metastatic cells frequently depend on mitochondrial respiration and oxidative phosphorylation (OxPhos). This reliance of metastatic cells on OxPhos can be exploited using drugs that target mitochondrial metabolism. Therefore, therapeutic agents that act via diverse mechanisms, including the activation of signaling pathways that promote the production of reactive oxygen species (ROS) and/or a reduction in antioxidant defenses may elevate oxidative stress and inhibit tumor cell survival. In this review, we will provide (1) a mechanistic analysis of function-selective extracellular signal-regulated kinase-1/2 (ERK1/2) inhibitors that inhibit cancer cells through enhanced ROS, (2) a review of the role of mitochondrial ATP synthase in redox regulation and drug resistance, (3) a rationale for inhibiting ERK signaling and mitochondrial OxPhos toward the therapeutic goal of reducing tumor metastasis and treatment resistance. Recent reports from our laboratories using metastatic melanoma and breast cancer models have shown the preclinical efficacy of novel and rationally designed therapeutic agents that target ERK1/2 signaling and mitochondrial ATP synthase, which modulate ROS events that may prevent or treat metastatic cancer. These findings and those of others suggest that targeting a tumor's metabolic requirements and vulnerabilities may inhibit metastatic pathways and tumor growth. Approaches that exploit the ability of therapeutic agents to alter oxidative balance in tumor cells may be selective for cancer cells and may ultimately have an impact on clinical efficacy and safety. Elucidating the translational potential of metabolic targeting could lead to the discovery of new approaches for treatment of metastatic cancer.
    Keywords:  cancer metastasis; drug mechanisms; kinase signaling; mitochondria; reactive oxygen species; targeting OxPhos
    DOI:  https://doi.org/10.1002/mc.23436
  14. Pharmaceutics. 2022 May 27. pii: 1142. [Epub ahead of print]14(6):
    Royal Jelly as a Nutraceutical Natural Product with a Focus on Its Antibacterial Activity.
    Lilla Bagameri, Gabriela-Maria Baci, Daniel Severus Dezmirean.
      Royal jelly (RJ) is one of the most valued natural products and is known for its health-promoting properties. Due to its therapeutic effects, it has been used in medicine since antiquity. Nowadays, several studies indicate that RJ acts as a powerful antimicrobial agent. Indeed, researchers shed light on its antioxidant and anticancer activity. RJ's biological properties are related to its bioactive compounds, such as proteins, peptides, phenolic, and fatty acids. The aim of this review is to highlight recent findings on RJ's main bioactive compounds correlated with its health-promoting properties. The available literature suggests that these bioactive compounds can be used as an alternative approach in order to enhance human health. Moreover, throughout this paper, we underline the prominent antibacterial effect of RJ against several target bacterial strains. In addition, we briefly discuss other therapeutic activities, such as antioxidative and anticancer effects, of this outstanding natural product.
    Keywords:  antibacterial activity; antibiotic resistance; anticancer activity; antioxidant effect; natural product; royal jelly
    DOI:  https://doi.org/10.3390/pharmaceutics14061142
  15. Angew Chem Int Ed Engl. 2022 Jun 22.
    Upconversion Luminescence-Boosted Escape of DNAzyme from Endosomes for Enhanced Gene-Silencing Efficacy.
    Yoaxuan Chen, Rupeng Zhao, Lele Li, Yuliang Zhao.
      Despite the enormous potential of DNAzyme for gene therapy, its efficacy is hampered by the limited endosomal escape capability. Here, we develop a near-infrared (NIR) light-controlled DNAzyme delivery platform to achieve enhanced gene-silencing efficacy. The nanoplatform is composed of therapeutic DNAzyme, photosensitizers (PSs) and upconversion nanoparticles (UCNPs) that can convert NIR light to visible light. The system allows NIR light-activatable generation of cytotoxic reactive oxygen species due to the energy transfer from the UCNPs to PSs, which boosts the endosomal escape of DNAzyme for an improved gene-silencing efficacy. We demonstrate that the nanocomposites represent a promising platform to integrate DNAzyme-based gene therapy with NIR light-triggered photodynamic therapy for combinational tumor treatment. This work highlights a robust approach to combat the current limitations of DNAzyme delivery systems.
    Keywords:  DNAzyme; Photodynamic Therapy; endosomal escape; gene therapy; upconversion nanoparticles
    DOI:  https://doi.org/10.1002/anie.202206485
  16. Front Pharmacol. 2022 ;13 847113
    Interactions Between Natural Products and Tamoxifen in Breast Cancer: A Comprehensive Literature Review.
    Christine Yen, Fan Zhao, Zhichao Yu, Xiaoshu Zhu, Chun Guang Li.
      Introduction: Tamoxifen (TAM) is the most commonly used hormone therapeutic drug for the treatment of estrogen receptor-positive (ER+) breast cancer. 30%-70% of clinical breast cancer patients use natural products, which may increase the likelihood of drug interactions. Objective: To evaluate the evidence for the interactions between natural products and TAM in breast cancer. Methods: Electronic databases, including PubMed, CINAHL Plus (via EbscoHost), European PMC, Medline, and Google Scholar, were searched for relevant publications. The search terms include complementary and alternative medicine, natural products, plant products, herbs, interactions, tamoxifen, breast cancer, and their combinations. Results: Various in vitro and in vivo studies demonstrated that the combined use of natural products with TAM produced synergistic anti-cancer effects, including improved inhibition of tumor cell growth and TAM sensitivity and reduced side effects or toxicity of TAM. In contrast, some natural products, including Angelica sinensis (Oliv.) Diels [Apiaceae], Paeonia lactiflora Pall., Rehmannia glutinosa (Gaertn.) DC., Astragalus mongholicus Bunge, and Glycyrrhiza glabra L. [Fabaceae], showed estrogen-like activity, which may reduce the anti-cancer effect of TAM. Some natural products, including morin, silybin, epigallocatechin gallate (EGCG), myricetin, baicalein, curcumin, kaempferol, or quercetin, were found to increase the bioavailability of TAM and its metabolites in vivo. However, three are limited clinical studies on the combination of natural products and TAM. Conclusion: There is evidence for potential interactions of various natural products with TAM in pre-clinical studies, although the relevant clinical evidence is still lacking. Further studies are warranted to evaluate the potential interactions of natural products with TAM in clinical settings.
    Keywords:  breast cancer; herbal medicines; interactions; mechanisms; natural products; pharmacodynamic; pharmacokinetic; tamoxifen
    DOI:  https://doi.org/10.3389/fphar.2022.847113
  17. Gastroenterol Res Pract. 2022 ;2022 9578307
    The Effect and Related Mechanism of Action of Astragalus Compatible with Curcumin against Colon Cancer Metastasis in Mice.
    Jiafei Wu, Decai Tang.
      Colon cancer (CC) is the third most common tumor worldwide. Colon carcinogenesis is strongly linked to inflammation. The initiation and progression of colon cancer may be influenced by epigenetic processes. Cancer metastasis is a multistep process involving several genes and their products. During tumor metastasis, cancer cells first enhance their proliferative capacity by lowering autophagy and apoptosis, and then, their capacity is stimulated by boosting tumors' ability to take nutrients from the outside via angiogenesis. Traditional treatment focuses on eliminating tumor cells by triggering cell death or activating the immune system, which often results in side effects or chemoresistance recurrence. On the contrary, Chinese medicine theory considers the patient's entire inner system and aids in tumor shrinkage while also taking into account the mouse' general health. Because many Chinese herbal medicines (CHM) are consumed as food, using edible CHMs as a diet resource therapy for colon cancer treatment is a viable option. Two traditional Chinese herbs, Astragalus membranaceus and Curcuma zedoaria, are commonly utilized jointly in colon cancer preventive therapy. As a result, the anticancer effect of astragalus and curcumin (AC) on colon cancer suppression in an 18-week AOM-DSS colon cancer mouse model is investigated in this research. These findings may offer a scientific foundation for investigating colon cancer diagnostic biomarkers and therapeutic application of AC in colon cancer treatment. These studies also highlighted the potential effect and mechanism of AC in the treatment of colon cancer, as well as providing insight into how to effectively use it.
    DOI:  https://doi.org/10.1155/2022/9578307
  18. Int J Oncol. 2022 Aug;pii: 93. [Epub ahead of print]61(2):
    Cellular metabolism in pancreatic cancer as a tool for prognosis and treatment (Review).
    Michal Zuzčák, Jan Trnka.
      Pancreatic cancer (PC) has one of the highest fatality rates and the currently available therapeutic options are not sufficient to improve its overall poor prognosis. In addition to insufficient effectiveness of anticancer treatments, the lack of clear early symptoms and early metastatic spread maintain the PC survival rates at a low level. Metabolic reprogramming is among the hallmarks of cancer and could be exploited for the diagnosis and treatment of PC. PC is characterized by its heterogeneity and, apart from molecular subtypes, the identification of metabolic subtypes in PC could aid in the development of more individualized therapeutic approaches and may lead to improved clinical outcomes. In addition to the deregulated utilization of glucose in aerobic glycolysis, PC cells can use a wide range of substrates, including branched‑chain amino acids, glutamine and lipids to fulfil their energy requirements, as well as biosynthetic needs. The tumor microenvironment in PC supports tumor growth, metastatic spread, treatment resistance and the suppression of the host immune response. Moreover, reciprocal interactions between cancer and stromal cells enhance their metabolic reprogramming. PC stem cells (PCSCs) with an increased resistance and distinct metabolic properties are associated with disease relapses and cancer spread, and represent another significant candidate for therapeutic targeting. The present review discusses the metabolic signatures observed in PC, a disease with a multifaceted and often transient metabolic landscape. In addition, the metabolic pathways utilized by PC cells, as well as stromal cells are discussed, providing examples of how they could present novel targets for therapeutic interventions and elaborating on how interactions between the various cell types affect their metabolism. Furthermore, the importance of PCSCs is discussed, focusing specifically on their metabolic adaptations.
    Keywords:  amino acid metabolism; cancer stem cells; cell metabolism; chemoresistance; glycolysis; metabolic profiling; mitochondrial oxidative metabolism; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.3892/ijo.2022.5383
  19. Int J Nanomedicine. 2022 ;17 2647-2659
    Construction Of High Loading Natural Active Substances Nanoplatform and Application in Synergistic Tumor Therapy.
    Haoqiang Liu, Zeyidan Jiapaer, Fanxing Meng, Wanfeng Wu, Chengyi Hou, Mengjiao Duan, Yanan Qin, Shuxuan Shao, Minwei Zhang.
       Background: Natural bioactive substances have been widely studied for their superior anti-tumor activity and low toxicity. However, natural bioactive substances suffer from poor water-solubility and poor stability in the physiological environment. Therefore, to overcome the drawbacks of natural bioactive substances in tumor therapy, there is an urgent need for an ideal nanocarrier to achieve high bioactive substance loading with low toxicity.
    Materials and Methods: Face-centered cubic hollow mesoporous Prussian Blue (HMPB) NPs were prepared by stepwise hydrothermal method. Among them, PVP served as a protective agent and HCl served as an etching agent. Firstly, MPB NPs were obtained by 0.01 M HCl etching. Then, the highly uniform dispersed HMPB NPs were obtained by further etching with 1 M HCl.
    Results: In this work, we report a pH-responsive therapeutic nanoplatform based on HMPB NPs. Surprisingly, as-prepared HMPB NPs with ultra-high bioactive substances loading capacity of 329 μg mg-1 owing to the large surface area (131.67 m2 g-1) and wide internal pore size distribution (1.8-96.2 nm). Moreover, with the outstanding photothermal conversion efficiency of HMPB NPs (30.13%), natural bioactive substances were released in the tumor microenvironment (TME). HMPB@PC B2 achieved excellent synergistic therapeutic effects of photothermal therapy (PTT) and chemotherapy (CT) in vivo and in vitro without causing any extraneous side effects.
    Conclusion: A biocompatible HMPB@PC B2 nanoplatform was constructed by simple physical adsorption. The in vitro and in vivo experiment results demonstrated that the synergy of PTT/CT provided excellent therapeutic efficiency for cervical cancer without toxicity. Altogether, as-designed nanomedicines based on natural bioactive substances may be provide a promising strategy for cancer therapy.
    Keywords:  HMPB NPs; natural bioactive substances; negligible side effect; synergistic therapy
    DOI:  https://doi.org/10.2147/IJN.S364108
  20. Pharmaceutics. 2022 May 25. pii: 1126. [Epub ahead of print]14(6):
    Natural Nanoparticles: A Safe Bullet for Treatment and Detection of Solid Tumors.
    Serena Mazzucchelli.
      In the last couple of decades, nanoparticles have been extensively studied as carriers for cancer imaging agents and as drug delivery platforms, due to their ability to positively affect the distribution and tumor-targeting properties of delivered compounds [...].
    DOI:  https://doi.org/10.3390/pharmaceutics14061126
  21. Hum Exp Toxicol. 2022 Jan-Dec;41:41 9603271221095929
    Curcumin and resveratrol inhibit chemoresistance in cisplatin-resistant epithelial ovarian cancer cells via targeting P13K pathway.
    Yalikun Muhanmode, Meng Ke Wen, Amina Maitinuri, Guqun Shen.
       BACKGROUND: The activation of the PI3K/AKT/mTOR pathway has been proved to be associated with survival as well as proliferation of various tumour cells in multiple cancer types, including epithelial ovarian cancer (EOC).
    PURPOSE: Moreover, the activation of the PI3K/AKT/mTOR pathway is the key mechanism responsible for higher invasiveness and migratory capacities of ovarian cancer cells. Furthermore, PI3K is crucial for activation of the PI3K/AKT/mTOR pathway; therefore, its inhibition might be an effective strategy against cancer.
    RESEARCH DESIGN: The combination approach is now an established strategy against cancer. So, the present study evaluated molecular mechanics behind the synergistic effects of curcumin and resveratrol along with cisplatin treatment on inhibition of the PI3K pathway in ovarian cancer cells.
    RESULTS: The present study confirmed significant inhibition of the PI3K/AKT/mTOR pathway as observed by Matrigel invasion assay, Western blot expression of important molecular markers and apoptotic markers.
    CONCLUSION:  The present study concludes that the combination of curcumin and resveratrol significantly sensitized the EOC cells to cisplatin treatment, thereby inhibiting chemoresistance in ovarian cancer cells by significant inhibition of the PI3K/AKT/mTOR pathway.
    Keywords:  AKT; Ovarian cancer; cisplatin; curcumin; p13k; resveratrol
    DOI:  https://doi.org/10.1177/09603271221095929
  22. ACS Appl Mater Interfaces. 2022 Jun 24.
    pH/Thermal-Sensitive Nanoplatform Capable of On-Demand Specific Release to Potentiate Drug Delivery and Combinational Hyperthermia/Chemo/Chemodynamic Therapy.
    Nian Liu, Liang Wu, Wenbao Zuo, Qian Lin, Jinxue Liu, Quanyi Jin, Zhimei Xiao, Luping Chen, Yilin Zhao, Jun Zhou, Xuan Zhu.
      Therapeutic platforms with spatiotemporal control were recently of considerable interest. However, the site-specific regulation of chemotherapeutics release remains an enormous challenge. Herein, a versatile nanoplatform capable of tumor-specific delivery and controlled drug release, coined as PDDFe, was constructed for elevating cancer theranostics. Iron-oxide nanoparticles (IONPs) and doxorubicin (Dox) were encapsulated in pH/thermal-sensitive micelles composed of poly(ethylene)glycol-poly(β-amino esters) and dipalmitoyl phosphatidylcholine to obtain tumor-targeted dual-responsive nanoplatforms. With remarkable magnetic targeting effects, PDDFe specifically accumulated at tumor locations. After internalization by cancer cells, the acidic environment and localized heat generated by hyperthermia therapy would spur PDDFe to become loose and collapse to liberate its payload. In addition to boosting the release, the increased temperature also resulted in direct tumor damage. Meanwhile, the released Dox and IONPs, respectively, stimulated chemotherapy and chemodynamic therapy to jointly destroy cancer, thus leading to a pronounced therapeutic effect. In vivo magnetic resonance/fluorescence/photoacoustic imaging experiments validated that the dual-sensitive nanoplatforms were able to accumulate at the tumor sites. Treatment with PDDFe followed by alternating magnetic field and laser irradiation could prime hyperthermia/chemo/chemodynamic therapy to effectively retard tumor growth. This work presents a nanoplatform with a site-specific controlled release characteristic, showing great promises in potentiating drug delivery and advancing combinational cancer therapy.
    Keywords:  combinational therapy; controlled drug release; magnetic resonance/photoacoustic imaging; magnetic targeting effects; pH/thermal-sensitive micelles
    DOI:  https://doi.org/10.1021/acsami.2c09685
  23. Molecules. 2022 Jun 14. pii: 3816. [Epub ahead of print]27(12):
    Anti-Cancer Effects of Dietary Polyphenols via ROS-Mediated Pathway with Their Modulation of MicroRNAs.
    Yasukiyo Yoshioka, Tomokazu Ohishi, Yoriyuki Nakamura, Ryuuta Fukutomi, Noriyuki Miyoshi.
      Consumption of coffee, tea, wine, curry, and soybeans has been linked to a lower risk of cancer in epidemiological studies. Several cell-based and animal studies have shown that dietary polyphenols like chlorogenic acid, curcumin, epigallocatechin-3-O-gallate, genistein, quercetin and resveratrol play a major role in these anticancer effects. Several mechanisms have been proposed to explain the anticancer effects of polyphenols. Depending on the cellular microenvironment, these polyphenols can exert double-faced actions as either an antioxidant or a prooxidant, and one of the representative anticancer mechanisms is a reactive oxygen species (ROS)-mediated mechanism. These polyphenols can also influence microRNA (miR) expression. In general, they can modulate the expression/activity of the constituent molecules in ROS-mediated anticancer pathways by increasing the expression of tumor-suppressive miRs and decreasing the expression of oncogenic miRs. Thus, miR modulation may enhance the anticancer effects of polyphenols through the ROS-mediated pathways in an additive or synergistic manner. More precise human clinical studies on the effects of dietary polyphenols on miR expression will provide convincing evidence of the preventive roles of dietary polyphenols in cancer and other diseases.
    Keywords:  anticancer pathway; cancer; dietary polyphenols; microRNA; reactive oxygen species
    DOI:  https://doi.org/10.3390/molecules27123816
  24. Pharmaceutics. 2022 Jun 16. pii: 1282. [Epub ahead of print]14(6):
    Ultrasound and Nanomedicine for Cancer-Targeted Drug Delivery: Screening, Cellular Mechanisms and Therapeutic Opportunities.
    Chien-Hsiu Li, Yu-Chan Chang, Michael Hsiao, Ming-Hsien Chan.
      Cancer is a disease characterized by abnormal cell growth. According to a report published by the World Health Organization (WHO), cancer is the second leading cause of death globally, responsible for an estimated 9.6 million deaths in 2018. It should be noted that ultrasound is already widely used as a diagnostic procedure for detecting tumorigenesis. In addition, ultrasound energy can also be utilized effectively for treating cancer. By filling the interior of lipospheres with gas molecules, these particles can serve both as contrast agents for ultrasonic imaging and as delivery systems for drugs such as microbubbles and nanobubbles. Therefore, this review aims to describe the nanoparticle-assisted drug delivery system and how it can enhance image analysis and biomedicine. The formation characteristics of nanoparticles indicate that they will accumulate at the tumor site upon ultrasonic imaging, in accordance with their modification characteristics. As a result of changing the accumulation of materials, it is possible to examine the results by comparing images of other tumor cell lines. It is also possible to investigate ultrasound images for evidence of cellular effects. In combination with a precision ultrasound imaging system, drug-carrying lipospheres can precisely track tumor tissue and deliver drugs to tumor cells to enhance the ability of this nanocomposite to treat cancer.
    Keywords:  cellular mechanisms; drug screening; nanomedicine; therapeutic drug delivery system; ultrasound
    DOI:  https://doi.org/10.3390/pharmaceutics14061282
  25. Evid Based Complement Alternat Med. 2022 ;2022 1337588
    PEGylated Magnetite/Hydroxyapatite: A Green Nanocomposite for T2-Weighted MRI and Curcumin Carrying.
    Nahideh Gharehaghaji, Baharak Divband.
       Background: The design of new magnetic resonance imaging (MRI) contrast media with chemotherapy drug-carrying capacity has an important role in diagnostic and therapeutic purposes. This study aimed to synthesize a polyethylene glycol (PEG)-coated magnetite/hydroxyapatite nanocomposite as an MRI contrast agent investigate its curcumin loading/release properties and consider the cytotoxicity effect of the curcumin-loaded nanocomposite on different cell lines.
    Materials and Methods: PEGylated magnetite/hydroxyapatite (PMHA) nanocomposite was synthesized and characterized using X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, vibrating sample magnetometry, and energy dispersive X-ray analysis. MTT assay was performed to consider the A549, MCF-7, and MRC-5 cells toxicity of the PMHA and the curcumin-loaded nanocomposite. The r2 relaxivity of the nanocomposite was determined by an MRI device. The curcumin loading and its release from the nanocomposite at pH of 7.4 and 5.5 were investigated.
    Results: The spherical nanocomposite showed an average size of 20 nm and a superparamagnetic property. PMHA nanocomposite was highly cytocompatible, while the curcumin-loaded nanocomposite showed significant cytotoxicity for A549 and a much higher toxic effect on MCF-7 cancer cells. The r2 relaxivity was measured as 120 mM-1S-1. The curcumin loading capacity of PMHA was 1.9 mg/g, and the curcumin release profile showed a pH-dependent sustained release of the anti-cancer drug that was higher for pH of 5.5.
    Conclusion: The high r2 relaxivity of PMHA nanocomposite and sustained release of curcumin from the loaded one at the pH of tumor environment suggest that the nanocomposite is a potential candidate for T2-weighted MRI and cancer treatment.
    DOI:  https://doi.org/10.1155/2022/1337588
  26. ACS Appl Mater Interfaces. 2022 Jun 22.
    Free-Radical Cascade Generated by AIPH/Fe3O4-Coloaded Nanoparticles Enhances MRI-Guided Chemo/Thermodynamic Hypoxic Tumor Therapy.
    Wenting Li, Baoyuan Li, Bin Wu, Baocheng Tian, Xiangjun Chen, Changrong Wang, Wei Hong, Jinrong Peng.
