bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022‒05‒22
eighty-two papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development
  1. Advanced nanomedicines for the regulation of cancer metabolism.
  2. Nanodrug-Loaded Bifidobacterium bifidum Conjugated with Anti-Death Receptor Antibody for Tumor-Targeted Photodynamic and Sonodynamic Synergistic Therapy.
  3. Metabolic Reprogramming in Cholangiocarcinoma.
  4. Exploring near-infrared absorbing nanocarriers to overcome cancer drug resistance.
  5. Albumin-based nanoparticles: a promising strategy to overcome cancer drug resistance.
  6. Inhalable Biomimetic Protein Corona-Mediated Nanoreactor for Self-Amplified Lung Adenocarcinoma Ferroptosis Therapy.
  7. A review on plant polysaccharide based on drug delivery system for construction and application, with emphasis on traditional Chinese medicine polysaccharide.
  8. A nanoreactor boosts chemodynamic therapy and ferroptosis for synergistic cancer therapy using molecular amplifier dihydroartemisinin.
  9. Therapeutic potentials of genistein: New insights and perspectives.
  10. Anisi Stellati Fructus, a Significant Traditional Chinese Medicine (TCM) Herb and Its Bioactivity against Gastric Cancer.
  11. Glutathione-Triggered Mitochondria-Targeting Reassembly from Polymeric Micelles to Nanofibers for a Synergistic Anticancer Effect.
  12. Current Update on Nanotechnology-Based Approaches in Ovarian Cancer Therapy.
  