      Free radicals, including reactive oxygen species (ROS), play a critical role in determining cell's fate. When the level of free radicals is increased to a fatal value, it causes cancer cells to undergo senescence or cell death. Strategies that target this mechanism offer promising therapies against cancer. However, efficient and sustainable systems that generate free radicals, especially oxygen-independent systems, remain deficient. Herein, functionalized PLGA-based nanocomposites that efficiently co-deliver magnetic nanoparticles and 2,2'-azobis[2-(2-imidazolin-2-yl) propane]-dihydrochloride (AIPH) were fabricated to achieve photothermal-induced thermodynamic therapy combined with macrophage polarization strategies; this therapy targets hypoxic tumors through the generation of an oxygen-independent free-radical cascade. These hybrid NPs can accumulate in the tumor microenvironment, and the encapsulated MNPs not only serve as contrast agents for enhanced magnetic resonance imaging but also exhibit the expected photothermal conversion and trigger the decomposition of AIPH to generate free radicals, thus causing cancer cell death. More importantly, the cell debris from apoptotic or necrotic cancer cells carries nondegraded MNPs, which can be endocytosed by recruited TAMs. MNPs can further induce TAMs to polarize to the M1 subtype to subsequently generate ROS. This study provides an alternative method for the generation of an oxygen-independent free-radical cascade for tumor co-therapy guided by magnetic resonance imaging PTT/TDT.
    Keywords:  AIPH; combinational therapy; delivery; hypoxia; magnetic nanoparticles; oxygen-independent free radicals
    DOI:  https://doi.org/10.1021/acsami.2c05748
  27. Cancers (Basel). 2022 Jun 08. pii: 2837. [Epub ahead of print]14(12):
    Synthetic Vulnerabilities in the KRAS Pathway.
    Marta Roman, Elizabeth Hwang, E Alejandro Sweet-Cordero.
      Mutations in Kristen Rat Sarcoma viral oncogene (KRAS) are among the most frequent gain-of-function genetic alterations in human cancer. Most KRAS-driven cancers depend on its sustained expression and signaling. Despite spectacular recent success in the development of inhibitors targeting specific KRAS alleles, the discovery and utilization of effective directed therapies for KRAS-mutant cancers remains a major unmet need. One potential approach is the identification of KRAS-specific synthetic lethal vulnerabilities. For example, while KRAS-driven oncogenesis requires the activation of a number of signaling pathways, it also triggers stress response pathways in cancer cells that could potentially be targeted for therapeutic benefit. This review will discuss how the latest advances in functional genomics and the development of more refined models have demonstrated the existence of molecular pathways that can be exploited to uncover synthetic lethal interactions with a promising future as potential clinical treatments in KRAS-mutant cancers.
    Keywords:  KRAS; cancer; synthetic lethality
    DOI:  https://doi.org/10.3390/cancers14122837
  28. Carbohydr Polym. 2022 Sep 15. pii: S0144-8617(22)00594-X. [Epub ahead of print]292 119689
    Sodium alginate based drug delivery in management of breast cancer.
    Mohammad Arshad Javed Shaikh, Khalid Saad Alharbi, Waleed Hassan Almalki, Syed Sarim Imam, Mohammed Albratty, Abdulkarim M Meraya, Sami I Alzarea, Imran Kazmi, Fahad A Al-Abbasi, Obaid Afzal, Abdulmalik Saleh Alfawaz Altamimi, Yogendra Singh, Sachin Kumar Singh, Kamal Dua, Gaurav Gupta.
      Among women, breast cancer (B·C.) is a common form of cancer that can strike either developed or developing countries. In addition to pregnancy-related variables, hormone therapy lifestyle factors (e.g., physical inactivity, smoking, and alcohol use) may all influence the progression of B·C. The creation of anti-B·C. medication carriers with better stability, controlled and targeted administration, and the goal of minimizing unwanted effects has taken a lot of time and effort. Naturally generated biopolymers-based pharmaceutical delivery techniques have attracted attention for their potential use in treating B·C. It's been shown that natural polymers can deliver high medication concentrations to the desired place and provide prolonged release of pharmaceuticals useful in treating B.C. Alginate is one of the most commonly used drug carriers for delayed and targeted release. In present review will discuss the utilization of sodium alginate as an carrier of anticancer drug, such as paclitaxel, doxorubicin, tamoxifen, curcumin, and others.
    Keywords:  Breast cancer; Drug carrier; Polysaccharides; Signaling pathway; Sodium alginate
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119689
  29. J Food Biochem. 2022 Jun 23. e14282
    Pharmacological effects of D-Pinitol - A comprehensive review.
    Anandakumar Pandi, Kamaraj Sattu, Vanitha M Kalappan, Vanita Lal, Seshadri R Varikasuvu, Anirban Ganguly, Jitender Prasad.
      In recent years, the application of phytochemicals to prevent or treat diseases has received greater attention. These phytochemicals have little or no toxicity against healthy tissues and are thus considered as ideal compounds. An impressive number of modern drugs are obtained from natural sources based on their traditional value. D-Pinitol is a natural compound that is derived from soy and soy products. It is a potentially active molecule that belongs to the class of inositols. D-pinitol has been pharmacologically evaluated for its potent antioxidant, anti-diabetic, anti-inflammatory, anti-cancer, hepatoprotective, cardioprotective, renoprotective, neuroprotective, immunosuppressive, and anti-osteoporotic efficacies. This review is an attempt to validate the plausible pharmacological effects of D-pinitol using various in vivo and in vitro studies. PRACTICAL IMPLICATIONS: The consumption of plant-based products has been significantly increased all over the world. The active phytochemicals that are found in plants are stated to have numerous health promoting functions for the treatment of diabetes, cancer, inflammation, cardiac diseases, liver dysfunction, and many other. D-Pinitol is abundantly present in soybeans that possess notable therapeutic activities. Understanding the effects of D-Pinitol would potentially help in applying this compound in clinical research for the treatment of different disorders.
    Keywords:  D-pinitol; anti-cancer; anti-diabetic; anti-inflammatory; antioxidant; cardioprotective; hepatoprotective; neuroprotective; renoprotective
    DOI:  https://doi.org/10.1111/jfbc.14282
  30. Pharmaceutics. 2022 May 28. pii: 1152. [Epub ahead of print]14(6):
    Beneath the Skin: A Review of Current Trends and Future Prospects of Transdermal Drug Delivery Systems.
    Ahlam Zaid Alkilani, Jehad Nasereddin, Rania Hamed, Sukaina Nimrawi, Ghaid Hussein, Hadeel Abo-Zour, Ryan F Donnelly.
      The ideal drug delivery system has a bioavailability comparable to parenteral dosage forms but is as convenient and easy to use for the patient as oral solid dosage forms. In recent years, there has been increased interest in transdermal drug delivery (TDD) as a non-invasive delivery approach that is generally regarded as being easy to administer to more vulnerable age groups, such as paediatric and geriatric patients, while avoiding certain bioavailability concerns that arise from oral drug delivery due to poor absorbability and metabolism concerns. However, despite its many merits, TDD remains restricted to a select few drugs. The physiology of the skin poses a barrier against the feasible delivery of many drugs, limiting its applicability to only those drugs that possess physicochemical properties allowing them to be successfully delivered transdermally. Several techniques have been developed to enhance the transdermal permeability of drugs. Both chemical (e.g., thermal and mechanical) and passive (vesicle, nanoparticle, nanoemulsion, solid dispersion, and nanocrystal) techniques have been investigated to enhance the permeability of drug substances across the skin. Furthermore, hybrid approaches combining chemical penetration enhancement technologies with physical technologies are being intensively researched to improve the skin permeation of drug substances. This review aims to summarize recent trends in TDD approaches and discuss the merits and drawbacks of the various chemical, physical, and hybrid approaches currently being investigated for improving drug permeability across the skin.
    Keywords:  drug delivery; iontophoresis; microneedles; nanoparticles; niosomes; permeability; skin barrier; transdermal
    DOI:  https://doi.org/10.3390/pharmaceutics14061152
  31. Biofactors. 2022 Jun 20.
    Revisiting the therapeutic potential of tocotrienol.
    Ranmali Ranasinghe, Michael Mathai, Anthony Zulli.
      The therapeutic potential of the tocotrienol group stems from its nutraceutical properties as a dietary supplement. It is largely considered to be safe when consumed at low doses for attenuating pathophysiology as shown by animal models, in vitro assays, and ongoing human trials. Medical researchers and the allied sciences have experimented with tocotrienols for many decades, but its therapeutic potential was limited to adjuvant or concurrent treatment regimens. Recent studies have focused on targeted drug delivery by enhancing the bioavailability through carriers, self-sustained emulsions, nanoparticles, and ethosomes. Epigenetic modulation and computer remodeling are other means that will help increase chemosensitivity. This review will focus on the systemic intracellular anti-cancer, antioxidant, and anti-inflammatory mechanisms that are stimulated and/or regulated by tocotrienols while highlighting its potent therapeutic properties in a diverse group of clinical diseases.
    Keywords:  antioxidant behavior; cancer studies; chemotherapy; disease pathology; tocotrienol in cancer immunology; tocotrienols; vitamin E
    DOI:  https://doi.org/10.1002/biof.1873
  32. Int J Nanomedicine. 2022 ;17 2707-2731
    Glucose Metabolism Intervention-Facilitated Nanomedicine Therapy.
    Zhiyan Li, Xianghui Li, Shichao Ai, Song Liu, Wenxian Guan.
      Ordinarily, cancer cells possess features of abnormally increased nutrient intake and metabolic pathways. The disorder of glucose metabolism is the most important among them. Therefore, starvation therapy targeting glucose metabolism specifically, which results in metabolic disorders, restricted synthesis, and inhibition of tumor growth, has been developed for cancer therapy. However, issues such as inadequate targeting effectiveness and drug tolerance impede their clinical transformation. In recent years, nanomaterial-assisted starvation treatment has made significant progress in addressing these challenges, whether as a monotherapy or in combination with other medications. Herein, representative researches on the construction of nanosystems conducting starvation therapy are introduced. Elaborate designs and interactions between different treatment mechanisms are meticulously mentioned. Not only are traditional treatments based on glucose oxidase involved, but also newly sprung small molecule agents targeting glucose metabolism. The obstacles and potential for advancing these anticancer therapies were also highlighted in this review.
    Keywords:  cancer metabolism; combined therapy; nanomedicine; starvation therapy
    DOI:  https://doi.org/10.2147/IJN.S364840
  33. Mar Drugs. 2022 May 24. pii: 342. [Epub ahead of print]20(6):
    Phytochemical and Potential Properties of Seaweeds and Their Recent Applications: A Review.
    Hossam S El-Beltagi, Amal A Mohamed, Heba I Mohamed, Khaled M A Ramadan, Aminah A Barqawi, Abdallah Tageldein Mansour.
      Since ancient times, seaweeds have been employed as source of highly bioactive secondary metabolites that could act as key medicinal components. Furthermore, research into the biological activity of certain seaweed compounds has progressed significantly, with an emphasis on their composition and application for human and animal nutrition. Seaweeds have many uses: they are consumed as fodder, and have been used in medicines, cosmetics, energy, fertilizers, and industrial agar and alginate biosynthesis. The beneficial effects of seaweed are mostly due to the presence of minerals, vitamins, phenols, polysaccharides, and sterols, as well as several other bioactive compounds. These compounds seem to have antioxidant, anti-inflammatory, anti-cancer, antimicrobial, and anti-diabetic activities. Recent advances and limitations for seaweed bioactive as a nutraceutical in terms of bioavailability are explored in order to better comprehend their therapeutic development. To further understand the mechanism of action of seaweed chemicals, more research is needed as is an investigation into their potential usage in pharmaceutical companies and other applications, with the ultimate objective of developing sustainable and healthier products. The objective of this review is to collect information about the role of seaweeds on nutritional, pharmacological, industrial, and biochemical applications, as well as their impact on human health.
    Keywords:  antioxidant activity; functional foods; health benefits; seaweeds; secondary metabolites
    DOI:  https://doi.org/10.3390/md20060342
  34. Int J Pharm. 2022 Jun 18. pii: S0378-5173(22)00497-5. [Epub ahead of print] 121942
    Co-encapsulation of flavonoids with anti-cancer drugs: a challenge ahead.
    Morgane Renault-Mahieux, Nathalie Mignet, Johanne Seguin, Khair Alhareth, Muriel Paul, Karine Andrieux.
      Flavonoids have been considered as promising molecules for cancer treatment due to their pleiotropic properties such as anti-carcinogenic, anti-angiogenic or efflux proteins inhibition. However, due to their lipophilic properties and their chemical instability, vectorization seems compulsory to administer flavonoids. Flavonoids have been co-encapsulated with other anti-cancer agents in a broad range of nanocarriers aiming to i) achieve a synergistic/additive effect at the tumor site, ii) delay drug resistance apparition by combining agents with different action mechanisms or iii) administer a lower dose of the anti-cancer drug, reducing its toxicity. However, co-encapsulation could lead to a change in the nanoparticles' diameter and drug-loading, as well as a decrease in their stability during storage. The preparation process should also take into accounts the physico-chemical properties of both the flavonoid and the anti-cancer agent. Moreover, the co-encapsulation could affect the release and activity of each drug. This review aims to study the formulation, preparation and characterization strategies of these co-loaded nanomedicines, as well as their stability. The in vitro assays to predict the nanomedicines' behavior in biological fluids, as well as their in vivo efficacy, are also discussed. A special focus concerns the evaluation of their synergistic effect on tumor treatment.
    Keywords:  Cancer; Co-Encapsulation; Flavonoids; Nanomedicine; Synergism
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121942
  35. Biomed Pharmacother. 2022 Jun 18. pii: S0753-3322(22)00663-1. [Epub ahead of print]153 113274
    Applications of resveratrol in the treatment of gastrointestinal cancer.
    Mohammad Roshani, Ameneh Jafari, Amirhossein Loghman, Amir Hossein Sheida, Taranomsadat Taghavi, Seyed Saeed Tamehri Zadeh, Michael R Hamblin, Mina Homayounfal, Hamed Mirzaei.
      Natural product compounds have lately attracted interest in the scientific community as a possible treatment for gastrointestinal (GI) cancer, due to their anti-inflammatory and anticancer properties. There are many preclinical, clinical, and epidemiological studies, suggesting that the consumption of polyphenol compounds, which are abundant in vegetables, grains, fruits, and pulses, may help to prevent various illnesses and disorders from developing, including several GI cancers. The development of GI malignancies follows a well-known path, in which normal gastrointestinal cells acquire abnormalities in their genetic composition, causing the cells to continuously proliferate, and metastasize to other sites, especially the brain and liver. Natural compounds with the ability to affect oncogenic pathways might be possible treatments for GI malignancies, and could easily be tested in clinical trials. Resveratrol is a non-flavonoid polyphenol and a natural stilbene, acting as a phytoestrogen with anti-cancer, cardioprotective, anti-oxidant, and anti-inflammatory properties. Resveratrol has been shown to overcome resistance mechanisms in cancer cells, and when combined with conventional anticancer drugs, could sensitize cancer cells to chemotherapy. Several new resveratrol analogs and nanostructured delivery vehicles with improved anti-GI cancer efficacy, absorption, and pharmacokinetic profiles have already been developed. This present review focuses on the in vitro and in vivo effects of resveratrol on GI cancers, as well as the underlying molecular mechanisms of action.
    Keywords:  Gastrointestinal cancer; Nanoformulation; Resveratrol; Therapy
    DOI:  https://doi.org/10.1016/j.biopha.2022.113274
  36. Cancer Sci. 2022 Jun 22.
    Silybin suppresses ovarian cancer cell proliferation by inhibiting isocitrate dehydrogenase 1 activity.
    Zibo Wei, Shuangyan Ye, Haipeng Feng, Chong Zeng, Xinhuai Dong, Xiaokang Zeng, Liming Zeng, Xu Lin, Qiuzhen Liu, Jie Yao.
      Metabolic reprogramming is a sign of malignant tumors, and targeting the metabolism of tumor cells has become a promising therapeutic approach. Here, we report that the Silybin (a nontoxic flavonoid commonly used liver protection) exhibits prominent anti-tumor effects on human ovarian cancer cells. Treatment of an ovarian cancer cell line with Silybin interfered with glutamine metabolism and the tricarboxylic acid cycle. We applied the drug affinity responsive target stability approach to show that Silybin binds to isocitrate dehydrogenase 1 (IDH1). This combination leads to reduced phosphorylation of IDH1 and inhibits enzyme activity. IDH1 dysfunction significantly increases the ratio of NADP/NADPH in the cell, causing an increase in reactive oxygen species (ROS) generation. Immunohistochemistry demonstrated that IDH1 was increased in samples of ovarian cancer compared with normal para-tumoral tissues. Xenograft murine experiments indicated that orally administered Silybin suppressed growth of the tumor formed by ovarian cancer cells. In combination, our data strongly suggest Silybin targets IDH1 in ovarian cancer cells and it may provide a novel treatment candidate.
    Keywords:  Ovarian cancer; cancer plasticity; energy metabolism reprogramming; redox homeostasis; tumor microenvironment
    DOI:  https://doi.org/10.1111/cas.15470
  37. Int J Mol Sci. 2022 Jun 15. pii: 6653. [Epub ahead of print]23(12):
    Profiling the Effect of Targeting Wild Isocitrate Dehydrogenase 1 (IDH1) on the Cellular Metabolome of Leukemic Cells.
    Mohammed Razeeth Shait Mohammed, Faisal Alzahrani, Salman Hosawi, Hani Choudhry, Mohammad Imran Khan.
      Leukemia is one of the most common primary malignancies of the hematologic system in both children and adults and remains a largely incurable or relapsing disease. The elucidation of disease subtypes based on mutational profiling has not improved clinical outcomes. IDH1/2 are critical enzymes of the TCA cycle that produces α-ketoglutarate (αKG). However, their mutated version is well reported in various cancer types, including leukemia, which produces D-2 hydroxyglutarate (D-2HG), an oncometabolite. Recently, some studies have shown that wild-type IDH1 is highly expressed in non-small cell lung carcinoma (NSCLC), primary glioblastomas (GBM), and several hematological malignancies and is correlated with disease progression. This work shows that the treatment of wild-type IDH1 leukemia cells with a specific IDH1 inhibitor shifted leukemic cells toward glycolysis from the oxidative phosphorylation (OXPHOS) phenotype. We also noticed a reduction in αKG in treated cells, possibly suggesting the inhibition of IDH1 enzymatic activity. Furthermore, we found that IDH1 inhibition reduced the metabolites related to one-carbon metabolism, which is essential for maintaining global methylation in leukemic cells. Finally, we observed that metabolic alteration in IDH1 inhibitor-treated leukemic cells promoted reactive oxygen species (ROS) formation and the loss of mitochondrial membrane potential, leading to apoptosis in leukemic cells. We showed that targeting wild-type IDH1 leukemic cells promotes metabolic alterations that can be exploited for combination therapies for a better outcome.
    Keywords:  OXPHOS; glutamine metabolism; metabolomics; reactive oxygen species; wild-type IDH1
    DOI:  https://doi.org/10.3390/ijms23126653
  38. Biomedicines. 2022 Jun 04. pii: 1320. [Epub ahead of print]10(6):
    Carbon Graphitization: Towards Greener Alternatives to Develop Nanomaterials for Targeted Drug Delivery.
    Davide Marin, Silvia Marchesan.
      Carbon nanomaterials have attracted great interest for their unique physico-chemical properties for various applications, including medicine and, in particular, drug delivery, to solve the most challenging unmet clinical needs. Graphitization is a process that has become very popular for their production or modification. However, traditional conditions are energy-demanding; thus, recent efforts have been devoted to the development of greener routes that require lower temperatures or that use waste or byproducts as a carbon source in order to be more sustainable. In this concise review, we analyze the progress made in the last five years in this area, as well as in their development as drug delivery agents, focusing on active targeting, and conclude with a perspective on the future of the field.
    Keywords:  cancer; carbon dots; carbon nanomaterials; carbon nanotubes; drug delivery; graphene; graphitization; sustainability; targeted delivery; waste
    DOI:  https://doi.org/10.3390/biomedicines10061320
  39. J Mater Chem B. 2022 Jun 21.
    Long circulation and tumor-targeting biomimetic nanoparticles for efficient chemo/photothermal synergistic therapy.
    Yifan Zhang, Xuanyu Yue, Shengchao Yang, Xianglong Li, Lin Cui, Xiaobin Cui, Yue Shi, Zhiyong Liu, Xuhong Guo, Yongsheng Li.
      Photothermal therapy combined with chemotherapy based on nanomedicine has been considered a promising strategy for improving therapeutic efficacy in a tumor. However, nanomedicine can be easily cleared by the immune system without specific surface engineering modifications, thus affecting the ultimate efficacy. Herein, multifunctional biomimetic nanoparticles (Bio-RBCm@PDA@MSN-DOX) with enhanced long circulation and targeting ability are constructed by coating large pore-sized mesoporous silica (MSN) with polydopamine (PDA) layers in a biotin modified red blood cell membrane (Bio-RBCm) for efficient chemo/photothermal synergistic therapy. It is demonstrated that Bio-RBCm@PDA@MSN-DOX presents high photothermal conversion efficiency (40.17%) and enhanced capability to accelerate the release of the anticancer drug (doxorubicin, DOX), thus showing a good synergistic therapeutic effect in cell experiments. More importantly, with the assistance of the biotin and RBC membrane, Bio-RBCm@PDA@MSN-DOX can successfully evade immune clearance and effectively target transport to HeLa tumor sites, finally accomplishing up to 98.95% tumor inhibition with negligible side effects to normal tissues. This multilayer structure presents a valuable model for future therapeutic applications with safe and effective tumor chemotherapy and photothermal therapy.
    DOI:  https://doi.org/10.1039/d2tb00748g
  40. Chem Commun (Camb). 2022 Jun 24.
    Stimuli-responsive prodrug of non-steroidal anti-inflammatory drug diclofenac: self-immolative drug release with turn-on near-infrared fluorescence.
    Abu Sufian, Debojit Bhattacherjee, Pallavi Barman, Abhay Srivastava, Rajkumar P Thummer, Krishna P Bhabak.
      Reactive oxygen species (ROS)-responsive near infrared (NIR) fluorogenic prodrug DCI-ROS is developed for the self-immolative release of diclofenac (DCF) with turn-on fluorescence. The non-toxic prodrug exhibited turn-on red fluorescence with endogenous ROS in cancer cells and inhibited COX-2 expression in the inflammation-induced macrophage cells. The prodrug strategy thus would be helpful for the controlled fluorogenic delivery of DCF for inflammatory diseases.
    DOI:  https://doi.org/10.1039/d2cc02132c
  41. Mater Today Bio. 2022 Jun;15 100316
    Synthesis of a versatile mitochondria-targeting small molecule for cancer near-infrared fluorescent imaging and radio/photodynamic/photothermal synergistic therapies.
    Mingquan Gao, Xie Huang, Zifei Wu, Liting Wang, Shaolong Yuan, Zaizhi Du, Shenglin Luo, Rong Li, Weidong Wang.
      Although as a mainstay modal for cancer treatment, the clinical effect of radiotherapy (RT) does not yet meet the need of cancer patients. Developing tumour-preferential radiosensitizers or combining RT with other treatments has been acknowledged highly necessary to enhance the efficacy of RT. The present study reported a multifunctional bioactive small-molecule (designated as IR-83) simultaneously exhibiting tumour-preferential accumulation, near-infrared imaging and radio/photodynamic/photothermal therapeutic effects. IR-83 was designed and synthesized by introducing 2-nitroimidazole as a radiosensitizer into the framework of heptamethine cyanine dyes inherently with tumour-targeting and photosensitizing effects. As results, IR-83 preferentially accumulated in tumours, suppressed tumour growth and metastasis by integrating radio/photodynamic/photothermal multimodal therapies. Mechanism studies showed that IR-83 accumulated in cancer cell mitochondria, induced excessive reactive oxygen species (ROS), and generated high heat after laser irradiation. On one hand, these phenomena led to mitochondrial dysfunction and a sharp decline in oxidative phosphorylation to lessen tissue oxygen consumption. On the other hand, excessive ROS in mitochondria destroyed the balance of antioxidants and oxidative stress balance by down-regulating the intracellular antioxidant system, and subsequently sensitized ionizing radiation-generated irreversible DNA double-strand breaks. Therefore, this study presented a promising radiosensitizer and a new alternative strategy to enhance RT efficacy via mitochondria-targeting multimodal synergistic treatment.
    Keywords:  ALT, alanine aminotransferase; AST, aspartate amino transferase; CLSM, confocal laser scanning microscope; CREA, creatinine; DSBs, DNA double-strand breaks; GSH, glutathione; H&E, hematoxylin and eosin; HO-1, heme oxygenase 1; Heptamethine cyanine dyes; LLC, Lewis lung carcinoma; MMP, mitochondrial membrane potential; NADPH, nicotinamide adenine dinucleotide phosphate; NIR, near-infrared; NMR, nuclear magnetic resonance; NSCLC, non-small cell lung cancer; Near-infrared imaging; Nrf2, nuclear factor erythroid-derived 2-like 2; OXPHOS, oxidative phosphorylation; PBS, phosphate-buffered saline; PDT, photodynamic therapy; PI, propidium iodide; PLT, Platelet; PSs, photosensitizers; PTAs, photothermal agents; PTT, photothermal therapy; Phototherapy; RBC, red blood cell; ROS, reactive oxygen species; RT, radiotherapy; Radiosensitizer; Radiotherapy; SER, sensitizer enhancement ratio; SOSG, Singlet oxygen sensor green; WBC, white blood cell
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100316
  42. Nanoscale. 2022 Jun 20.
    A plasmon-enhanced fluorescent gold coated novel lipo-polymeric hybrid nanosystem: synthesis, characterization and application for imaging and photothermal therapy of breast cancer.
    Tejaswini Appidi, Rajalakshmi P S, Shubham A Chinchulkar, Arpan Pradhan, Hajira Begum, Veeresh Shetty, Rohit Srivastava, Prabhusankar Ganesan, Aravind Kumar Rengan.
      This study reports a hybrid lipo-polymeric nanosystem (PDPC NPs) synthesized by a modified hydrogel-isolation technique. The ability of the nanosystem to encapsulate hydrophilic and hydrophobic molecules has been demonstrated, and their enhanced cellular uptake has been observed in vitro. The PDPC NPs, surface coated with gold by in situ reduction of chloroauric acid (PDPC-Au NPs), showed a photothermal transduction efficacy of ∼65%. The PDPC-Au NPs demonstrated an increase in intracellular ROS, triggered DNA damage and resulted in apoptotic cell death when tested against breast cancer cells (MCF-7). The disintegration of PDPC-Au NPs into smaller nanoparticles with near-infrared (NIR) laser irradiation was understood using transmission electron microscopy imaging. The lipo-polymeric hybrid nanosystem exhibited plasmon-enhanced fluorescence when loaded with IR780 (a NIR dye), followed by surface coating with gold (PDPC-IR-Au NPs). This paper is one of the first reports on the plasmon-enhanced fluorescence within a nanosystem by simple surface coating of Au, to the best of our knowledge. This plasmon-enhanced fluorescence was unique to the lipo-polymeric hybrid system, as the same was not observed with a liposomal nanosystem. The plasmon-enhanced fluorescence of PDPC-IR-Au NPs, when applied for imaging cancer cells and zebrafish embryos, showed a strong fluorescence signal at minimal concentrations of the dye. The PDPC-IR-Au NPs were also applied for photothermal therapy of breast cancer in vitro and in vivo, and the results depicted significant therapeutic benefits.
    DOI:  https://doi.org/10.1039/d2nr01378a
  43. Drug Deliv Transl Res. 2022 Jun 21.
    Polymeric micelles and cancer therapy: an ingenious multimodal tumor-targeted drug delivery system.
    Sharath Kumar Hari, Ankita Gauba, Neeraj Shrivastava, Ravi Mani Tripathi, Sudhir Kumar Jain, Akhilesh Kumar Pandey.
      Since the beginning of pharmaceutical research, drug delivery methods have been an integral part of it. Polymeric micelles (PMs) have emerged as multifunctional nanoparticles in the current technological era of nanocarriers, and they have shown promise in a range of scientific fields. They can alter the release profile of integrated pharmacological substances and concentrate them in the target zone due to their improved permeability and retention, making them more suitable for poorly soluble medicines. With their ability to deliver poorly soluble chemotherapeutic drugs, PMs have garnered considerable interest in cancer. As a result of their remarkable biocompatibility, improved permeability, and minimal toxicity to healthy cells, while also their capacity to solubilize a wide range of drugs in their micellar core, PMs are expected to be a successful treatment option for cancer therapy in the future. Their nano-size enables them to accumulate in the tumor microenvironment (TME) via the enhanced permeability and retention (EPR) effect. In this review, our major aim is to focus primarily on the stellar applications of PMs in the field of cancer therapeutics along with its mechanism of action and its latest advancements in drug and gene delivery (DNA/siRNA) for cancer, using various therapeutic strategies such as crossing blood-brain barrier, gene therapy, photothermal therapy (PTT), and immunotherapy. Furthermore, PMs can be employed as "smart drug carriers," allowing them to target specific cancer sites using a variety of stimuli (endogenous and exogenous), which improve the specificity and efficacy of micelle-based targeted drug delivery. All the many types of stimulants, as well as how the complex of PM and various anticancer drugs react to it, and their pharmacodynamics are also reviewed here. In conclusion, commercializing engineered micelle nanoparticles (MNPs) for application in therapy and imaging can be considered as a potential approach to improve the therapeutic index of anticancer drugs. Furthermore, PM has stimulated intense interest in research and clinical practice, and in light of this, we have also highlighted a few PMs that have previously been approved for therapeutic use, while the majority are still being studied in clinical trials for various cancer therapies.
    Keywords:  Blood–brain barrier; Mechanism; Nanoparticles; Polymeric micelles; Stimuli-sensitive polymeric micelles; Targeted drug delivery
    DOI:  https://doi.org/10.1007/s13346-022-01197-4
  44. Pharmaceuticals (Basel). 2022 Jun 20. pii: 767. [Epub ahead of print]15(6):
    The Potential Application of Natural Photosensitizers Used in Antimicrobial Photodynamic Therapy against Oral Infections.
    Shima Afrasiabi, Alireza Partoazar, Nasim Chiniforush, Ramin Goudarzi.
      Oral health problems and the emergence of antimicrobial resistance among pathogenic bacterial strains have become major global challenges and are essential elements that negatively affect general well-being. Antimicrobial photodynamic therapy (APDT) is based on a light source and oxygen that activates a nontoxic photosensitizer, resulting in microbial destruction. Synthetic and natural products can be used to help the APDT against oral microorganisms. The undesirable consequences of conventional photosensitizers, including toxicity, and cost encourage researchers to explore new promising photosensitizers based on natural compounds such as curcumin, chlorella, chlorophyllin, phycocyanin, 5-aminolevulinic acid, and riboflavin. In this review, we summarize in vitro studies describing the potential use of APDT therapy conjugated with some natural products against selected microorganisms that are considered to be responsible for oral infections.
    Keywords:  biofilms; dental infection control; drug resistance; nanoparticles; photochemotherapy; photosensitizing agents
    DOI:  https://doi.org/10.3390/ph15060767
  45. Polymers (Basel). 2022 Jun 16. pii: 2436. [Epub ahead of print]14(12):
    Shea Butter Potentiates the Anti-Bacterial Activity of Fusidic Acid Incorporated into Solid Lipid Nanoparticle.
    Heba S Elsewedy, Tamer M Shehata, Wafaa E Soliman.
      Fusidic acid (FA) is an efficient anti-bacterial drug proven to be efficient against a wide range of bacteria. Nevertheless, the main restriction in its formulation is the limited solubility. To avoid such an obstacle, the drug is incorporated into the lipid core of the nanolipid formulation. Consequently, the present study was an attempt to formulate nanolipid preparation, mainly, solid lipid nanoparticle (SLN) integrating FA. FA-SLN was prepared using shea butter as a lipid phase owing to its reported anti-bacterial activity. Different FA-SLNs were fabricated using the central composite design (CCD) approach. The optimized formula was selected and integrated into a hydrogel base to be efficiently used topically. FA-SLN-hydrogel was evaluated for its character, morphology, in vitro release and stability. The formula was examined for irritation reaction and finally evaluated for its anti-bacterial performance. The optimized formula showed particle size 283.83 nm and entrapment 73.057%. The formulated FA-SLN-hydrogel displayed pH 6.2, viscosity 15,610 cP, spreadability 51.1 mm and in vitro release 64.6% following 180 min. FA-SLN-hydrogel showed good stability for three months at different conditions (room temperature and refrigerator). It exhibited no irritation reaction on the treated rats. Eventually, shea butter displayed a noteworthy effect against bacterial growth that improved the effect of FA. This would indicate prospective anti-bacterial activity of FA when combined with shea butter in SLN formulation as a promising nanocarrier.
    Keywords:  anti-bacterial activity; fusidic acid; optimization; shea butter; solid lipid nanoparticle; topical delivery
    DOI:  https://doi.org/10.3390/polym14122436
  46. Apoptosis. 2022 Jun 20.
    Phosphodiesterase 5 inhibitor sildenafil potentiates the antitumor activity of cisplatin by ROS-mediated apoptosis: a role of deregulated glucose metabolism.
    Shiv Govind Rawat, Rajan Kumar Tiwari, Pradip Kumar Jaiswara, Vishal Kumar Gupta, Pratishtha Sonker, Naveen Kumar Vishvakarma, Santosh Kumar, Chandramani Pathak, Vibhav Gautam, Ajay Kumar.
      Cyclic nucleotide phosphodiesterase 5 (PDE5) has been recently identified to play a crucial role in the progression of many cancers. PDE5 promotes tumorigenesis by dysregulating various cellular processes such as proliferation, apoptosis, angiogenesis, and invasion and migration. Interestingly, multiple studies have reported the promising chemosensitizing potential of PDE5 inhibitor sildenafil in breast, colon, prostate, glioma, and lung cancers. However, to date, the chemosensitizing action of sildenafil is not evaluated in T cell lymphoma, a rare and challenging neoplastic disorder. Hence, the present investigation was undertaken to examine the chemosensitizing potential of sildenafil against T cell lymphoma along with elucidation of possible involvement of altered apoptosis and glucose metabolism. The experimental findings of this study showed that sildenafil enhances the cytotoxic ability of cisplatin by apoptosis induction through altering the levels of apoptosis regulatory molecules: Bcl-2, Bax, cytochrome c (Cyt c), cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP). These molecular alterations were possibly driven by sildenafil through reactive oxygen species (ROS). Sildenafil deregulates glucose metabolism by markedly lowering the expression of glycolysis regulatory molecules, namely glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), hexokinase II (HKII), pyruvate kinase M2 (PKM2), and pyruvate dehydrogenase kinase 1 (PDK1) via suppressing hypoxia-inducible factor 1-alpha (HIF-1α) expression. Hence, sildenafil potentiates the tumor cell killing ability of cisplatin by augmenting ROS production through switching the glucose metabolism from glycolysis to oxidative phosphorylation (OXPHOS). Overall, our study demonstrates that sildenafil might be a promising adjunct therapeutic candidate in designing novel combinatorial chemotherapeutic regimens against T cell lymphoma.
    Keywords:  Altered glucose metabolism; Apoptosis; Chemosensitization; Sildenafil; T cell lymphoma
    DOI:  https://doi.org/10.1007/s10495-022-01741-0
  47. Int J Pharm. 2022 Jun 15. pii: S0378-5173(22)00459-8. [Epub ahead of print]623 121904
    Effects of particle size and release property of paclitaxel-loaded nanoparticles on their peritoneal retention and therapeutic efficacy against mouse malignant ascites.
    Yusuke Kono, Aya Fushimi, Yuta Yoshizawa, Kazutaka Higaki, Ken-Ichi Ogawara.
      Malignant ascites accounts for abdominal pain, dyspnea and anorexia, all of which decrease quality of life in cancer patients. Intraperitoneal chemotherapy is a useful method for managing malignant ascites and nanoparticulate drug delivery system makes it more effective by increasing peritoneal retention of anti-cancer drugs. In this study, we prepared paclitaxel-loaded emulsions and liposomes with different particle sizes and drug release properties, and evaluated their peritoneal retention and therapeutic efficacy in Ehrlich's ascites carcinoma (EAC)-bearing mice. Liposomes with the size of 100 nm were rapidly absorbed from peritoneal cavity into blood after intraperitoneal injection into EAC-bearing mice, whereas 1000-nm liposomes were highly retained in peritoneal cavity. Accordingly, 1000 nm liposomes significantly prolonged survival time of EAC-bearing mice but did not inhibit the ascites accumulation because of too poor paclitaxel release. On the other hand, although peritoneal retention of emulsions themselves was similar irrespective of their sizes, 270-nm emulsions showed the higher PTX retention in ascites than other emulsions, and resulted in significantly prolonged survival time and lower accumulation of ascites in EAC-bearing mice. These results indicate that not only particle size but drug release property is one of key determinants of the biodisposition and therapeutic efficacy of intraperitoneally injected nanoparticulate PTX against malignant ascites.
    Keywords:  Emulsion; Intraperitoneal chemotherapy; Liposome; Malignant ascites; Paclitaxel
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121904
  48. Pharmaceuticals (Basel). 2022 Jun 03. pii: 711. [Epub ahead of print]15(6):
    High-Dose Vitamin C for Cancer Therapy.
    Ali Mussa, Ros Akmal Mohd Idris, Naveed Ahmed, Suhana Ahmad, Ahmad Hafiz Murtadha, Tengku Ahmad Damitri Al Astani Tengku Din, Chan Yean Yean, Wan Faiziah Wan Abdul Rahman, Norhafiza Mat Lazim, Vuk Uskoković, Khalid Hajissa, Noor Fatmawati Mokhtar, Rohimah Mohamud, Rosline Hassan.
      In recent years, the idea that Vitamin C (Vit-C) could be utilized as a form of anti-cancer therapy has generated many contradictory arguments. Recent insights into the physiological characteristics of Vit-C, its pharmacokinetics, and results from preclinical reports, however, suggest that high-dose Vit-C could be effectively utilized in the management of various tumor types. Studies have shown that the pharmacological action of Vit-C can attack various processes that cancerous cells use for their growth and development. Here, we discuss the anti-cancer functions of Vit-C, but also the potential for the use of Vit-C as an epigenetic regulator and immunotherapy enhancer. We also provide a short overview of the current state of systems for scavenging reactive oxygen species (ROS), especially in the context of their influencing high-dose Vit-C toxicity for the inhibition of cancer growth. Even though the mechanisms of Vit-C action are promising, they need to be supported with robust randomized and controlled clinical trials. Moreover, upcoming studies should focus on how to define the most suitable cancer patient populations for high-dose Vit-C treatments and develop effective strategies that combine Vit-C with various concurrent cancer treatment regimens.
    Keywords:  ROS-scavenging systems; anti-cancer; cancer; high-dose; immunotherapy; pharmacokinetics; pharmacological; vitamin-C
    DOI:  https://doi.org/10.3390/ph15060711
  49. J Microencapsul. 2022 Jun 24. 1-31
    Multifunctional Magnetic Nanoparticles for MRI-guided Co-delivery of Erlotinib and L-Asparaginase to Ovarian Cancer.
    Seraj Mohaghegh, Ali Tarighatnia, Yadollah Omidi, Jaleh Barar, Ayuob Aghanejad, Khosro Adibkia.
       AIM(S): The use of magnetic nanoparticles (MNPs) in biomedical applications has been wildly opted due to their unique properties. The objective of this study was to evaluate the effects of aptamer-armed MNPs in ovarian cancer treatment and as T2 weighted MRI contrast agent.
    METHODS: Here, we designed MNPs loaded with erlotinib (ERL/SPION-Val-PEG) and conjugated them with anti-mucin16 (MUC16) aptamer to introduce new image-guided nanoparticles (NPs) for targeted drug delivery as well as non-invasive magnetic resonance imaging (MRI) contrast agents. Also, the combination of our nanosystem (NS) along with L-Asparaginase (L-ASPN) led to synergistic effects in terms of reducing cell viability in ovarian cancer cells, which could suggest a novel combination therapy.
    RESULTS: The mean size of our NS was about 63.4 ± 3.4 nm evaluated by DLS analysis and its morphology was confirmed using TEM. Moreover, the functional groups, as well as magnetic properties of our NS, were examined by FT-IR and VSM tests, respectively. The loading efficacy of erlotinib on MNPs was about 80% and its release reached 70.85% over 7 days in the pH value of 5.4. The MR images and flow cytometry results revealed that the cellular uptake of ERL/SPION-Val-PEG-MUC16 NPs in cells with MUC16 overexpression was considerably higher than unarmed NPs. In addition, T2-weight MR images of ovarian cancer-bearing mice indicated significant signal intensity changes at the tumor site 4 h after intravenous injection compared to the non-target MNPs.
    CONCLUSIONS: Our data suggest ERL/SPION-Val-PEG NPs as an image-guided co-drug delivery system for ovarian cancer.
    Keywords:  Erlotinib; L-Asparaginase; MRI; MUC16; Magnetic nanoparticles; Ovarian cancer
    DOI:  https://doi.org/10.1080/02652048.2022.2094487
  50. Pharmaceutics. 2022 Jun 10. pii: 1230. [Epub ahead of print]14(6):
    Biodegradable Carbonate Apatite Nanoparticle as a Delivery System to Promote Afatinib Delivery for Non-Small Cell Lung Cancer Treatment.
    Nian N N Maarof, Emilia Abdulmalek, Sharida Fakurazi, Mohd Basyaruddin Abdul Rahman.
      Nanomedicine-based drug-delivery systems have significant interest in cancer treatment, such as improving the stabilities and biocompatibilities, precise targeting, and reducing toxicities for non-cancerous cells. Herein, this study presents the synthesis and characterisation of carbonate apatite nanoparticles (nCA) and encapsulated afatinib (AFA) as promising drug delivery candidates for lung cancer treatment. nCA/AFA was synthesised and physicochemically characterised, then the encapsulation capacity, drug loading, and cumulative drug release profile were evaluated. Powder X-ray diffraction (PXRD) confirmed that the synthesised nCA is apatite. Fourier-transform infrared spectroscopy (FTIR) results confirmed the drug loading into the nanoparticles. High-resolution transmission electron microscopy (HR-TEM) determined the morphology of nCA and nCA/AFA and the diameters of 47.36 ± 3.16 and 42.97 ± 2.78 nm, respectively, without an unaltered nCA phase. Encapsulation efficiency (%) and drug loading (%) were 55.08% ± 1.68% and 8.19% ± 0.52%. Brunauer-Emmett-Teller (BET) and dynamic light-scattering (DLS) results revealed that the synthesised nCA is mesoporous, with a surface area of 55.53 m2/g, and is negatively charged. Atomic force microscopy (AFM) showed increasing roughness of nCA/AFA compared to nCA. The drug release from the nano-formulation nCA/AFA demonstrated slow and sustained release compared to the pure drug. Accordingly, nCA/AFA represents a promising drug delivery system for NSCLC treatment.
    Keywords:  afatinib; carbonate apatite nanoparticle (nCA); drug delivery; lung cancer; nanomedicine
    DOI:  https://doi.org/10.3390/pharmaceutics14061230
  51. Mar Drugs. 2022 May 25. pii: 349. [Epub ahead of print]20(6):
    Natural Marine Products: Anti-Colorectal Cancer In Vitro and In Vivo.
    Ningning Han, Jianjiang Li, Xia Li.
      Colorectal cancer, a malignant tumor with high mortality, has a poor prognosis due to drug resistance and toxicity in clinical surgery and chemotherapy. Thus, finding safer and more efficient drugs for clinical trials is vital and urgent. Natural marine compounds, with rich resources and original chemical structures, are applied widely in anticancer treatments. We provide a systematic overview of recently reported marine compounds such as alkaloids, peptides, terpenoids, polysaccharides, and carotenoids from in vitro, in vivo, and clinical studies. The in vitro studies summarized the marine origins and pharmacological mechanisms, including anti-proliferation, anti-angiogenesis, anti-migration, anti-invasion, the acceleration of cycle arrest, and the promotion of tumor apoptosis, of various compounds. The in vivo studies outlined the antitumor effects of marine compounds on colorectal cancer model mice and evaluated their efficacy in terms of tumor inhibition, hepatotoxicity, and nephrotoxicity. The clinical studies summarized the major chemical classifications and targets of action of the clinical drugs that have entered clinical approval and completed approval for marine anticancer. In summary, we present the current situation regarding the application of natural anti-colorectal cancer marine compounds and prospects for their clinical application.
    Keywords:  anti-tumor mechanism; chemical structures; colorectal cancer; natural marine products
    DOI:  https://doi.org/10.3390/md20060349
  52. J Control Release. 2022 Jun 18. pii: S0168-3659(22)00365-0. [Epub ahead of print]
    Hollow microneedle assisted intradermal delivery of hypericin lipid nanocapsules with light enabled photodynamic therapy against skin cancer.
    Heba Abd-El-Azim, Ismaiel A Tekko, Ahlam Ali, Alyaa Ramadan, Noha Nafee, Nawal Khalafallah, Taifur Rahman, William Mcdaid, Rania G Aly, Lalitkumar K Vora, Steven J Bell, Fiona Furlong, Helen O McCarthy, Ryan F Donnelly.
      Photodynamic therapy (PDT) to manage non-melanoma skin cancers has garnered great attention over the past few years. Hypericin (Hy) is a potent lipid-soluble photosensitiser with promising anticancer therapeutic activities. Nevertheless, its poor water-solubility, aggregation in biological systems and insufficient skin penetration restricted its effective exploitation. Herein, we report for the first-time encapsulation of Hy into lipid nanocapsules (Hy-LNCs), and then application of an AdminPen™ hollow microneedles (Ho-MNs) array and an in-house fabricated Ho-MN to enable efficient intradermal delivery. The physicochemical properties, photoactivity, ex vivo drug distribution and cellular uptake were evaluated. Results showed that Hy-LNCs were successfully formed with a particle size of 47.76 ± 0.49 nm, PDI of 0.12 ± 0.02, high encapsulation efficiency (99.67% ± 0.35), 396 fold higher photoactivity, 7 fold higher skin drug deposition, significantly greater cellular uptake and higher photocytotoxicity compared to free Hy. The therapeutic effect of Hy-LNCs was finally assessed in vivo using a nude mouse model with transplanted tumours. Interestingly, Hy-LNCs delivered by Ho-MN exhibited remarkable anti-tumour destruction (85.84%) after irradiation with 595 nm. This study showed that Ho-MNs-driven delivery of Hy-LNCs followed by irradiation could form a promising minimally invasive, effective and site-specific approach for managing non-melanoma skin cancers.
    Keywords:  Lipid nanocapsule, hollow microneedle; Non-melanoma skin cancer, hypericin; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.jconrel.2022.06.027
  53. J Nanobiotechnology. 2022 Jun 18. 20(1): 289
    Cell membrane-camouflaged inorganic nanoparticles for cancer therapy.
    Wanli Song, Pengfei Jia, Ting Zhang, Keke Dou, Lubin Liu, Yaping Ren, Fujun Liu, Junmiao Xue, Mohamed Sayed Hasanin, Hongzhao Qi, Qihui Zhou.
      Inorganic nanoparticles (INPs) have been paid great attention in the field of oncology in recent past years since they have enormous potential in drug delivery, gene delivery, photodynamic therapy (PDT), photothermal therapy (PTT), bio-imaging, driven motion, etc. To overcome the innate limitations of the conventional INPs, such as fast elimination by the immune system, low accumulation in tumor sites, and severe toxicity to the organism, great efforts have recently been made to modify naked INPs, facilitating their clinical application. Taking inspiration from nature, considerable researchers have exploited cell membrane-camouflaged INPs (CMCINPs) by coating various cell membranes onto INPs. CMCINPs naturally inherit the surface adhesive molecules, receptors, and functional proteins from the original cell membrane, making them versatile as the natural cells. In order to give a timely and representative review on this rapidly developing research subject, we highlighted recent advances in CMCINPs with superior unique merits of various INPs and natural cell membranes for cancer therapy applications. The opportunity and obstacles of CMCINPs for clinical translation were also discussed. The review is expected to assist researchers in better eliciting the effect of CMCINPs for the management of tumors and may catalyze breakthroughs in this area.
    Keywords:  Active targeting; Cancer therapy; Cell membrane; Inorganic nanoparticles; Multifunction nanoplatform
    DOI:  https://doi.org/10.1186/s12951-022-01475-w
  54. Molecules. 2022 Jun 14. pii: 3836. [Epub ahead of print]27(12):
    Advances on Delivery of Cytotoxic Enzymes as Anticancer Agents.
    Akmal M Asrorov, Bahtiyor Muhitdinov, Bin Tu, Sharafitdin Mirzaakhmedov, Huiyuan Wang, Yongzhuo Huang.
      Cancer is one of the most serious human diseases, causing millions of deaths worldwide annually, and, therefore, it is one of the most investigated research disciplines. Developing efficient anticancer tools includes studying the effects of different natural enzymes of plant and microbial origin on tumor cells. The development of various smart delivery systems based on enzyme drugs has been conducted for more than two decades. Some of these delivery systems have been developed to the point that they have reached clinical stages, and a few have even found application in selected cancer treatments. Various biological, chemical, and physical approaches have been utilized to enhance their efficiencies by improving their delivery and targeting. In this paper, we review advanced delivery systems for enzyme drugs for use in cancer therapy. Their structure-based functions, mechanisms of action, fused forms with other peptides in terms of targeting and penetration, and other main results from in vivo and clinical studies of these advanced delivery systems are highlighted.
    Keywords:  asparaginase; cancer therapy; diphtheria toxin; enzyme drugs; exotoxin; gelonin; glucose oxidase; peroxidase; trichosanthin
    DOI:  https://doi.org/10.3390/molecules27123836
  55. Clin Transl Oncol. 2022 Jun 25.
    Essential role of aerobic glycolysis in epithelial-to-mesenchymal transition during carcinogenesis.
    Chandra Prakash Prasad, Ajay Gogia, Atul Batra.
      Epithelial-to-mesenchymal transition (EMT) confers the most lethal characteristics to cancer cells i.e., metastasis and resistance to chemo-and-radio-therapy, and therefore exhibit an appealing target in the field of oncology. Research in the past decade has demonstrated the crucial role of aerobic glycolysis in EMT, which is generally credited as the glucose metabolism for the creation of biomass such as fatty acids, amino acids, and nucleotides thereby providing building blocks for limitless proliferation. In the present review, apart from discussing EMT's evident role in the metastatic process and cancer stemness, we also talked about the vital role of glycolytic enzymes viz. GLUTs, HKs, PGI, PFK-1, aldolase, enolase, PK, LDHA, etc. in the induction of the EMT process in cancerous cells.
    Keywords:  Aerobic glycolysis; Cancer; Cancer stem cells (CSCs); Epithelial-to-mesenchymal transition (EMT); Metastasis
    DOI:  https://doi.org/10.1007/s12094-022-02851-6
  56. Antioxidants (Basel). 2022 Jun 13. pii: 1158. [Epub ahead of print]11(6):
    Phytochemicals, Nutrition, Metabolism, Bioavailability, and Health Benefits in Lettuce-A Comprehensive Review.
    Min Shi, Jingyu Gu, Hanjing Wu, Abdur Rauf, Talha Bin Emran, Zidan Khan, Saikat Mitra, Abdullah S M Aljohani, Fahad A Alhumaydhi, Yahya S Al-Awthan, Omar Bahattab, Muthu Thiruvengadam, Hafiz A R Suleria.
      Lettuce is one of the most famous leafy vegetables worldwide with lots of applications from food to other specific uses. There are different types in the lettuce group for consumers to choose from. Additionally, lettuce is an excellent source of bioactive compounds such as polyphenols, carotenoids, and chlorophyll with related health benefits. At the same time, nutrient composition and antioxidant compounds are different between lettuce varieties, especially for green and red lettuce types. The benefit of lettuce consumption depends on its composition, particularly antioxidants, which can function as nutrients. The health benefits rely on their biochemical effect when reaching the bloodstream. Some components can be released from the food matrix and altered in the digestive system. Indeed, the bioaccessibility of lettuce is measuring the quantity of these compounds released from the food matrix during digestion, which is important for health-promoting features. Extraction of bioactive compounds is one of the new trends observed in lettuce and is necessarily used for several application fields. Therefore, this review aims to demonstrate the nutritional value of lettuce and its pharmacological properties. Due to their bioaccessibility and bioavailability, the consumer will be able to comprehensively understand choosing a healthier lettuce diet. The common utilization pattern of lettuce extracted nutrients will also be summarized for further direction.
    Keywords:  Lactuca sativa L.; antioxidant; bioactive phytochemicals; health benefits; nutrients
    DOI:  https://doi.org/10.3390/antiox11061158
  57. Front Pharmacol. 2022 ;13 906301
    Rediscovery of Traditional Plant Medicine: An Underestimated Anticancer Drug of Chelerythrine.
    Nianzhi Chen, Yulin Qi, Xiao Ma, Xiaolin Xiao, Qingsong Liu, Ting Xia, Juyi Xiang, Jinhao Zeng, Jianyuan Tang.
      In many studies, the extensive and significant anticancer activity of chelerythrine (CHE) was identified, which is the primary natural active compound in four traditional botanical drugs and can be applied as a promising treatment in various solid tumors. So this review aimed to summarize the anticancer capacities and the antitumor mechanism of CHE. The literature searches revolving around CHE have been carried out on PubMed, Web of Science, ScienceDirect, and MEDLINE databases. Increasing evidence indicates that CHE, as a benzophenanthridine alkaloid, exhibits its excellent anticancer activity as CHE can intervene in tumor progression and inhibit tumor growth in multiple ways, such as induction of cancer cell apoptosis, cell cycle arrest, prevention of tumor invasion and metastasis, autophagy-mediated cell death, bind selectively to telomeric G-quadruplex and strongly inhibit the telomerase activity through G-quadruplex stabilization, reactive oxygen species (ROS), mitogen-activated protein kinase (MAPK), and PKC. The role of CHE against diverse types of cancers has been investigated in many studies and has been identified as the main antitumor drug candidate in drug discovery programs. The current complex data suggest the potential value in clinical application and the future direction of CHE as a therapeutic drug in cancer. Furthermore, the limitations and the present problems are also highlighted in this review. Despite the unclearly delineated molecular targets of CHE, extensive research in this area provided continuously fresh data exploitable in the clinic while addressing the present requirement for further studies such as toxicological studies, combination medication, and the development of novel chemical methods or biomaterials to extend the effects of CHE or the development of its derivatives and analogs, contributing to the effective transformation of this underestimated anticancer drug into clinical practice. We believe that this review can provide support for the clinical application of a new anticancer drug in the future.
    Keywords:  anticancer; chelerythrine; future direction; molecular mechanism; traditional botanical drugs
    DOI:  https://doi.org/10.3389/fphar.2022.906301
  58. Front Mol Biosci. 2022 ;9 938348
    Editorial: Drug Delivery System Based on Nanoparticles for Inflammation and Cancer Therapy.
    Mingxin Zhang, Ning Lu, Qian Li, Manli Cui, Mingzhen Zhang.
      
    Keywords:  cancer; drug delivery system; inflammation; nanoparticles; therapy; vaccine
    DOI:  https://doi.org/10.3389/fmolb.2022.938348
  59. Sci Rep. 2022 Jun 23. 12(1): 10686
    Evaluation of anticancer effects of carboplatin-gelatin nanoparticles in different sizes synthesized with newly self-assembly method by exposure to IR light.
    Ferdane Danışman-Kalındemirtaş, İshak Afşin Kariper, Gökçe Erdemir, Esra Sert, Serap Erdem-Kuruca.
      Carboplatin (CP), a platinum analog, is one of the most widely used chemotherapeutic agents in the treatment of colorectal cancer. Although platinum-based drugs are quite effective in anticancer treatments, their use in a wide spectrum and effective treatment possibilities are limited due to their systemic side effects and drug resistance development. In recent years, studies have focused on increasing the therapeutic efficacy of platinum-based drugs with drug delivery systems. Gelatin, a protein, obtained by the hydrolysis of collagen, is a biocompatible and biodegradable material that can be used in nano drug delivery systems. In this study, CP-loaded gelatin-based NPs (CP-NPs) were exposed to IR light in different temperatures at 30, 35, 40, 45, and 50 °C and characterized by FESEM-EDX, FTIR, UV-Vis, DLS. Accordingly, we synthesized gelatin-based CP-NPs of different sizes between 10-290 nm by exposure to IR. We found that CP-NPs-50, 16 nm nano-sized, obtained at 50 °C had the most cytotoxicity and was 2.2 times more effective than the free drug in HCT 116 colon cancer cells. Moreover, we showed that the cytotoxicity of CP-NPs-50 in normal HUVEC cells was lower. Additionally, we demonstrated that CP-NPs enhanced apoptotic activity while not developing MDR1-related resistance in colon cancer cells. In this study, for the first time drug loaded gelatin-based nanoparticles were synthesized in different sizes with a newly self-assembly method by exposing them to infrared light at different temperatures and their anticancer effects were evaluated subsequently.
    DOI:  https://doi.org/10.1038/s41598-022-15051-7
  60. Int J Pharm. 2022 Jun 21. pii: S0378-5173(22)00501-4. [Epub ahead of print] 121946
    Amino acid coordination complex mediates cisplatin entrapment within PEGylated liposome: an implication in colorectal cancer therapy.
    Elaheh Mirhadi, Fatemeh Gheybi, Nadia Mahmoudi, Maliheh Hemmati, Fatemeh Soleimanian, Atefeh Ghasemi, Anis Askarizadeh, Mehrdad Iranshahi, Mahmoud Reza Jaafari, Seyedeh Hoda Alavizadeh.
      Cis-Diaminedichloroplatinum (cisplatin, CDDP) remained among the most widely used anti-cancer agents; however, management of the dose-limiting side effects is still a great hurdle to its therapeutic potential. In the framework of this investigation, novel approach was developed for CDDP encasement within liposome based on the formation of a coordination bond between the platinum (II) atom and a carboxylic group in aspartic acid (AA) and glutamic acid (GA). We have also compared two methods of preparation based on equilibration and conventional lipid film hydration. For this, first FTIR spectra of the conjugates confirmed coordination bond between Pt and the carboxylate moieties. The PEGylated liposomes composed of HSPC, cholesterol and DPPG had a size of 134 to 197 nm and negative zeta potential (-14.20 to -20.90 mv). Cytotoxicity study revealed IC50 values of less than 7 µg/ml for liposomes. In vivo plasma retention following iv administration indicated the potential of liposome in maintaining cisplatin levels within the circulation, while free cisplatin and cisplatin conjugates were promptly eliminated. Anti-tumor efficacy studies following iv injections at 3 mg/kg cisplatin weekly for three weeks in C26 tumor bearing BALB/c mice demonstrated the potential of the cisplatin liposomes in tumor growth inhibition. Pt-complexes were not as effective as liposomal formulations showing the crucial role of liposomes in maintaining cisplatin levels within blood circulation. Overall, the developed cisplatin liposome seems to be a promising therapeutic approach for targeting solid tumors.
    Keywords:  Acidic amino acid; Cancer; Cisplatin; Equilibration method; Nanoliposomes
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121946
  61. Phytomedicine. 2022 Aug;pii: S0944-7113(22)00328-2. [Epub ahead of print]103 154249
    Shuanghua decoction exerts anticancer activity by activating NLRP3 inflammasome via ROS and inhibiting NF-κB signaling in hepatocellular carcinoma cells.
    Bingling Dai, Mengying Fan, Xiaoyue Huang, Zhengyan Gong, Hanbing Cao, Yu Hu, Qi Su, Tianfeng Yang, Yanbin Chen, Xiujuan Peng, Feng Liu, Yanmin Zhang.
       BACKGROUND: Hepatocellular carcinoma (HCC) is a major subtype of liver cancer, with a high mortality rate, and close relation to chronic hepatitis. The components of the NLRP3 inflammasome are poorly expressed or even lost in HCC. Downregulation of the NLRP3 inflammasome expression significantly affects the clinical stages and pathological grade of HCC. According to previous research, Shuanghua decoction (SHD), a traditional folk prescription, has an inhibitory effect on nasopharyngeal cancer.
    PURPOSE: This study aimed to reveal the therapeutic potential of the traditional folk recipe, SHD and its demolition recipe for HCC, and to explore the underlying mechanism.
    METHODS: The effect of SHD and its demolition recipe on HCC cell biological behaviors was assessed using the MTT assay, colony formation, LDH release assay, KFluor-Edu staining, annexin V-FITC/PI staining assay, Hoechst staining, wound-healing assay, transwell assay, reactive oxygen species (ROS) release assay, HPLC, nude mice model, HE staining, IHC, western blot, and immunofluorescence staining in vitro and in vivo.
    RESULTS: SHD was found to inhibit HCC, and Oldenlandia and OP (Oldenlandia: Prunella spike = 2.5:1) were identified as the main ingredients that inhibited the proliferation and migration of HCC cells via the activation of the ROS-mediated NLRP3 inflammasome and inhibition of the NF-κB signaling pathway in vitro and in vivo.
    CONCLUSION: Overall, Chinese medicine theory and pharmacology research revealed that SHD, Oldenlandia and OP may be promising traditional Chinese medicine for the treatment of HCC.
    Keywords:  HCC cells; NF-κB signaling; NLRP3 inflammasome; ROS; Shuanghua decoction
    DOI:  https://doi.org/10.1016/j.phymed.2022.154249
  62. Horm Mol Biol Clin Investig. 2022 Jun 22.
    Potential role of melatonin in prevention and treatment of lung cancer.
    Zi Ni Ngai, Kian Chung Chok, Khuen Yen Ng, Rhun Yian Koh, Soi Moi Chye.
      Lung cancer is the second most common cancer and the most lethal cancer worldwide. Melatonin, an indoleamine produced in the pineal gland, shows anticancer effects on a variety of cancers, especially lung cancer. Herein, we clarify the pathophysiology of lung cancer, the association of circadian rhythm with lung, and the relationship between shift work and the incidence of lung cancer. Special focus is placed on the role of melatonin receptors in lung cancer, the relationship between inflammation and lung cancer, control of cell proliferation, apoptosis, autophagy, and immunomodulation in lung cancer by melatonin. A review of the drug synergy of melatonin with other anticancer drugs suggests its usefulness in combination therapy. In summary, the information compiled may serve as a comprehensive reference for the various mechanisms of action of melatonin against lung cancer, as a guide for the design of future experimental research and for advancing melatonin as a therapeutic agent for lung cancer.
    Keywords:  alternative medicines; circadian rhythm; drug synergy; lung cancer; melatonin
    DOI:  https://doi.org/10.1515/hmbci-2022-0018
  63. Pharmaceutics. 2022 May 27. pii: 1149. [Epub ahead of print]14(6):
    Solid Dispersions Incorporated into PVP Films for the Controlled Release of Trans-Resveratrol: Development, Physicochemical and In Vitro Characterizations and In Vivo Cutaneous Anti-Inflammatory Evaluation.
    Bruno Vincenzo Fiod Riccio, André Luiz Carneiro Soares do Nascimento, Andréia Bagliotti Meneguin, Camila Fernanda Rodero, Kaio Pini Santos, Rafael Miguel Sábio, Sarah Raquel de Annunzio, Carla Raquel Fontana, Hernane da Silva Barud, Priscileila Colerato Ferrari, Marlus Chorilli.
      Trans-resveratrol can promote various dermatological effects. However, its high crystallinity decreases its solubility and bioavailability. Therefore, solid dispersions have been developed to promote its amorphization; even so, they present as powders, making cutaneous controlled drug delivery unfeasible and an alternative necessary for their incorporation into other systems. Thus, polyvinylpyrrolidone (PVP) films were chosen with the aim of developing a controlled delivery system to treat inflammation and bacterial infections associated with atopic dermatitis. Four formulations were developed: two with solid dispersions (and trans-resveratrol) and two as controls. The films presented with uniformity, as well as bioadhesive and good barrier properties. X-ray diffraction showed that trans-resveratrol did not recrystallize. Fourier-transform infrared spectroscopy (FT-IR) and thermal analysis evidenced good chemical compatibilities. The in vitro release assay showed release values from 82.27 ± 2.60 to 92.81 ± 2.50% (being a prolonged release). In the in vitro retention assay, trans-resveratrol was retained in the skin, over 24 h, from 42.88 to 53.28%. They also had low cytotoxicity over fibroblasts. The in vivo assay showed a reduction in inflammation up to 66%. The films also avoided Staphylococcus aureus's growth, which worsens atopic dermatitis. According to the results, the developed system is suitable for drug delivery and capable of simultaneously treating inflammation and infections related to atopic dermatitis.
    Keywords:  amorphization; anti-inflammatory activity; antimicrobial effect; crystallinity; skin permeation; solubility; technological innovation
    DOI:  https://doi.org/10.3390/pharmaceutics14061149
  64. Molecules. 2022 Jun 14. pii: 3818. [Epub ahead of print]27(12):
    Ascorbate as a Bioactive Compound in Cancer Therapy: The Old Classic Strikes Back.
    Jaime González-Montero, Silvia Chichiarelli, Margherita Eufemi, Fabio Altieri, Luciano Saso, Ramón Rodrigo.
      Cancer is a disease of high mortality, and its prevalence has increased steadily in the last few years. However, during the last decade, the development of modern chemotherapy schemes, new radiotherapy techniques, targeted therapies and immunotherapy has brought new hope in the treatment of these diseases. Unfortunately, cancer therapies are also associated with frequent and, sometimes, severe adverse events. Ascorbate (ascorbic acid or vitamin C) is a potent water-soluble antioxidant that is produced in most mammals but is not synthesised endogenously in humans, which lack enzymes for its synthesis. Ascorbate has antioxidant effects that correspond closely to the dose administered. Interestingly, this natural antioxidant induces oxidative stress when given intravenously at a high dose, a paradoxical effect due to its interactions with iron. Importantly, this deleterious property of ascorbate can result in increased cell death. Although, historically, ascorbate has been reported to exhibit anti-tumour properties, this effect has been questioned due to the lack of available mechanistic detail. Recently, new evidence has emerged implicating ferroptosis in several types of oxidative stress-mediated cell death, such as those associated with ischemia-reperfusion. This effect could be positively modulated by the interaction of iron and high ascorbate dosing, particularly in cell systems having a high mitotic index. In addition, it has been reported that ascorbate may behave as an adjuvant of favourable anti-tumour effects in cancer therapies such as radiotherapy, radio-chemotherapy, chemotherapy, immunotherapy, or even in monotherapy, as it facilitates tumour cell death through the generation of reactive oxygen species and ferroptosis. In this review, we provide evidence supporting the view that ascorbate should be revisited to develop novel, safe strategies in the treatment of cancer to achieve their application in human medicine.
    Keywords:  ascorbate; cancer; ferroptosis; iron; oxidative stress
    DOI:  https://doi.org/10.3390/molecules27123818
  65. Nat Metab. 2022 Jun 20.
    Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia.
    Javier Garcia-Bermudez, Michael A Badgley, Sheela Prasad, Lou Baudrier, Yuyang Liu, Konnor La, Mariluz Soula, Robert T Williams, Norihiro Yamaguchi, Rosa F Hwang, Laura J Taylor, Elisa de Stanchina, Bety Rostandy, Hanan Alwaseem, Henrik Molina, Dafna Bar-Sagi, Kıvanç Birsoy.
      Stress-adaptive mechanisms enable tumour cells to overcome metabolic constraints under nutrient and oxygen shortage. Aspartate is an endogenous metabolic limitation under hypoxic conditions, but the nature of the adaptive mechanisms that contribute to aspartate availability and hypoxic tumour growth are poorly understood. Here we identify GOT2-catalysed mitochondrial aspartate synthesis as an essential metabolic dependency for the proliferation of pancreatic tumour cells under hypoxic culture conditions. In contrast, GOT2-catalysed aspartate synthesis is dispensable for pancreatic tumour formation in vivo. The dependence of pancreatic tumour cells on aspartate synthesis is bypassed in part by a hypoxia-induced potentiation of extracellular protein scavenging via macropinocytosis. This effect is mutant KRAS dependent, and is mediated by hypoxia-inducible factor 1 (HIF1A) and its canonical target carbonic anhydrase-9 (CA9). Our findings reveal high plasticity of aspartate metabolism and define an adaptive regulatory role for macropinocytosis by which mutant KRAS tumours can overcome nutrient deprivation under hypoxic conditions.
    DOI:  https://doi.org/10.1038/s42255-022-00583-z
  66. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 Jun 23. e1828
    Rethinking nanoparticulate polymer-drug conjugates for cancer theranostics.
    Yaoqi Wang, Heming Xia, Binlong Chen, Yiguang Wang.
      Polymer-drug conjugates (PDCs) fabricated as nanoparticles have hogged the limelight in cancer theranostics in the past decade. Many researchers have devoted to developing novel and efficient polymeric drug delivery system since the first generation of poly(N-[2-hydroxypropyl]methacrylamide) copolymer-drug conjugates. However, none of them has been approved for chemotherapy in clinic. An ideal PDC nanoparticle for cancer theranostics should possess several properties, including prolonged circulation in blood, sufficient accumulation and internalization in tumors, and efficient drug release in target sites. To achieve these goals, it is important to rationally design the nanoparticulate PDCs based on circulation, accumulation, penetration, internalization, and drug release (CAPIR) cascade. Specifically, CAPIR cascades are divided into five steps: (1) circulation in the vascular compartment without burst release, (2) accumulation in tumors via enhanced permeability and retention effect, (3) subsequent penetration into the deep regions of tumors, (4) internalization into tumor cells, and (5) release of drugs as free molecules to exert their pharmacological effects. In this review, we focus on the development and novel approaches of nanoparticulate PDCs based on CAPIR cascade, and provide an outlook on future clinical application. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
    Keywords:  CAPIR cascade; Cancer theranostics; Drug delivery systems; Polymer-drug conjugates; Ultra-pH sensitive nanoparticle
    DOI:  https://doi.org/10.1002/wnan.1828
  67. Mar Drugs. 2022 Jun 08. pii: 386. [Epub ahead of print]20(6):
    Antitumor Potential of Immunomodulatory Natural Products.
    Genoveffa Nuzzo, Giuseppina Senese, Carmela Gallo, Federica Albiani, Lucia Romano, Giuliana d'Ippolito, Emiliano Manzo, Angelo Fontana.
      Cancer is one of the leading causes of death globally. Anticancer drugs aim to block tumor growth by killing cancerous cells in order to prevent tumor progression and metastasis. Efficient anticancer drugs should also minimize general toxicity towards organs and healthy cells. Tumor growth can also be successfully restrained by targeting and modulating immune response. Cancer immunotherapy is assuming a growing relevance in the fight against cancer and has recently aroused much interest for its wider safety and the capability to complement conventional chemotherapeutic approaches. Natural products are a traditional source of molecules with relevant potential in the pharmacological field. The huge structural diversity of metabolites with low molecular weight (small molecules) from terrestrial and marine organisms has provided lead compounds for the discovery of many modern anticancer drugs. Many natural products combine chemo-protective and immunomodulant activity, thus offering the potential to be used alone or in association with conventional cancer therapy. In this review, we report the natural products known to possess antitumor properties by interaction with immune system, as well as discuss the possible immunomodulatory mechanisms of these molecules.
    Keywords:  anticancer; antitumor; immunomodulators; marine products; natural products
    DOI:  https://doi.org/10.3390/md20060386
  68. Front Bioeng Biotechnol. 2022 ;10 919235
    Albumin-Stabilized Manganese Oxide/Semiconducting Polymer Nanocomposites for Photothermal-Chemodynamic Therapy of Hepatic Carcinoma.
    Qi Su, Changcun Liu, Jingyi Zhu, Mengbin Ding, Zhen Zhang, Jingchao Li, Qin Zhang.
      Hepatic carcinoma is one of the most common cancers worldwide, while its treatment remains a great challenge. Traditional therapeutic methods often have disadvantages such as limited therapeutic efficacy and potential side effects. In this study, we report the construction of bovine serum albumin (BSA)-stabilized manganese oxide (MnO2)/semiconducting polymer (SP) nanocomposites to combine photothermal therapy (PTT) and chemodynamic therapy (CDT) for treatment of hepatic carcinoma in living mouse models. Such nanocomposites are composed of BSA, SP, and MnO2 as the stabilizer, PTT, and CDT agent, respectively. SP produced local heat under near-infrared (NIR) laser irradiation for PTT, and MnO2 nanoparticles mediated CDT in the tumor microenvironment, leading to apoptosis of cancer cells. Such nanocomposite-mediated combinational therapy showed a much higher efficacy in inhibiting growth of subcutaneous HepG2 tumors in nude mice than sole treatment. This study thus provides a multifunctional nanoplatform for safe and effective treatment of hepatic carcinoma.
    Keywords:  chemodynamic therapy; combinational therapy; hepatic carcinoma; nanocomposites; photothermal therapy
    DOI:  https://doi.org/10.3389/fbioe.2022.919235
  69. Pharmaceutics. 2022 May 30. pii: 1166. [Epub ahead of print]14(6):
    Efficient Delivery of Curcumin by Alginate Oligosaccharide Coated Aminated Mesoporous Silica Nanoparticles and In Vitro Anticancer Activity against Colon Cancer Cells.
    Chennan Liu, Fangyuan Jiang, Zifeng Xing, Lihong Fan, Yuan Li, Shaoning Wang, Junhong Ling, Xiao-Kun Ouyang.
      We designed and synthesized aminated mesoporous silica (MSN-NH2), and functionally grafted alginate oligosaccharides (AOS) on its surface to get MSN-NH2-AOS nanoparticles as a delivery vehicle for the fat-soluble model drug curcumin (Cur). Dynamic light scattering, thermogravimetric analysis, and X-ray photoelectron spectroscopy were used to characterize the structure and performance of MSN-NH2-AOS. The nano-MSN-NH2-AOS preparation process was optimized, and the drug loading and encapsulation efficiencies of nano-MSN-NH2-AOS were investigated. The encapsulation efficiency of the MSN-NH2-Cur-AOS nanoparticles was up to 91.24 ± 1.23%. The pH-sensitive AOS coating made the total release rate of Cur only 28.9 ± 1.6% under neutral conditions and 67.5 ± 1% under acidic conditions. According to the results of in vitro anti-tumor studies conducted by MTT and cellular uptake assays, the MSN-NH2-Cur-AOS nanoparticles were more easily absorbed by colon cancer cells than free Cur, achieving a high tumor cell targeting efficiency. Moreover, when the concentration of Cur reached 50 μg/mL, MSN-NH2-Cur-AOS nanoparticles showed strong cytotoxicity against tumor cells, indicating that MSN-NH2-AOS might be a promising tool as a novel fat-soluble anticancer drug carrier.
    Keywords:  brown algae oligosaccharides; colon cancer cells; curcumin; pH-sensitive drug release; silica
    DOI:  https://doi.org/10.3390/pharmaceutics14061166
  70. Biomaterials. 2022 Jun 09. pii: S0142-9612(22)00269-1. [Epub ahead of print]287 121629
    Biofunctionalized graphene oxide nanosheet for amplifying antitumor therapy: Multimodal high drug encapsulation, prolonged hyperthermal window, and deep-site burst drug release.
    Zhen Wang, Hao Cheng, Yu Sheng, Zongkai Chen, Xiaohong Zhu, Jianye Ren, Xiangze Zhang, Lingyu Lv, Huaqing Zhang, Jianping Zhou, Yang Ding.
      Biofunctional surface-modification surpassed critical limitation of graphene oxide (GO) in biocompatibility and drug delivery efficiency, contributing to versatile biomedical applications. Here, a protein corona-bridged GO nanoplatform with high drug loading, longstanding hyperthermia, and controllable drug release, was engineered for amplified tumor therapeutic benefits. Structurally, GO surface was installed with phenylboronic acid (PBA) layer, on which iRGD conjugated apolipoprotein A-I (iRGD-apoA-I) was coordinated via boron electron-deficiency, to form the sandwich-like GO nanosheet (iAPG). The GO camouflaging by iRGD-apoA-I corona provided multimodal high doxorubicin (DOX) loading by π-π stacking and coordination, and generated a higher photothermal transformation efficiency simultaneously. In vitro studies demonstrated that iAPG significantly improved drug penetration and internalization, then achieved tumor-targeted DOX release through near-infrared (NIR) controlled endo/lysosome disruption. Moreover, iAPG mediated site-specific drug shuttling to produce a 3.53-fold enhancement of tumor drug-accumulation compared to the free DOX in vivo, and induced deep tumor penetration dramatically. Primary tumor ablation and spontaneous metastasis inhibition were further demonstrated with negligible side effects under optimal NIR. Taken together, our work provided multifunctional protein corona strategy to inorganic nanomaterials toward advantageous biomedical applications.
    Keywords:  Biofunctionalized graphene oxide; Deep tumor penetration; High drug loading; Prolonged hyperthermal window; Site-specific release; Thermo-chemotherapy
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121629
  71. Comb Chem High Throughput Screen. 2022 Jun 17.
    Solid lipid nanoformulation of berberine attenuates Doxorubicin triggered in vitro inflammation in H9c2 rat cardiomyocytes.
    Rawal S, Gupta P, Bhatnagar P, Yadav Hn, Dinda Ak.
       AIM: To evaluate berberine solid lipid nanoparticles' efficacy against doxorubicin-induced cardiotoxicity.
    BACKGROUND: Berberine (Ber) is cardioprotective, but its oral bioavailability is low and its effect in chemotherapy-induced cardiotoxicity has not been studied.
    OBJECTIVE: Solid lipid nanoparticles (SLNs) of berberine chloride were prepared, characterized and evaluated in vitro against Doxorubicin induced cardiomyocyte injury.
    METHODOLOGY: Berberine loaded SLNs (Ber-SLNs) were synthesized using water-in-oil microemulsion technique with tripalmitin, Tween 80 and poloxamer 407. Ber-SLNs were evaluated for preventive effect against toxicity of Doxorubicin in H9c2 cells. The culture was pre-treated (24 h) with Ber (10 µM) and Ber-SLNs (1 and 10 µM) and exposed to 1 µM of Doxorubicin (Dox) was added for 3 h. The cell viability (LDH (Lactate dehydrogenase) assay and MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)), levels of Creatine kinase-MB (CK-MB), Nitrite, MDA (Malondialdehyde), ROS (Reactive oxygen species) generation and apoptotic DNA (Deoxyribonucleic acid) content were assessed.
    RESULTS: Ber-SLNs had a mean particle size of 13.12±1.188 nm, zeta potential of -1.05 ± 0.08 mV, poly-dispersity index (PDI) of 0.317 ± 0.05 and entrapment efficiency of 50 ± 4.8%. Cell viability was 81  0.17% for Ber-SLNs (10 µM) and 73.22  0.83% for Ber (10 µM) treated cells in MTT assay. Percentage cytotoxicity calculated from LDH release was 58.91  0.54% after Dox, 40.3  1.3% with Ber (10 µM) and 40.7  1.3% with Ber-SLNs (1 µM) (p<0.001). Inflammation and oxidative stress markers were lower with Ber and Ber-SLNs. Attenuation of ROS generation and apoptosis of cardiomyocytes were noted on fluorescence microscopy.
    CONCLUSION: Ber loaded SLNs effectively prevented Doxorubicin-induced inflammation and oxidative stress in rat cardiomyocytes. The results demonstrate that microemulsion is a simple, cost-effective technique to prepare Ber-SLNs and may be considered as a drug delivery vehicle for berberine.
    Keywords:  Berberine; Chemotherapy-induced cardiotoxicity; Doxorubicin; H9c2 cells; Microemulsion; Solid lipid nanoparticles
    DOI:  https://doi.org/10.2174/1386207325666220617113744
  72. Drug Deliv. 2022 Dec;29(1): 1878-1891
    Anti-lung cancer effect of paclitaxel solid lipid nanoparticles delivery system with curcumin as co-loading partner in vitro and in vivo.
    Chao Pi, Wenmei Zhao, Mingtang Zeng, Jiyuan Yuan, Hongping Shen, Ke Li, Zhilian Su, Zerong Liu, Jie Wen, Xinjie Song, Robert J Lee, Yumeng Wei, Ling Zhao.
      The main aim of this study was to improve the therapeutic potential of a paclitaxel (PTX) and curcumin (CU) combination regimen using solid lipid nanoparticles (SLNs). PTX and CU were successfully co-encapsulated at a predetermined ratio in SLNs (PC-SLNs) with high encapsulation efficiency (CU: 97.6%, PTX: 95.8%), appropriate particle size (121.8 ± 1.69 nm), small PDI (0.267 ± 0.023), and negative zeta potential (-30.4 ± 1.25 mV). Compared with PTX or the combination of CU and PTX (CU + PTX), PC-SLNs can greatly reduce the dose of PTX while still achieving the same therapeutic effect on four cancer cell lines, among which the inhibitory effect on A549 lung cancer cells was the strongest. PC-SLNs improved the area under the curve (CU: 1.40-fold; PTX: 2.88-fold), prolonged the residence time (CU: 6.94-fold; PTX: 2.51-fold), and increased the half-life (CU: 5.62-fold; PTX: 6.46-fold), achieving long circulation. PC-SLNs were used to treat lung cancer in a nude mouse xenograft tumor model and the tumor suppression rate reached 78.42%, while those of PTX and (CU + PTX) were 40.53% and 51.56%, respectively. As PC-SLNs can prevent P-glycoprotein efflux, reverse MDR and downregulate the NF-κB pathway. PC-SLNs are a potential antineoplastic agent that is more effective and less toxic in treating lung cancer.
    Keywords:  Paclitaxel; combination therapy; curcumin; solid lipid nanoparticles
    DOI:  https://doi.org/10.1080/10717544.2022.2086938
  73. J Am Chem Soc. 2022 Jun 22.
    Trident Molecule with Nanobrush-Nanoparticle-Nanofiber Transition Property Spatially Suppresses Tumor Metastasis.
    Ge Gao, Yao-Wen Jiang, Wenjun Zhan, Xiaoyang Liu, Runqun Tang, Xianbao Sun, Yu Deng, Lingling Xu, Gaolin Liang.
      Metastasis-induced high mortality of cancers urgently demands new approaches to simultaneously inhibit primary tumor metastasis and distant tumor growth. Herein, by rational design of a trident molecule Nap-Phe-Phe-Lys(SA-CPT)-Lys(SA-HCQ)-Tyr(H2PO3)-OH (Nap-CPT-HCQ-Yp) with three functional "spears" (i.e., a phosphotyrosine motif for enzymatic self-assembly, camptothecin (CPT) motif for chemotherapy, and hydroxychloroquine (HCQ) motif for autophagy inhibition) and nanobrush-nanoparticle-nanofiber transition property, we propose a novel strategy of intracellular enzymatic nanofiber formation and synergistic autophagy inhibition-enhanced chemotherapy and immunotherapy for spatial suppression of tumor metastasis. Under sequential alkaline phosphatase catalysis and carboxylesterase hydrolysis, Nap-CPT-HCQ-Yp undergoes nanobrush-nanoparticle-nanofiber transition, accompanied by the releases of CPT and HCQ. The formed intracellular nanofibers effectively inhibit the metastasis and invasion behaviors of cancer cells. Meanwhile, the released CPT and HCQ synergistically induce a prominent therapeutic effect through autophagy inhibition-enhanced chemotherapy. Furthermore, chemotherapy of Nap-CPT-HCQ-Yp enhances immunogenic cell death, resulting in the activation of toxic T-cells. Finally, a combination of checkpoint blockade therapy and Nap-CPT-HCQ-Yp-mediated chemotherapy elicits systemic antitumor immunity, thereby achieving efficient inhibitions of primary tumors as well as distant tumors in a breast tumor model. Our work offers a simple and feasible strategy for the design of "smart" multifunctional prodrugs to spatially suppress tumor metastasis.
    DOI:  https://doi.org/10.1021/jacs.2c05743
  74. Front Oncol. 2022 ;12 879828
    Current Researches on Nanodrug Delivery Systems in Bladder Cancer Intravesical Chemotherapy.
    Yilei Lu, Siqi Wang, Yuhang Wang, Mingshan Li, Yili Liu, Dongwei Xue.
      Bladder cancer is one of the most common malignant tumors in urinary system. Intravesical chemotherapy is a common adjuvant therapy after transurethral resection of bladder tumors. However, it has several disadvantages such as low drug penetration rate, short residence time, unsustainable action and inability to release slowly, thus new drug delivery and new modalities in delivery carriers need to be continuously explored. Nano-drug delivery system is a novel way in treatment for bladder cancer that can increase the absorption rate and prolong the duration of drug, as well as sustain the action by controlling drug release. Currently, nano-drug delivery carriers mainly included liposomes, polymers, and inorganic materials. In this paper, we reveal current researches in nano-drug delivery system in bladder cancer intravesical chemotherapy by describing the applications and defects of liposomes, polymers and inorganic material nanocarriers, and provide a basis for the improvement of intravesical chemotherapy drugs in bladder cancer.
    Keywords:  bladder cancer; inorganic material; intravesical chemotherapy; liposomes; nano-drug delivery system; polymers
    DOI:  https://doi.org/10.3389/fonc.2022.879828
  75. Gels. 2022 May 30. pii: 337. [Epub ahead of print]8(6):
    Poly(curcumin β-amino ester)-Based Tablet Formulation for a Sustained Release of Curcumin.
    Vinod S Patil, Benjamin C Burdette, J Zach Hilt, Douglass S Kalika, Thomas D Dziubla.
      Oral drug delivery remains the most common and well tolerated method for drug administration. However, its applicability is often limited due to low drug solubility and stability. One approach to overcome the solubility and stability limitations is the use of amorphous polymeric prodrug formulations, such as poly(β-amino ester) (PBAE). PBAE hydrogels, which are biodegradable and pH responsive, have shown promising results for the controlled release of drugs by improving the stability and increasing the solubility of these drugs. In this work, we have evaluated the potential use of PBAE prodrugs in an oral tablet formulation, studying their sustained drug release potential and storage stability. Curcumin, a low solubility, low stability antioxidant drug was used as a model compound. Poly(curcumin β-amino ester) (PCBAE), a crosslinked amorphous network, was synthesized by a previously published method using a commercial diacrylate and a primary diamine, in combination with acrylate-functionalized curcumin. PCBAE-based tablets were made and exhibited a sustained release for 16 h, following the hydrolytic degradation of PCBAE particles into native curcumin. In addition to the release studies, preliminary storage stability was assessed using standard and accelerated stability conditions. As PCBAE degradation is hydrolysis driven, tablet stability was found to be sensitive to moisture.
    Keywords:  Poy(β-amino ester); amorphous; controlled drug delivery; crosslinked systems; curcumin; hydrogels; oral dosage form; prodrug; solubility; tablets
    DOI:  https://doi.org/10.3390/gels8060337
  76. Front Chem. 2022 ;10 926002
    Preparation of NIR-Responsive Gold Nanocages as Efficient Carrier for Controlling Release of EGCG in Anticancer Application.
    Weiran Gao, Xiangyi Fan, Yunlong Bi, Zipeng Zhou, Yajiang Yuan.
      Hepatocellular carcinoma (HCC) is a type of cancer that has a restricted therapy option. Epigallocatechin gallate (EGCG) is one of the main biologically active ingredients in tea. A large number of studies have shown that EGCG has preventive and therapeutic effects on various tumors. In addition, the development of near-infrared (NIR)-responsive nano-platforms has been attracting cancer treatment. In this work, we designed and synthesized a strategy of gold nanocages (AuNCs) as an efficient carrier for controlling release of EGCG for anti-tumor to achieve the synergistic functions of NIR-response and inhibited tumor cell proliferation. The diameter of AuNCs is about 50 nm and has a hollow porous (8 nm) structure. Thermal imaging-graphic studies proved that the AuNCs-EGCG obtained have photothermal response to laser irradiation under near-infrared light and still maintain light stability after multiple cycles of laser irradiation. The resulted AuNCs-EGCG reduced the proliferation rate of HepG2 cells to 50% at 48 h. Western blot analysis showed that NIR-responsive AuNCs-EGCG can promote the expression of HepG2 cell apoptosis-related proteins HSP70, Cytochrome C, Caspase-9, Caspase-3, and Bax, while the expression of Bcl-2 is inhibited. Cell confocal microscopy analysis proved that AuNCs-EGCG irradiated by NIR significantly upregulates Caspase-3 by nearly 2-fold and downregulates Bcl-2 by nearly 0.33-fold, which is beneficial to promote HepG2 cell apoptosis. This study provides useful information for the NIR-responsive AuNCs-EGCG as a new type of nanomedicine for HCC.
    Keywords:  NIR responsive; epigallocatechin gallate; gold nanocages; hepatocellular carcinoma; photothermal therapy
    DOI:  https://doi.org/10.3389/fchem.2022.926002
  77. J Mater Chem B. 2022 Jun 23.
    Fabrication of injectable hydrogels from an anticancer peptide for local therapeutic delivery and synergistic photothermal-chemotherapy.
    Na Liu, Shunjie Wu, Xin Tian, Xinming Li.
      The susceptibility of anticancer peptides to proteolytic degradation is often considered as a major weakness that limits systemic therapeutic applications. However, localized delivery of anticancer peptides via injectable hydrogels is expected to improve drug efficacy and reduce systemic toxicity. Herein, an injectable hydrogel with drug releasing properties, NIR responsiveness and pH sensitivity was developed from an anticancer peptide (KL), Fe3+ ions and protocatechualdehyde via dynamic and reversible interactions. Benefiting from the formation of Fe(III)-catechol complexes between Fe3+ ions and protocatechualdehyde within gel networks, the obtained hydrogel exhibited intrinsic NIR absorption properties for photothermal ablation of tumor cells, and remote light control of drug release. Besides, the pH-labile imine bonds between KL and protocatechualdehyde endowed the injectable gel with pH sensitivity for sustained release of KL under a mildly acidic environment, inducing membrane destabilization and facilitating the cell uptake of DOX for combinational chemotherapy. Both in vitro and in vivo experiments revealed that the injectable hydrogel exhibited a synergistic therapeutic effect on inhibiting tumor growth via combinational photothermal-chemotherapy. Therefore, this work provides a promising attempt to develop a therapeutic hydrogel from an anticancer peptide, which could work as a localized drug delivery platform for synergistic photothermal-chemotherapy.
    DOI:  https://doi.org/10.1039/d2tb00917j
  78. Int J Mol Sci. 2022 Jun 18. pii: 6807. [Epub ahead of print]23(12):
    Use of Self-Assembled Colloidal Prodrug Nanoparticles for Controlled Drug Delivery of Anticancer, Antifibrotic and Antibacterial Mitomycin.
    Mohamed M Abdelghafour, Ágota Deák, Diána Szabó, Imre Dékány, László Rovó, László Janovák.
      Herein we present the synthesis of a polymeric prodrug nanomaterial capable of spontaneous, self-assembled nanoparticle formation and of the conjugation (encapsulation) of drugs with amino and/or carboxyl and/or hydroxyl groups via ester and/or amide linkage. Mitomycin C (MMC) a versatile drug with antibiotic, antibacterial and antineoplastic properties, was used to prove this concept. The in vitro drug release experiments showed a fast release for the pure MMC (k = 49.59 h-n); however, a significantly lower MMC dissolution rate (k = 2.25, 1.46, and 1.35 h-n) was obtained for the nanoparticles with increased cross-link density (3, 10, 21%). The successful modification and conjugation reactions were confirmed using FTIR and EDX measurements, while the mucoadhesive properties of the self-assembled particles synthesized in a simple one-pot reaction were proved by rheological measurement. The prepared biocompatible polymeric prodrugs are very promising and applicable as a drug delivery system (DDS) and useful in the area of cancer treatment.
    Keywords:  Mitomycin; modified PVA; mucoadhesive properties; prolonging/adjusted drug release; self-assembled polymeric particle formation
    DOI:  https://doi.org/10.3390/ijms23126807
  79. Nutrients. 2022 Jun 08. pii: 2376. [Epub ahead of print]14(12):
    Liver Metastatic Breast Cancer: Epidemiology, Dietary Interventions, and Related Metabolism.
    Qianying Zuo, Nicole Hwajin Park, Jenna Kathryn Lee, Zeynep Madak Erdogan.
      The median overall survival of patients with metastatic breast cancer is only 2-3 years, and for patients with untreated liver metastasis, it is as short as 4-8 months. Improving the survival of women with breast cancer requires more effective anti-cancer strategies, especially for metastatic disease. Nutrients can influence tumor microenvironments, and cancer metabolism can be manipulated via a dietary modification to enhance anti-cancer strategies. Yet, there are no standard evidence-based recommendations for diet therapies before or during cancer treatment, and few studies provide definitive data that certain diets can mediate tumor progression or therapeutic effectiveness in human cancer. This review focuses on metastatic breast cancer, in particular liver metastatic forms, and recent studies on the impact of diets on disease progression and treatment.
    Keywords:  breast cancer liver metastasis; fasting-mimicking diet; western diet
    DOI:  https://doi.org/10.3390/nu14122376
  80. Int J Biol Macromol. 2022 Jun 15. pii: S0141-8130(22)01306-X. [Epub ahead of print]214 278-289
    Novel multifunctional bionanoparticles modified with sialic acid for stroke treatment.
    Yanguo Su, Chunjing Guo, Qiang Chen, Huimin Guo, Jinqiu Wang, Mu Kaihang, Daquan Chen.
      Oxidative stress and inflammation are two key pathophysiological mechanisms that lead to neuronal apoptosis and brain damage following ischemia/reperfusion (I/R) injury. Because of their complex pathological mechanisms and the presence of the blood-brain barrier, the treatment of I/R is severely limited. Inspired by the fact that Macrophage membranes (MM) can cross the blood-brain barrier, we have developed a new multifunctional bionic particle (MSAOR@Cur). The modification of Sialic acid (SA) on the surface of Angelica polysaccharides (APS), the attachment of Resveratrol (Res) using the ROS-responsive bond oxalate bond as a linker arm, constitutes amphiphilic nanoparticles with an inner core encapsulated with curcumin (SAOR@Cur), and finally the use of MM camouflage to integrate the neuroprotection of APS, the free radical scavenging of Res, and the anti-inflammation of curcumin (Cur) in one strategy. Interestingly, the experimental results show that MSAOR@Cur can successfully deliver curcumin to the area of ischemia-reperfusion injury.
    Keywords:  Bionanoparticles; Cell membrane; Drug delivery; Ischemic stroke
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.06.102
  81. Biomedicines. 2022 Jun 10. pii: 1378. [Epub ahead of print]10(6):
    Emerging Prospects of Nanozymes for Antibacterial and Anticancer Applications.
    Nayanika Chakraborty, Sona Gandhi, Rajni Verma, Indrajit Roy.
      The ability of some nanoparticles to mimic the activity of certain enzymes paves the way for several attractive biomedical applications which bolster the already impressive arsenal of nanomaterials to combat deadly diseases. A key feature of such 'nanozymes' is the duplication of activities of enzymes or classes of enzymes, such as catalase, superoxide dismutase, oxidase, and peroxidase which are known to modulate the oxidative balance of treated cells for facilitating a particular biological process such as cellular apoptosis. Several nanoparticles that include those of metals, metal oxides/sulfides, metal-organic frameworks, carbon-based materials, etc., have shown the ability to behave as one or more of such enzymes. As compared to natural enzymes, these artificial nanozymes are safer, less expensive, and more stable. Moreover, their catalytic activity can be tuned by changing their size, shape, surface properties, etc. In addition, they can also be engineered to demonstrate additional features, such as photoactivated hyperthermia, or be loaded with active agents for multimodal action. Several researchers have explored the nanozyme-mediated oxidative modulation for therapeutic purposes, often in combination with other diagnostic and/or therapeutic modalities, using a single probe. It has been observed that such synergistic action can effectively by-pass the various defense mechanisms adapted by rogue cells such as hypoxia, evasion of immuno-recognition, drug-rejection, etc. The emerging prospects of using several such nanoparticle platforms for the treatment of bacterial infections/diseases and cancer, along with various related challenges and opportunities, are discussed in this review.
    Keywords:  antibacterial therapy; anticancer therapy; enzyme mimics; nanozyme; reactive oxygen species
    DOI:  https://doi.org/10.3390/biomedicines10061378
  82. Chembiochem. 2022 Jun 24.
    Iron Oxide Nanoparticles Functionalized with Fucoidan: a Potential Theranostic Nanotool for Hepatocellular Carcinoma.
    Frederic Geinguenaud, Odile Sainte Catherine, Florence Poirier, Valérie Besnard, Oualid Haddad, Frederic Chaubet, Y Lalatonne, Didier Lutomski, A Sutton, Laurence Motte.
      Fucoidan is a natural sulfated polysaccharide with a large range of biological activities including anticancer and anti-oxidation activities. Hepatocellular carcinoma is the fourth most common aggressive cancer type. The aim of this study was to investigate the bioactivity of free fucoidan versus its vectorization using nanoparticles (NPs) in human hepatoma cells, Huh-7. Iron oxide NPs were functionalized with fucoidan by a one-step surface complexation. NP cellular uptake was quantified by magnetic measurement at various extracellular iron concentrations. Cell invasion and migration were reduced with NPs while free fucoidan increases these events at low fucoidan concentration (≤ 0.5 mM). Concomitantly, a high decrease of reactive oxygen species production related with a decrease of the matrix metalloproteinase-9 activity and an increase of its expression was observed with NPs compared to free fucoidan. A proteomic analysis evidenced that some fucoidan regulated proteins appeared related to protein synthesis, N-glycan processing, and cellular stress. To our knowledge, this is the first study which reveals such activity induced by fucoidan. These results pave the way for USPIO-fucoidan-NPs as potential theranostic nanotool for hepatocellular carcinoma treatment.
    Keywords:  Fucoidan, natural polysaccharide, iron oxide nanoparticles, Hepatocellular carcinoma, vectorization, proteome
    DOI:  https://doi.org/10.1002/cbic.202200265
  83. Carbohydr Polym. 2022 Sep 15. pii: S0144-8617(22)00567-7. [Epub ahead of print]292 119662
    Recent advances in hyaluronic acid-based nanomedicines: Preparation and application in cancer therapy.
    Xingyu Hou, Dan Zhong, Hongying Chen, Zhongwei Gu, Qiyong Gong, Xuelei Ma, Hu Zhang, Hongyan Zhu, Kui Luo.
      Rapid development of stimuli-responsive drug delivery systems (DDSs) for tumor therapy has raised increasing interest in recent decades, and many nanomedicines are prepared to achieve accurate or sustained drug release. However, the fabrication process for these nanomedicines has been far too intricate and their potential biosafety has not been fully understood, which has hampered their clinical translation. Challenges for developing DDSs remain on balancing the complexity of the fabrication process with their translational feasibility. Owing to water-solubility, biocompatibility, biodegradability and CD44-targetability, hyaluronic acid (HA) as a versatile building block has gained great popularity due to a simplified fabrication process and unique characteristics of HA for DDSs. In this review, we overviewed the biological function and multiple chemical modifications of HA, and discussed the fabrication of HA-based drug delivery systems (HA-DDSs) with specific tumor microenvironmental stimuli-responsive linkers. We systemically surveyed the applications of HA-DDSs for chemotherapy, photothermal therapy, photodynamic therapy, immunotherapy, gene delivery and combination therapy.
    Keywords:  Anti-tumor therapy; Drug delivery systems; Hyaluronic acid; Nanomedicines; Stimuli-responsive
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119662
  84. Oncol Lett. 2022 Jul;24(1): 236
    Polymethoxylated flavone sudachitin is a safe anticancer adjuvant that targets glycolysis in cancer-associated fibroblasts.
    Shuhai Chen, Masaaki Nishi, Yuji Morine, Kozo Yoshikawa, Takuya Tokunaga, Hideya Kashihara, Chie Takasu, Yuma Wada, Toshiaki Yoshimoto, Akiko Nakamoto, Tohru Sakai, Mitsuo Shimada.
      Sudachitin is a polymethoxylated flavone found in the peel of Citrus sudachi, a unique specialty citrus fruit in Tokushima Prefecture, Japan. Previous reports have demonstrated that sudachitin has anti-inflammatory and metabolic regulatory activities. However, to the best of our knowledge, no studies have explored whether sudachitin can act as an antitumor therapeutic agent by regulating metabolic functions in the tumor microenvironment. In the present study, cell proliferation and cytotoxicity assays were used to determine whether sudachitin inhibited the in vitro growth of liver cancer and pancreatic carcinoma, cholangiocarcinoma and colorectal cancer cells and to compare its toxicity against normal fibroblasts and induced cancer-associated fibroblasts (CAFs). Using lactate assays and reverse transcription-quantitative PCR, the effects of sudachitin on glycolysis in CAFs were investigated. The effects of CAFs on malignant tumor cells were evaluated in vitro using cell proliferation, wound healing and invasion assays. As result, sudachitin inhibited various types of tumor cells with different half-maximal inhibitory concentrations. Treatment with 50 µM sudachitin for 48 h suppressed tumor and CAFs proliferation but was not cytotoxic against normal fibroblasts. This dose also inhibited glycolysis in CAFs and, thus, diminished their pro-tumorigenic activities. Overall, the present study revealed that sudachitin has promise as a safe and widely available natural antitumor adjuvant.
    Keywords:  antitumor; cancer-associated fibroblasts; glycolysis; reverse Warburg effect; sudachitin
    DOI:  https://doi.org/10.3892/ol.2022.13356
  85. Biomed Res Int. 2022 ;2022 4438518
    PEGylated Protamine Letrozole Nanoparticles: A Promising Strategy to Combat Human Breast Cancer via MCF-7 Cell Lines.
    Muhammad Tafhim Khan, Zia Uddin, Muhammad Arslan Javed, Nabi Shah, Hamid Bashir, Ahson Jabbar Shaikh, Muhammad Shahid Riaz Rajoka, Muhammad Imran Amirzada, Muhammad Hassham Hassan Bin Asad.
      The objective of the study was to develop PEGylated protamine letrozole nanoparticles to combat human breast cancer by modifying the release pattern of letrozole. Breast cancer is amongst the most prevalent diseases in women due to overactivity of human epidermal growth factor receptor 2 (HER2). PEG-protamine letrozole nanoparticle formulation was designed and optimized to alter the release pattern of the drug. The size, morphology, and structure of PEG-protamine letrozole NP were characterized by FTIR, XRD, Zetasizer, and SEM analysis. The result showed the PEG-protamine letrozole nanoparticles were irregular in shape and have size ranging from 258 nm to 388 nm, polydispersity index 0.114 to 0.45, zeta potential of 11.2 mV, and entrapment efficiency 89.93%. XRD studies have confirmed that the crystal structure of letrozole has become amorphous. The drug release study maintained the prolonged release for 72 hours. Moreover, the PEG-protamine letrozole NPs displayed a strong anticancer action compared to MCF-7 cells with an IC50 70 μM for letrozole and 50 μM for PEG-protamine letrozole NPs. Overall, our results indicate that letrozole PEG-protamine NPs alter the release profile of letrozole, which could be an excellent approach for overcoming letrozole resistance in human breast cancer.
    DOI:  https://doi.org/10.1155/2022/4438518
  86. Carbohydr Polym. 2022 Sep 15. pii: S0144-8617(22)00604-X. [Epub ahead of print]292 119699
    Diselenide-crosslinked carboxymethyl chitosan nanoparticles for doxorubicin delivery: Preparation and in vivo evaluation.
    Jun Wang, Justin Liu, Dao-Qiang Lu, Lijing Chen, Rujia Yang, Dahai Liu, Bin Zhang.
      In this paper, we report a simple approach to fabricate diselenide-crosslinked carboxymethyl chitosan nanoparticles (DSe-CMC NPs) for doxorubicin (DOX) delivery, with disulfide analogs (DS-CMC NPs) as control. DS-CMC NPs and DSe-CMC NPs featured a spherical morphology and narrow size distribution with the average size about 200 nm. Carboxymethyl chitosan (CMC) as the starting material not only improved the biocompatibility of the nanocarriers but also enhanced physiological stability. Due to electrostatic interactions between DOX and CMC, the nanoparticles had high drug encapsulation efficiency (∼25 %). The nanoparticles disintegration and drug release were accelerated by the cleavage of diselenide bonds through oxidation by H2O2 or reduction by GSH. In vitro cell experiments revealed that DOX-loaded DSe-CMC NPs possessed the highest drug accumulation and cytotoxicity in tumor cells. Moreover, DOX-loaded DSe-CMC NPs performed the enhanced growth inhibition in vivo than that of DS-CMC NPs. Thus, the diselenide-crosslinked nanoparticles possess great potentials for DOX delivery.
    Keywords:  Carboxymethyl chitosan; Diselenide; Disulfide; Drug delivery; Nanoparticles
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119699
  87. Biomolecules. 2022 Jun 20. pii: 855. [Epub ahead of print]12(6):
    Bio-Assisted Synthesis and Characterization of Zinc Oxide Nanoparticles from Lepidium sativum and Their Potent Antioxidant, Antibacterial and Anticancer Activities.
    Bisma Meer, Anisa Andleeb, Junaid Iqbal, Hajra Ashraf, Kushif Meer, Joham Sarfraz Ali, Samantha Drouet, Sumaira Anjum, Azra Mehmood, Taimoor Khan, Mohammad Ali, Christophe Hano, Bilal Haider Abbasi.
      Nanotechnology is an emerging area of research that deals with the production, manipulation, and application of nanoscale materials. Bio-assisted synthesis is of particular interest nowadays, to overcome the limitations associated with the physical and chemical means. The aim of this study was to synthesize ZnO nanoparticles (NPs) for the first time, utilizing the seed extract of Lepidium sativum. The synthesized NPs were confirmed through various spectroscopy and imagining techniques, such as XRD, FTIR, HPLC, and SEM. The characterized NPs were then examined for various in vitro biological assays. Crystalline, hexagonal-structured NPs with an average particle size of 25.6 nm were obtained. Biosynthesized ZnO NPs exhibited potent antioxidant activities, effective α-amylase inhibition, moderate urease inhibition (56%), high lipase-inhibition (71%) activities, moderate cytotoxic potential, and significant antibacterial activity. Gene expression of caspase in HepG2 cells was enhanced along with elevated production of ROS/RNS, while membrane integrity was disturbed upon the exposure of NPs. Overall results indicated that bio-assisted ZnO NPs exhibit excellent biological potential and could be exploited for future biomedical applications. particularly in antimicrobial and cancer therapeutics. Moreover, this is the first comprehensive study on Lepidium sativum-mediated synthesis of ZnO nanoparticles and evaluation of their biological activities.
    Keywords:  ZnO NPs; anticancer activity; antioxidant activity; bio-assisted synthesis; cytotoxicity; phytochemicals
    DOI:  https://doi.org/10.3390/biom12060855
  88. Molecules. 2022 Jun 16. pii: 3855. [Epub ahead of print]27(12):
    In Vitro Evaluation of Curcumin Encapsulation in Gum Arabic Dispersions under Different Environments.
    Dwi Hudiyanti, Muhammad Fuad Al Khafiz, Khairul Anam, Parsaoran Siahaan, Sherllyn Meida Christa.
      Biopolymers, especially polysaccharides (e.g., gum Arabic), are widely applied as drug carriers in drug delivery systems due to their advantages. Curcumin, with high antioxidant ability but limited solubility and bioavailability in the body, can be encapsulated in gum Arabic to improve its solubility and bioavailability. When curcumin is encapsulated in gum Arabic, it is essential to understand how it works in various conditions. As a result, in Simulated Intestinal Fluid and Simulated Gastric Fluid conditions, we investigated the potential of gum Arabic as the drug carrier of curcumin. This study was conducted by varying the gum Arabic concentrations, i.e., 5, 10, 15, 20, 30, and 40%, to encapsulate 0.1 mg/mL of curcumin. Under both conditions, the greater the gum Arabic concentration, the greater the encapsulation efficiency and antioxidant activity of curcumin, but the worse the gum Arabic loading capacity. To achieve excellent encapsulation efficiency, loading capacity, and antioxidant activity, the data advises that 10% is the best feasible gum Arabic concentration. Regarding the antioxidant activity of curcumin, the findings imply that a high concentration of gum Arabic was effective, and the Simulated Intestinal Fluid brought an excellent surrounding compared to the Simulated Gastric Fluid solution. Moreover, the gum Arabic releases curcumin faster in the Simulated Gastric Fluid condition.
    Keywords:  Simulated Gastric Fluid; Simulated Intestinal Fluid; antioxidant activity; curcumin; drug delivery system; encapsulation efficiency; gum Arabic; loading capacity; release rate
    DOI:  https://doi.org/10.3390/molecules27123855
  89. Drug Des Devel Ther. 2022 ;16 1811-1825
    Evaluation of Different Surface Coating Agents for Selenium Nanoparticles: Enhanced Anti-Inflammatory Activity and Drug Loading Capacity.
    Aml I Mekkawy, M Fathy, Hebatallah B Mohamed.
       Background: Inflammation is the keystone in the disease's pathological process in response to any damaging stimuli. Therefore, any agent that inhibits the inflammatory response is under focus, either a drug or a bioactive compound. Selenium nanoparticles have drawn attention in various biomedical applications, including the anti-inflammatory activity.
    Purpose: In the current study, we aimed to evaluate the capacity of different surface coating materials (soybean lecithin, PEG 6000, and β-cyclodextrin) to enhance the anti-inflammatory activity of the synthesized selenium nanoparticles (SeNPs). The capability of the coated SeNPs to adsorb indomethacin (IND) on their surfaces compared to the uncoated SeNPs was also evaluated.
    Methods: SeNPs were synthesized, coated with different materials, and characterized in vitro using X-ray diffraction, UV-Vis spectrophotometer, FTIR, SEM, TEM, and particle size and zeta potential measurements. The in vivo anti-inflammatory activity of the uncoated/coated SeNPs loaded into hydrogel was evaluated using a carrageenan-induced paw edema rat model. The effect of SeNPs surface coatings was further evaluated for IND loading capacity.
    Results: Our findings proved the superior anti-inflammatory activity of all coated SeNPs compared to the uncoated SeNPs, especially with β-cyclodextrin surface coating. Regarding the IND loading capacity of the prepared uncoated/coated SeNPs, the amount of drug loaded was 0.12, 1.12, 0.3, and 0.14 µg IND/µg SeNPs for the uncoated, lecithin-, PEG- and β-CD-coated SeNPs, respectively.
    Conclusion: Surface functionalization of SeNPs can provide a synergistic therapeutic activity. Our results are promising for further investigation of the in vivo anti-inflammatory synergistic activity of the IND-loaded surface-coated SeNPs.
    Keywords:  carrageenan; indomethacin; polyethylene glycol; selenium nanoparticles; soybean lecithin; synergistic activity; β-cyclodextrin
    DOI:  https://doi.org/10.2147/DDDT.S360344
  90. Trends Cancer. 2022 Jun 22. pii: S2405-8033(22)00128-5. [Epub ahead of print]
    Radiotherapy-induced metabolic hallmarks in the tumor microenvironment.
    Anjali Mittal, Minal Nenwani, Itisam Sarangi, Abhinav Achreja, Theodore S Lawrence, Deepak Nagrath.
      Radiation is frequently administered for cancer treatment, but resistance or remission remains common. Cancer cells alter their metabolism after radiotherapy to reduce its cytotoxic effects. The influence of altered cancer metabolism extends to the tumor microenvironment (TME), where components of the TME exchange metabolites to support tumor growth. Combining radiotherapy with metabolic targets in the TME can improve therapy response. We review the metabolic rewiring of cancer cells following radiotherapy and put these observations in the context of the TME to describe the metabolic hallmarks of radiotherapy in the TME.
    Keywords:  DNA repair; fatty acid metabolism; metabolic reprogramming; radioresistance; redox metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2022.05.005
  91. ACS Appl Mater Interfaces. 2022 Jun 21.
    Liposomal Co-delivery of PD-L1 siRNA/Anemoside B4 for Enhanced Combinational Immunotherapeutic Effect.
    Xiang Li, Xiong Zhou, Jun Liu, Jing Zhang, Yulin Feng, Fang Wang, Yao He, Anping Wan, Nina Filipczak, Satya Siva Kishan Yalamarty, Yi Jin, Vladimir P Torchilin.
      Combination therapy has gained a lot of attention thanks to its superior activity against cancer. In the present study, we report a cRGD-targeted liposomal preparation for co-delivery of programmed cell death ligand 1 (PD-L1) small interfering RNA (siRNA) and anemoside B4 (AB4)─AB4/siP-c-L─and evaluate its anticancer efficiency in mouse models of LLC and 4T1 tumors. AB4/siP-c-L showed a particle size of (180.7 ± 7.3) nm and a ζ-potential of (32.8 ± 1.5) mV, with high drug encapsulation, pH-sensitive release properties, and good stability in serum. AB4/siP-c-L demonstrated prolonged blood circulation and increased tumor accumulation. Elevated cellular uptake was dependent on the targeting ligand cRGD. This combination induced significant tumor inhibition in LLC xenograft tumor-bearing mice by downregulating PD-L1 protein expression and modulating the immunosuppressive microenvironment. Liposomes favored the antitumor T-cell response with long-term memory, without obvious toxicity. A similar tumor growth inhibition was also demonstrated in the 4T1 tumor model. In summary, our results indicate that cRGD-modified and AB4- and PD-L1 siRNA-coloaded liposomes have potential as an antitumor preparation, and this approach may lay a foundation for the development of a new targeted drug delivery system.
    Keywords:  anemoside B4; antitumor efficacy; immunosuppressive microenvironment; programmed cell death ligand 1; targeted liposomes
    DOI:  https://doi.org/10.1021/acsami.2c01123
  92. J Biotechnol. 2022 Jun 17. pii: S0168-1656(22)00143-2. [Epub ahead of print]
    A review on anticancer, antibacterial and photo catalytic activity of various nanoparticles synthesized by probiotics.
    Mohadese Abdoli, Ghobad Mohammadi, Kamran Mansouri, Salar Khaledian, Mojtaba Taran, Fleming Martinez.
      Probiotics are beneficial bacteria that have a significant effect on host health and they are widely used in preventing and treating diseases. Nowadays probiotics are present in food, drug and several commercial complement products. In recent years the use of probiotics in the nanotechnology area, especially in nanoparticle synthesis, has significantly been increased. In this review, after some introduction about probiotic and their advantages, all the nanoparticles produced by probiotics are reviewed and discussed. Furthermore, biosynthetic mechanisms of nanoparticles and its applications in cancer therapy, antibacterial and photo catalytic activities, are also discussed.
    Keywords:  cancer therapy; metal nanoparticles; nanotechnology; probiotic
    DOI:  https://doi.org/10.1016/j.jbiotec.2022.06.005
  93. ChemMedChem. 2022 Jun 21.
    Functional Nanomaterials in Biomedicine: Current Uses and Potential Applications.
    Ana Maria Diez-Pascual, Abbas Rahdar.
      Nanomaterials, that is, materials made up of individual units between 1 and 100 nanometers, have lately involved a lot of attention since they offer a lot of potential in many fields, including pharmacy and biomedicine, owed to their exceptional physicochemical properties arising from their high surface area and nanoscale size. Smart engineering of nanostructures through appropriate surface or bulk functionalization endows them with multifunctional capabilities, opening up new possibilities in the biomedical field such as biosensing, drug delivery, imaging, medical implants, cancer treatment and tissue engineering. This article highlights up-to-date research in nanomaterials functionalization for biomedical applications. A summary of the different types of nanomaterials and the surface functionalization strategies is provided. Besides, the use of nanomaterials in diagnostic imaging, drug/gene delivery, regenerative medicine, cancer treatment and medical implants is reviewed. Finally, conclusions and future perspectives are provided.
    Keywords:  Biomedical applications; cancer treatment; drug delivery; functional nanomaterials; tissue engineering
    DOI:  https://doi.org/10.1002/cmdc.202200142
  94. Front Chem. 2022 ;10 889083
    Chemical Conjugation in Drug Delivery Systems.
    Alexis Eras, Danna Castillo, Margarita Suárez, Nelson Santiago Vispo, Fernando Albericio, Hortensia Rodriguez.
      Cancer is one of the diseases with the highest mortality rate. Treatments to mitigate cancer are usually so intense and invasive that they weaken the patient to cure as dangerous as the own disease. From some time ago until today, to reduce resistance generated by the constant administration of the drug and improve its pharmacokinetics, scientists have been developing drug delivery system (DDS) technology. DDS platforms aim to maximize the drugs' effectiveness by directing them to reach the affected area by the disease and, therefore, reduce the potential side effects. Erythrocytes, antibodies, and nanoparticles have been used as carriers. Eleven antibody-drug conjugates (ADCs) involving covalent linkage has been commercialized as a promising cancer treatment in the last years. This review describes the general features and applications of DDS focused on the covalent conjugation system that binds the antibody carrier to the cytotoxic drug.
    Keywords:  biomolecules; carriers; covalent bioconjugation; drug delivery systems; linkers
    DOI:  https://doi.org/10.3389/fchem.2022.889083
  95. Antioxidants (Basel). 2022 May 25. pii: 1049. [Epub ahead of print]11(6):
    Biological Evaluation of Avocado Residues as a Potential Source of Bioactive Compounds.
    Alejandro Rojas-García, Eduardo Fuentes, María de la Luz Cádiz-Gurrea, Lyanne Rodriguez, María Del Carmen Villegas-Aguilar, Iván Palomo, David Arráez-Román, Antonio Segura-Carretero.
      Avocado seed and peel are the main by-products from avocado industrialisation, and account for nearly 30% of fruit weight. Although they are usually discarded, their high phenolic content has been deeply associated with several nutritional and functional benefits. Thus, for a comprehensive analytical evaluation of both semi-industrial extracts, various steps have been developed: tentative characterisation and quantification of the phenolic composition using HPLC-ESI-qTOF-MS, determination of TPC and antioxidant activity by Folin-Ciocalteu, FRAP, TEAC and ORAC methods, evaluation of scavenging capacity against different ROS and measurement of the enzymatic inhibitory potential against potentially harmful enzymes. Finally, their bioactive potential was tested in a human platelet model where antiaggregatory activity was measured. Hence, 48 different compounds were identified, where flavonoids and procyanidins were the most representative groups. The higher TPC was found in avocado peel extract (190 ± 3 mg/g), which showed more antioxidant power and more capacity to decrease ROS generation than seed extract (60 ± 2 mg/g). In addition, both extracts showed enzymatic inhibition, especially against hyaluronidase, xanthine oxidase and acetylcholinesterase. Lastly, avocado peel was proven to inhibit platelet aggregation with significant results at 1, 0.75 and 0.5 mg/mL, where the extract showed reducing effects on agonists' expression such as p-selectin or GPIIb/IIIa complex. These results demonstrate that both semi-industrial extracts-above all, avocado peel-have an interesting potential to be exploited as a natural by-product with antioxidant properties with multiple applications for the prevention of different pathologies.
    Keywords:  HPLC-MS; avocado by-products; enzyme inhibition; phenolic compounds; platelet aggregation; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox11061049
  96. Polymers (Basel). 2022 Jun 16. pii: 2459. [Epub ahead of print]14(12):
    Boosting the Anticancer Activity of Sunitinib Malate in Breast Cancer through Lipid Polymer Hybrid Nanoparticles Approach.
    Mohammed Muqtader Ahmed, Md Khalid Anwer, Farhat Fatima, Mohammed F Aldawsari, Ahmed Alalaiwe, Amer S Alali, Abdulrahman I Alharthi, Mohd Abul Kalam.
      In the current study, lipid-polymer hybrid nanoparticles (LPHNPs) fabricated with lipoid-90H and chitosan, sunitinib malate (SM), an anticancer drug was loaded using lecithin as a stabilizer by employing emulsion solvent evaporation technique. Four formulations (SLPN1-SLPN4) were developed by varying the concentration of chitosan polymer. Based on particle characterization, SLPN4 was optimized with size (439 ± 5.8 nm), PDI (0.269), ZP (+34 ± 5.3 mV), and EE (83.03 ± 4.9%). Further, the optimized formulation was characterized by FTIR, DSC, XRD, SEM, and in vitro release studies. In-vitro release of the drug from SPN4 was found to be 84.11 ± 2.54% as compared with pure drug SM 24.13 ± 2.67%; in 48 h, release kinetics followed the Korsmeyer-Peppas model with Fickian release mechanism. The SLPN4 exhibited a potent cytotoxicity against MCF-7 breast cancer, as evident by caspase 3, 9, and p53 activities. According to the findings, SM-loaded LPHNPs might be a promising therapy option for breast cancer.
    Keywords:  breast cancer; caspase; chitosan; lipoid 90H; nanoparticles; sunitinib
    DOI:  https://doi.org/10.3390/polym14122459
  97. Adv Sci (Weinh). 2022 Jun 25. e2200681
    Tumor-Targeted Injectable Double-Network Hydrogel for Prevention of Breast Cancer Recurrence and Wound Infection via Synergistic Photothermal and Brachytherapy.
    Yuanhao Wu, Yuan Yao, Jiamin Zhang, Han Gui, Jinjian Liu, Jianfeng Liu.
      The high locoregional recurrence rate and potential wound infection in breast cancer after surgery pose enormous risks to patient survival. In this study, a polyethylene glycol acrylate (PEGDA)-alginate double-network nanocomposite hydrogel (GPA) embedded with 125 I-labeled RGDY peptide-modified gold nanorods (125 I-GNR-RGDY) is fabricated. The double-network hydrogel is formed by injection of GPA precursor solutions into the cavity of resected cancerous breasts of mice where gelation occurred rapidly. The enhanced temperature-induced PEGDA polymerization driven by near-infrared light irradiation, and then, the second polymer network is crosslinked between alginate and endogenous Ca2+ around the tumor. The double-network hydrogel possesses a dense polymer network and tightly fixes 125 I-GNR-RGDY, which exhibit superior persistent photothermal and radioactive effects. Hyperthermia induced by photothermal therapy can inhibit self-repair of damaged DNA and promote blood circulation to improve the hypoxic microenvironment, which can synergistically enhance the therapeutic efficacy of brachytherapy and simultaneously eliminate pathogenic bacteria. Notably, this nanocomposite hydrogel facilitates antibacterial activity to prevent potential wound infection and is tracked by single-photon emission computerized tomography imaging owing to isotope labeling of loaded 125 I-GNR-RGDY. The combination of photothermal therapy and brachytherapy has enabled the possibility of proposing a novel postoperative adjuvant strategy for preventing tumor recurrence and wound infection.
    Keywords:  brachytherapy; breast cancer; double-network hydrogel; photothermal therapy; wound infection
    DOI:  https://doi.org/10.1002/advs.202200681
  98. Expert Opin Drug Deliv. 2022 Jun 24.
    Phage in cancer treatment - Biology of therapeutic phage and screening of tumor targeting peptide.
    Arun Chandra Manivannan, Ranjithkumar Dhandapani, Palanivel Velmurugan, Sathiamoorthi Thangavelu, Ragul Paramasivam, Latha Ragunathan, Muthupandian Saravanan.
       INTRODUCTION: There is a constant drive to improve disease treatments. Much effort has been directed at identifying less immunogenic anti-cancer agents that produce fewer and less severe side effects. For more than a decade, bacteriophages have been discussed as an effective treatment for cancer with an exact mode of delivery.
    AREAS COVERED: We review how bacteriophages are used in cancer treatment, the underlying therapeutic mechanisms, and the tumour attacking peptide screening process. The filamentous bacteriophages are an effective vehicle for delivering displayed peptides toward the tumour target. The peptide must be expressed at the appropriate coat protein, and the peptide must be effective enough to disrupt the complex cancer matrix. The present review also sheds light on the dynamic use of phage in cancer treatment, from detection and diagnostics to treatment.
    EXPERT OPINION: Phage has a versatile role as a diagnostic and therapeutic tool. By acting as an appropriate recombinant drug, this phage has every potential to replace existing laborious, high capital investing therapies that may at many times result in failure or drastic side effects. One of the most significant challenges would be identifying tumour homing peptides. Although a few have been discovered, the most effective ones are yet to be determined. This therapeutic method plays a significant role in tumour therapy with high accuracy and efficiency, irrespective of the target location.
    Keywords:  Anti-cancer agents; Bacteriophage; Cancer treatment; Phage therapy
    DOI:  https://doi.org/10.1080/17425247.2022.2094363
  99. J Control Release. 2022 Jun 19. pii: S0168-3659(22)00364-9. [Epub ahead of print]
    Stem cell membrane, stem cell-derived exosomes and hybrid stem cell camouflaged nanoparticles: A promising biomimetic nanoplatforms for cancer theranostics.
    Neda Khosravi, Elham Pishavar, Behzad Baradaran, Fatemeh Oroojalian, Ahad Mokhtarzadeh.
      Nanomedicine research has advanced dramatically in recent decades. Nonetheless, traditional nanomedicine faces significant obstacles such as the low concentration of the drug at target sites and accelerated removal of the drug from blood circulation. Various techniques of nanotechnology, including cell membrane coating, have been developed to address these challenges and to improve targeted distribution and redcue cell membrane-mediated immunogenicity. Recently, stem cell (SC) membranes, owing to their immunosuppressive and regenerative properties, have grabbed attention as attractive therapeutic carriers for targeting specific tissues or organs. Bioengineering strategies that combine synthetic nanoparticles (NPs) with SC membranes, because of their homing potential and tumor tropism, have recently received a lot of publicity. Several laboratory experiments and clinical trials have indicated that the benefits of SC-based technologies are mostly related to the effects of SC-derived exosomes (SC-Exos). Exosomes are known as nano-sized extracellular vehicles (EVs) that deliver particular bioactive molecules for cell-to-cell communication. In this regard, SC-derived exosome membranes have recently been employed to improve the therapeutic capability of engineered drug delivery vehicles. Most recently, for further enhancing NPs' functionality, a new coating approach has been offered that combines membranes from two separate cells. These hybrid membrane delivery vehicles have paved the way for the development of biocompatible, high-efficiency, biomimetic NPs with varying hybrid capabilities that can overcome the drawbacks of present NP-based treatment techniques. This review explores stem cell membranes, SC-Exos, and hybrid SC-camouflaged NPs preparation methods and their importance in cancer therapy.
    Keywords:  Drug delivery; Exosomes; Hybrid cell membrane; Nanoparticles; Stem cell membrane
    DOI:  https://doi.org/10.1016/j.jconrel.2022.06.026
  100. Sci Rep. 2022 Jun 21. 12(1): 10423
    CD73 downregulation by EGFR-targeted liposomal CD73 siRNA potentiates antitumor effect of liposomal doxorubicin in 4T1 tumor-bearing mice.
    Anvar Soleimani, Farshad Mirzavi, Sara Nikoofal-Sahlabadi, Amin Reza Nikpoor, Bita Taghizadeh, Mehdi Barati, Mohammad Soukhtanloo, Mahmoud Reza Jaafari.
      Blocking CD73 ectonucleotidase has been proposed as a potential therapeutic approach for cancer treatment. The present study aimed to investigate the antitumor effect of a novel EGFR-Targeted liposomal CD73 siRNA formulation in combination therapy with liposomal doxorubicin in the 4T1 mouse model. CD73 siRNA was encapsulated into nanoliposomes by the ethanol injection method. After preparation, characterization, morphology, and stability evaluation of formulations, the toxicity was measured by MTT assay. Uptake assay and efficiency of the liposomal formulations were investigated on the 4T1 cell line. The liposomal formulation containing CD73 siRNA was targeted with GE11 peptide for in vivo evaluations. Following biodistribution analysis, the antitumor activity of prepared formulations in combination with liposomal doxorubicin was studied in mice bearing 4T1 metastatic breast cancer cells. Finally, the induction of immune response of formulations in concomitant treatment with liposomal doxorubicin was evaluated in the tumor microenvironment of a mouse model of breast cancer. The size of prepared liposomal formulations at N/P = 16 for the liposomal CD73 siRNA and GE11-liposomal CD73 siRNA groups were 89 nm ± 4.4 and 95 nm ± 6.6, respectively. The nanoparticle's PDI was less than 0.3 and their surface charge was below 10 mV. The results demonstrated that N/P = 16 yielded the best encapsulation efficiency which was 94% ± 3.3. AFM results showed that the liposomes were spherical in shape and were less than 100 nm in size. The results of the MTT assay showed significant toxicity of the liposomes containing CD73 siRNA during the 48-h cell culture. Real-time PCR and flow cytometry results showed that liposomes containing CD73 siRNA could effectively downregulate CD73 expression. Liposomal formulations were able to significantly downregulate CD73 gene expression, in vivo. However, CD73 downregulation efficiency was significantly higher for the targeted form compared to the non-targeted formulation (P value < 0.01). The combination showed maximum tumor growth delay with remarkable survival improvement compared to the control group. Studying the immune responses in the treatment groups which received doxorubicin, showed decreased number of lymphocytes in the tumor environment. However, this decrease was lower in the combination therapy group. Finally, our results clearly showed that CD73 downregulation increases the activity of CD8+ lymphocytes (IFN-ℽ production) and also significantly decreases the Foxp3 in the CD25+ lymphocytes compared to the control group. GE11-Lipo CD73 siRNA formulation can efficiently knockdown CD73 ectonucleotidase. Also, the efficacy of liposomal doxorubicin is significantly enhanced via the downregulation of CD73 ectonucleotidase.
    DOI:  https://doi.org/10.1038/s41598-022-14392-7
  101. Gels. 2022 Jun 16. pii: 385. [Epub ahead of print]8(6):
    Design and Development of Neomycin Sulfate Gel Loaded with Solid Lipid Nanoparticles for Buccal Mucosal Wound Healing.
    Khaled M Hosny, N Raghavendra Naveen, Mallesh Kurakula, Amal M Sindi, Fahad Y Sabei, Adel Al Fatease, Abdulmajeed M Jali, Waleed S Alharbi, Rayan Y Mushtaq, Majed Felemban, Hossam H Tayeb, Eman Alfayez, Waleed Y Rizg.
      Drug administration to the wound site is a potential method for wound healing. The drug retention duration should be extended, and drug permeability through the buccal mucosal layer should be regulated. Oral wounds can be caused by inflammation, ulcers, trauma, or pathological lesions; if these wounds are not treated properly, they can lead to pain, infection, and subsequent undesirable scarring. This study aimed to develop Kolliphor-407 P-based gel containing neomycin sulfate (NES) loaded in solid lipid nanoparticles (SLNs) and enhance the antimicrobial activity. By considering lipid concentrations and achieving the lowest particle size (Y1) and maximum entrapment (EE-Y2) effectiveness, the formulation of NES-SLN was optimized using the Box-Behnken design. For the selected responses, 17 runs were formulated (as anticipated by the Design-Expert software) and evaluated accordingly. The optimized formulation could achieve a particle size of 196.25 and EE of 89.27% and was further utilized to prepare the gel formulation. The NES-SLN-G formula was discovered to have a smooth, homogeneous structure and good mechanical and rheological properties. After 24 h of treatment, NES-SLN-G showed a regulated in vitro drug release pattern, excellent ex vivo permeability, and increased in vitro antibacterial activity. These findings indicate the potential application of NES-SLN-loaded gels as a promising formulation for buccal mucosal wound healing.
    Keywords:  gels; health care; neomycin sulfate; optimization; solid lipid nanoparticles; sustainability of natural resources; wound healing
    DOI:  https://doi.org/10.3390/gels8060385
  102. Int J Mol Sci. 2022 Jun 09. pii: 6458. [Epub ahead of print]23(12):
    Antagonistic Pharmacological Interaction between Sirtuin Inhibitor Cambinol and Paclitaxel in Triple-Negative Breast Cancer Cell Lines: An Isobolographic Analysis.
    Anna Wawruszak, Jarogniew Luszczki, Estera Okon, Arkadiusz Czerwonka, Andrzej Stepulak.
      Breast cancer (BC) is a heterogeneous disease with different intrinsic subtypes. The most aggressive subtype of BC-triple-negative breast cancer (TNBC) is characterized by high heterogeneity and metastasis rate, poor prognosis and lack of therapeutic targets due to the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Targeted therapies have been approved for many other cancers and even other subtypes of BC, but treatment options for TNBC are still mainly limited to chemotherapy. Therefore, new, more effective treatment regimens are needed. Combined chemotherapy with two or more active agents is considered a promising anti-neoplasm tool in order to achieve better therapeutic response and reduce therapy-related adverse effects. The study demonstrated an antagonistic effect commonly used in TNBC therapy cytostatic drug-paclitaxel (PAX) and sirtuin inhibitor: cambinol (CAM) in BT-549, MDA-MB-468 and HCC1937 TNBC cell lines. The type of pharmacological interaction was determined by a precise and rigorous pharmacodynamic method-isobolographic analysis. The cytotoxic and anti-proliferative effects of CAM used alone or combined with PAX were determined utilizing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-bromo-2'-deoxyuridine (BrdU) assays, respectively. Induction of apoptosis in TNBC cell lines after PAX and CAM treatment applied individually or in combination was determined by flow cytometry (FACS) as a number of cells with active caspase-3. It has been observed that both agents used separately inhibit cell proliferation and induce apoptosis; however, applying them in combination ameliorated antiproliferative and pro-apoptotic effects in all analyzed TNBC cell lines. Our results demonstrate that CAM and PAX used in combination act antagonistically, limiting anti-cancer efficacy and showing the importance of preclinical testing.
    Keywords:  anti-cancer drugs; breast cancer (BC); cambinol (CAM); combined therapy; histone deacetylase inhibitor (HDI); isobolography; paclitaxel (PAX); sirtuin (SIRT); sirtuin inhibitor (SIRTi)
    DOI:  https://doi.org/10.3390/ijms23126458
  103. Adv Mater. 2022 Jun 20. e2201054
    Extracellular Vesicle-Based Drug Delivery Systems for Enhanced Anti-Tumor Therapies through Modulating Cancer-Immunity Cycle.
    Tuying Yong, Zhaohan Wei, Lu Gan, Xiangliang Yang.
      Although immunotherapy that harnesses the activity of the immune system against tumors has made great progress, the treatment efficacy remains limited in most cancers. Current anticancer immunotherapy is primarily based on T cell-mediated cellular immunity, which highly relies on the efficiency of triggering cancer-immunity cycle, namely tumor antigen release, antigen presentation by antigen presenting cells, T cell activation, recruitment and infiltration of T cells into tumors, and recognition and killing of tumor cells by T cells. Unfortunately, these immunotherapies are restricted by inefficient drug delivery and acting on only a single step of the cancer-immunity cycle. Due to the high biocompatibility, low immunogenicity, intrinsic cell targeting and easy chemical and genetic manipulation, extracellular vesicle-based drug delivery systems have been widely used to amplify the anticancer immune responses by serving as an integrated platform for multiple drugs or therapeutic strategies to synergistically activate several steps of cancer-immunity cycle. This review summarizes the various mechanisms related to affecting the cancer-immunity cycle disorders. Meanwhile, the preparation and application of extracellular vesicle-based drug delivery systems in modulating cancer-immunity cycle are introduced, especially in the improvement of T cell recruitment and infiltration into tumors. Finally, we briefly discuss the opportunities and challenges of extracellular vesicle-based drug delivery systems in translational clinical applications. This article is protected by copyright. All rights reserved.
    Keywords:  Anti-tumor immunotherapy; Cancer-immunity cycle; Exosomes; Extracellular vesicles; Microparticles; T cell activation and infiltration; Tumor targeting delivery
    DOI:  https://doi.org/10.1002/adma.202201054
  104. Cancers (Basel). 2022 Jun 10. pii: 2864. [Epub ahead of print]14(12):
    Targeting Breast Cancer-Derived Stem Cells by Dietary Phytochemicals: A Strategy for Cancer Prevention and Treatment.
    Kumari Sunita Prajapati, Sanjay Gupta, Shashank Kumar.
      Breast cancer is heterogeneous disease with variable prognosis and therapeutic response. Approximately, 70% of diagnosed breast cancer represents the luminal A subtype. This subpopulation has a fair prognosis with a lower rate of relapse than the other clinical subtypes. Acquisition of stemness in luminal A subtype modifies the phenotype plasticity to accomplish increased aggressiveness and therapeutic resistance. Therefore, targeting luminal A-derived breast cancer stem cells (BCSCs) could be a promising strategy for its prevention and treatment. Extensive studies reveal that dietary phytochemicals have the potential to target BCSCs by modulating the molecular and signal transduction pathways. Dietary phytochemicals alone or in combination with standard therapeutic modalities exert higher efficacy in targeting BCSCs through changes in stemness, self-renewal properties and hypoxia-related factors. These combinations offer achieving higher radio- and chemo- sensitization through alteration in the key signaling pathways such as AMPK, STAT3, NF-ĸB, Hedgehog, PI3K/Akt/mTOR, Notch, GSK3β, and Wnt related to cancer stemness and drug resistance. In this review, we highlight the concept of targeting luminal A-derived BCSCs with dietary phytochemicals by summarizing the pathways and underlying mechanism(s) involved during therapeutic resistance.
    Keywords:  breast cancer stem cells; cancer prevention; dietary phytochemical; luminal A subtype; signaling pathway; therapeutic resistance
    DOI:  https://doi.org/10.3390/cancers14122864
  105. Cell Death Dis. 2022 Jun 20. 13(6): 557
    Co-loaded lapatinib/PAB by ferritin nanoparticles eliminated ECM-detached cluster cells via modulating EGFR in triple-negative breast cancer.
    Xinghan Wu, Huan Sheng, Liping Zhao, Mingxia Jiang, Han Lou, Yue Miao, Ni Cheng, Weifen Zhang, Dejun Ding, Wentong Li.
      Cancer stem cell (CSC) cluster of triple-negative breast cancer (TNBC) is suggested to be responsible for therapy resistance, metastatic process and cancer recurrence, yet the sensitivity of CSC clusters of TNBC to ferroptosis remains elusive in a great measure. Current research revealed that epidermal growth factor receptor (EGFR) reinforced CD44-mediated TNBC cell clustering, whether blockade of EGFR has synergistic effects on erastin-induced tumor inhibition of CSC clusters is still poorly understood. Here, we found that fraction of CD24lowCD44high cells and size of tumor spheres clearly decreased following EGFR inhibition in TNBC cells. Inhibition of EGFR promoted expression of LC3B-II via YAP/mTOR signaling pathway, indicating that EGFR-mediated autophagy which contributed to ferroptosis. In order to further verify the protective effects of EGFR on ferroptosis induced by small molecules in TNBC cells, pseudolaric acid B (PAB) which led to ferroptosis of malignant cells was selected. In our experiment, lapatinib and PAB cotreatment inhibited TNBC cells viability and restrained formation of tumor spheres, accompanied with a high level of intracellular ROS. To target delivery lapatinib and PAB to TNBC cells, lapatinib/PAB@Ferritin (L/P@Ferritin) nanoparticles were prepared; results of in vitro and in vivo showed a higher tumor suppression efficiency of L/P@Ferritin, highlighting that it might provide a new perspective for treatment of CSC clusters of TNBC.
    DOI:  https://doi.org/10.1038/s41419-022-05007-0
  106. J Immunol Res. 2022 ;2022 3119375
    Tumor Microenvironment: Lactic Acid Promotes Tumor Development.
    Yuting Gao, Hao Zhou, Gege Liu, Junlu Wu, Yi Yuan, Anquan Shang.
      Lactic acid is a "metabolic waste" product of glycolysis that is produced in the body. However, the role of lactic acid in the development of human malignancies has gained increasing interest lately as a multifunctional small molecule chemical. There is evidence that tumor cells may create a large amount of lactic acid through glycolysis even when they have abundant oxygen. Tumor tissues have a higher quantity of lactic acid than normal tissues. Lactic acid is required for tumor development. Lactate is an immunomodulatory chemical that affects both innate and adaptive immune cells' effector functions. In immune cells, the lactate signaling pathway may potentially serve as a link between metabolism and immunity. Lactate homeostasis is significantly disrupted in the TME. Lactate accumulation results in acidosis, angiogenesis, immunosuppression, and tumor cell proliferation and survival, all of which are deleterious to health. Thus, augmenting anticancer immune responses by lactate metabolism inhibition may modify lactate levels in the tumor microenvironment. This review will evaluate the role of lactic acid in tumor formation, metastasis, prognosis, treatment, and histone modification. Our findings will be of considerable interest to readers, particularly those engaged in the therapeutic treatment of cancer patients. Treatments targeting the inhibition of lactate synthesis and blocking the source of lactate have emerged as a potential new therapeutic option for oncology patients. Additionally, lactic acid levels in the plasma may serve as biomarkers for disease stage and may be beneficial for evaluating therapy effectiveness in individuals with tumors.
    DOI:  https://doi.org/10.1155/2022/3119375
  107. Pharmacol Res. 2022 Jun 19. pii: S1043-6618(22)00264-X. [Epub ahead of print] 106319
    Flexion of Nrf2 by tea phytochemicals: A review on the chemopreventive and chemotherapeutic implications.
    Suchisnigdha Datta, Sukanya Ghosh, Anupam Bishayee, Dona Sinha.
      Nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2), the redox-sensitive transcription factor, plays a key role in stress-defense and detoxification. Nrf2 is tightly controlled by its negative regulator cum sensor Kelch-[ECH]-associated protein 1 (Keap1). Nrf2 is well known for its dual nature owing to its cancer preventive and cancer promoting abilities. Modulation of this biphasic nature of Nrf2 signaling by phytochemicals may be a potential cancer preventive and anticancer therapeutic strategy. Phytocompounds may either act as Nrf2-activator or Nrf2-inhibitor depending on their differential concentration and varied cellular environment. Tea is not just the most popular global beverage with innumerable health-benefits but has well-established chemopreventive and chemotherapeutic effects. Various types of tea infusions contain a wide range of bioactive compounds, such as polyphenolic catechins and flavonols, which are endowed with potent antioxidant properties. Despite of their rapid biotransformation and poor bioavailability, regular tea consumption is risk-reductive for several cancer forms. Tea catechins show their dual Nrf2-modulatory effect by directly acting on Nrf2-Keap1 or their upstream regulators and downstream effectors in a highly case-specific manner. In this review, we have tried to present a comprehensive evaluation of the Nrf2-mediated chemopreventive and chemotherapeutic applications of tea in various preclinical cancer models, the Nrf2-modulatory mechanisms, and the limitations which need to be addressed in future research.
    Keywords:  EGCG; Nrf2-Keap1 signaling; chemoprevention; chemotherapy; tea polyphenols; theaflavin
    DOI:  https://doi.org/10.1016/j.phrs.2022.106319
  108. J Drug Target. 2022 Jun 20. 1-34
    Lymphatic targeting for therapeutic application using nanoparticulate systems.
    Nidhi Singh, Mayank Handa, Vanshikha Singh, Prashant Kesharwani, Rahul Shukla.
      The lymphatic system has grasped attention of researchers to a greater extent. The conventional methods of lymphatic delivery are now being modified to include nanotechnology to enhance the targeting of the drug at the specific pathological site. Scientists have worked successfully on different drug loaded nanocarriers that are modulated for the lymphatic system targeting for the treatment of various fatal diseases. Huge strides have been made in methods of delivery of these drugs either individually or in combination along with nanoparticles, therapeutic genes, and vaccines. However, the products introduced for commercial use are almost near nil. Altogether, there are challenges that need to be resolved and studies that are meant to be done for further improvements. The current review focuses on the understanding and pathophysiology of the lymphatic system and changes that occur during disease, drug characteristics, and physicochemical parameters that influence the lymphatic uptake of drugs and different nanocarriers. We further highlight different potential results obtained over the years with nanocarriers and other delivery methods to effectively target the lymphatic system for their therapeutic application. The challenges and drawbacks governing the lack of products available clinically have also been discussed.
    Keywords:  Lymphatic targeted delivery; anticancer; antimicrobials; drug delivery; immunotherapy; nanocarriers; vaccines
    DOI:  https://doi.org/10.1080/1061186X.2022.2092741
  109. Pharmaceutics. 2022 Jun 16. pii: 1283. [Epub ahead of print]14(6):
    A Historical Review of Brain Drug Delivery.
    William M Pardridge.
      The history of brain drug delivery is reviewed beginning with the first demonstration, in 1914, that a drug for syphilis, salvarsan, did not enter the brain, due to the presence of a blood-brain barrier (BBB). Owing to restricted transport across the BBB, FDA-approved drugs for the CNS have been generally limited to lipid-soluble small molecules. Drugs that do not cross the BBB can be re-engineered for transport on endogenous BBB carrier-mediated transport and receptor-mediated transport systems, which were identified during the 1970s-1980s. By the 1990s, a multitude of brain drug delivery technologies emerged, including trans-cranial delivery, CSF delivery, BBB disruption, lipid carriers, prodrugs, stem cells, exosomes, nanoparticles, gene therapy, and biologics. The advantages and limitations of each of these brain drug delivery technologies are critically reviewed.
    Keywords:  IgG fusion proteins; blood–brain barrier; carrier-mediated transport; endothelium; genetic engineering; liposomes; nanoparticles; receptor-mediated transport
    DOI:  https://doi.org/10.3390/pharmaceutics14061283
  110. Pharmaceutics. 2022 May 27. pii: 1138. [Epub ahead of print]14(6):
    Multifunctional PLA/Gelatin Bionanocomposites for Tailored Drug Delivery Systems.
    Carmen Moya-Lopez, Alberto Juan, Murillo Donizeti, Jesus Valcarcel, José A Vazquez, Eduardo Solano, David Chapron, Patrice Bourson, Ivan Bravo, Carlos Alonso-Moreno, Pilar Clemente-Casares, Carlos Gracia-Fernández, Alessandro Longo, Georges Salloum-Abou-Jaoude, Alberto Ocaña, Manuel M Piñeiro, Carolina Hermida-Merino, Daniel Hermida-Merino.
      A series of bionanocomposites composed of shark gelatin hydrogels and PLA nanoparticles featuring different nanostructures were designed to generate multifunctional drug delivery systems with tailored release rates required for personalized treatment approaches. The global conception of the systems was considered from the desired customization of the drug release while featuring the viscoelastic properties needed for their ease of storage and posterior local administration as well as their biocompatibility and cell growth capability for the successful administration at the biomolecular level. The hydrogel matrix offers the support to develop a direct thermal method to convert the typical kinetic trapped nanostructures afforded by the formulation method whilst avoiding the detrimental nanoparticle agglomeration that diminishes their therapeutic effect. The nanoparticles generated were successfully formulated with two different antitumoral compounds (doxorubicin and dasatinib) possessing different structures to prove the loading versatility of the drug delivery system. The bionanocomposites were characterized by several techniques (SEM, DLS, RAMAN, DSC, SAXS/WAXS and rheology) as well as their reversible sol-gel transition upon thermal treatment that occurs during the drug delivery system preparation and the thermal annealing step. In addition, the local applicability of the drug delivery system was assessed by the so-called "syringe test" to validate both the storage capability and its flow properties at simulated physiological conditions. Finally, the drug release profiles of the doxorubicin from both the PLA nanoparticles or the bionanocomposites were analyzed and correlated to the nanostructure of the drug delivery system.
    Keywords:  bionanocomposite; drug delivery; gelatin; hydrogel; nanoparticles; polylactide; stereocomplex
    DOI:  https://doi.org/10.3390/pharmaceutics14061138
  111. Molecules. 2022 Jun 07. pii: 3661. [Epub ahead of print]27(12):
    Signaling Pathways and Natural Compounds in Triple-Negative Breast Cancer Cell Line.
    Citra Dewi, Adryan Fristiohady, Riezki Amalia, Nur Kusaira Khairul Ikram, Sugeng Ibrahim, Muchtaridi Muchtaridi.
      Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, having a poor prognosis and rapid metastases. TNBC is characterized by the absence of estrogen, progesterone, and human epidermal growth receptor-2 (HER2) expressions and has a five-year survival rate. Compared to other breast cancer subtypes, TNBC patients only respond to conventional chemotherapies, and even then, with limited success. Shortages of chemotherapeutic medication can lead to resistance, pressured index therapy, non-selectivity, and severe adverse effects. Finding targeted treatments for TNBC is difficult owing to the various features of cancer. Hence, identifying the most effective molecular targets in TNBC pathogenesis is essential for predicting response to targeted therapies and preventing TNBC cell metastases. Nowadays, natural compounds have gained attention as TNBC treatments, and have offered new strategies for solving drug resistance. Here, we report a systematic review using the database from Pubmed, Science Direct, MDPI, BioScince, Springer, and Nature for articles screening from 2003 to 2022. This review analyzes relevant signaling pathways and the prospect of utilizing natural compounds as a therapeutic agent to improve TNBC treatments in the future.
    Keywords:  cell lines inhibitors; natural compounds; triple-negative breast cancer (TNBC)
    DOI:  https://doi.org/10.3390/molecules27123661
  112. J Control Release. 2022 Jun 20. pii: S0168-3659(22)00348-0. [Epub ahead of print]348 660-671
    A Fe(III)-porphyrin-oxaliplatin(IV) nanoplatform for enhanced ferroptosis and combined therapy.
    Xiaochun Hu, Ruihao Li, Wenjing Wu, Kang Fang, Zhounan Zhu, Yixuan Wang, Lulu Zhou, Mengyao Chen, Chunyan Dong, Shuo Shi.
      Since there are several limitations in cancer treatment for traditional chemotherapy, such as side effects, poor prognosis and drug resistance, developing new combined therapy is urgently needed. In this work, a biocompatible, simple and tumor microenvironment-responsive nanotheranostics (PCN-Oxpt/PEG) was built to favor the chemotherapy/ferroptosis/immunomodulation synergism in cancer. This nanotheranostics is constructed by modifying oxaliplatin prodrug and PEG on Fe(III) - porphyrin metal-organic frameworks (PCN(Fe) MOFs). After intravenous injection, the cloak of PEG leads to long circulation, and the Fe(III)-porphyrin MOFs enables dual-model guidance with fluorescence (FL) and magnetic resonance imaging (MRI). Inside the tumor, the intracellular H2O2 would be transferred into hydroxyl radicals (•OH) by iron ions released from MOFs, which could trigger the lethal ferroptosis to cancer cells. Meanwhile, oxaliplatin(II) transformed from the loaded oxaliplatin prodrug would result in the chemotherapy, as well as immunogenic cell death (ICD), and the prodrug strategy could also avoid the occurring of liver damage by the direct administration of oxaliplatin(II). It was noticed that the ferroptosis effect was enhanced by triple-assistance during the combined therapy, as followed: (1) glutathione (GSH) would be consumed in the process of oxaliplatin(II) generation from oxaliplatin prodrug; (2) the increased CD8+ T cells induced by ICD were able to produce interferon-γ (IFN-γ), which could inhibit the transport of cystine by tumor cells, and impair the activation of glutathione peroxidase 4 (GPX4); (3) the amount of H2O2 could be increased by the internalized oxaliplatin and thus further promote the Fenton reaction and ferroptosis. Both in vivo and in vitro results revealed that tumor growing was significantly inhibited by PCN-Oxpt/PEG, taken together, the concomitant of oxaliplatin-mediated chemotherapy and ICD with triple-enhanced ferroptosis offer great prospect in the clinical treatment of cancer.
    Keywords:  Combined therapy; Ferroptosis; Immunogenic cell death; Metal-organic frameworks; Oxaliplatin prodrug
    DOI:  https://doi.org/10.1016/j.jconrel.2022.06.019
  113. Mini Rev Med Chem. 2022 Jun 22.
    Nutraceuticals, a Bridge Between Past and Future: Focus on Mushrooms Biological Activities and Myco-Chemistry.
    Gitishree Das, Roberta Budriesi, Han-Seung Shin, Francesco Urso, Sankhadip Bose, Sabyasachi Banerjee, Maria Del Pilar Rodriguez-Torres, Laura Beatrice Mattioli, Jayanta Kumar Patra, Matteo Micucci.
       BACKGROUND: Mushrooms are consumed throughout the world due to their high nutritional and nutraceutical values. In addition to the presence of various vitamins, low-fat, and proteins; they are also an important source of trace elements, dietary fibers, and bioactive compounds. Their potential therapeutic properties are due to their multiple biological effects, such as antimicrobial, antiviral, antioxidant, anticancer, immune-modulating, cardioprotective, and antidiabetic properties. The global market of mushroom farming is anticipated to witness remarkable progress for its potential application in health products, profitable production and a rising demand for the healthy foods across the globe. The Asia Pacific marketplace seems to represent the major market of mushrooms, due to the higher per capita consumption of culinary and medical purposes.
    OBJECTIVE: Mushrooms have generally low calories, low levels of cholesterol, fats, gluten and sodium. Several biological effects of mushroom are due to the presence of phenolic components, polysaccharides, terpenoids, terphenyl-related compounds, and many other lower molecular weight molecules. This review aims at describing the chemical characterization of several mushrooms species and their biological effects.
    CONCLUSION: The current review describes different secondary metabolites found in several mushrooms and mushrooms extracts, and the molecular mechanisms underlying the biological activities. Also the antimicrobial activities of mushrooms, mushrooms extracts and isolated compounds from mushrooms were described. The description of these activities, related to the presence of specific classes of secondary metabolites and isolated compounds, may lead to the identification of mycomplexes and mushrooms compounds that may be further studied for their potential application in nutraceutical products.
    Keywords:  Antimicrobial; anti-viral; anticancer; medicinal mushrooms; pharmacological potential.; respiratory diseases
    DOI:  https://doi.org/10.2174/1389557522666220622104845
  114. Zhongguo Zhong Yao Za Zhi. 2022 May;47(10): 2643-2651
    [Preparation and effect against cervical cancer invasion in vitro of harmine-loaded photosensitive liposomes].
    Shi-Ming Huang, Shu-Bei Li, Hong-Tao Deng, Qing-Qing Jiang, Yi-Bo Gu, Xue Ying.
      Despite the development of HPV vaccines and screening programs, cervical cancer is still a serious threat to women's health. Early-stage cervical cancer is mainly treated by surgery. However, considering the serious complications after surgery, hyperthermia is recommended to enhance the effect of chemotherapy, retain the integrity of cervix, improve the treatment effect, which provides a therapeutic basis for the early treatment of cervical cancer. The photosensitive liposomes containing harmine and dye IR-780 were prepared by thin-film dispersion method and separated by Sephadex G-50 dextran gel column. The preparation conditions were optimized as the mass ratio of phospholipid to cholesterol membrane material being 8∶1 and that of drug to lipid being 1∶20. The results of HPLC showed that the encapsulation efficiency of harmine was 55.6%±0.18%. The prepared photosensitive liposomes were round and evenly distributed under transmission electron microscope, with the particle size of(125.2±0.62) nm determined by Marvin particle size analyzer and the Zeta potential of(-2.55±0.76) mV. Additionally, the photosensitive liposomes had the photothermal conversion efficiency, an important property of photothermal agent, of 27.1%±0.86%. The photosensitive liposomes stored at 4 ℃ showed stable encapsulation efficiency in the first 14 days without flocculation. The sulforhodamine B(SRB) assay was employed to determine the inhibitory effect of the liposomes on the proliferation of HeLa cells under near-infrared(NIR) irradiation or not, which showcased stronger inhibitory effect under NIR irradiation. The results of Transwell assay indicated that the prepared liposomes significantly inhibited the invasion and migration of HeLa cells in vitro. The findings of this study provide a basis for the treatment of cervical cancer with harmine.
    Keywords:  IR-780; antitumor; harmine; invasion; liposomes; prescription optimization
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20210520.301
  115. Antioxidants (Basel). 2022 Jun 08. pii: 1128. [Epub ahead of print]11(6):
    Antioxidant Therapy in Cancer: Rationale and Progress.
    Maochao Luo, Li Zhou, Zhao Huang, Bowen Li, Edouard C Nice, Jia Xu, Canhua Huang.
      Cancer is characterized by increased oxidative stress, an imbalance between reactive oxygen species (ROS) and antioxidants. Enhanced ROS accumulation, as a result of metabolic disturbances and signaling aberrations, can promote carcinogenesis and malignant progression by inducing gene mutations and activating pro-oncogenic signaling, providing a possible rationale for targeting oxidative stress in cancer treatment. While numerous antioxidants have demonstrated therapeutic potential, their clinical efficacy in cancer remains unproven. Here, we review the rationale for, and recent advances in, pre-clinical and clinical research on antioxidant therapy in cancer, including targeting ROS with nonenzymatic antioxidants, such as NRF2 activators, vitamins, N-acetylcysteine and GSH esters, or targeting ROS with enzymatic antioxidants, such as NOX inhibitors and SOD mimics. In addition, we will offer insights into prospective therapeutic options for improving the effectiveness of antioxidant therapy, which may expand its applications in clinical cancer treatment.
    Keywords:  antioxidants; cancer therapy; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox11061128
  116. Nutrients. 2022 Jun 16. pii: 2496. [Epub ahead of print]14(12):
    Active Compounds in Fruits and Inflammation in the Body.
    Magdalena Majdan, Barbara Bobrowska-Korczak.
      Inflammation plays an important role in the pathogenesis of many diseases, including cardiovascular diseases, atherosclerosis, diabetes, asthma, and cancer. An appropriate diet and the active compounds contained in it can affect various stages of the inflammatory process and significantly affect the course of inflammatory diseases. Recent reports indicate that polyphenolic acids, vitamins, minerals, and other components of fruits may exhibit activity stimulating an anti-inflammatory response, which may be of importance in maintaining health and reducing the risk of disease. The article presents the latest data on the chemical composition of fruits and the health benefits arising from their anti-inflammatory and antioxidant effects. The chemical composition of fruits determines their anti-inflammatory and antioxidant properties, but the mechanisms of action are not fully understood.
    Keywords:  antioxidant; fruits; inflammation; phytochemical compounds
    DOI:  https://doi.org/10.3390/nu14122496
  117. Biomater Sci. 2022 Jun 21.
    A glutathione-responsive sulfur dioxide polymer prodrug selectively induces ferroptosis in gastric cancer therapy.
    Mingjie Xia, Zhihui Guo, Xinming Liu, Yang Wang, Chunsheng Xiao.
      Nanoparticle-induced ferroptosis has been proven to be an appealing strategy in cancer treatment. Previously, we reported the synthesis of an amphiphilic polymer prodrug of SO2, mPEG-PLG(DNs), which could self-assemble to formulate nanoparticles (NP-DNs) and trigger cancer cell death by GSH consumption and SO2 release. In the current study, the potential mechanism of NP-DNs-induced cell death was further investigated. We demonstrated that NP-DNs exhibited efficient antitumor activity against gastric cancer via ferroptosis. NP-DNs could selectively accelerate lipid peroxidation through GSH depletion and SO2 generation in gastric cancer cells. In addition, the NP-DNs-induced GPX4 reduction played a collaborative role in ferroptosis. Concurrently, in vivo evaluations revealed that NP-DNs not only exhibited excellent antitumor efficiency via ferroptosis but also caused little systemic toxicity in mice. All the results showed that NP-DNs would be a promising prodrug in precision-targeted ferroptosis therapy.
    DOI:  https://doi.org/10.1039/d2bm00678b
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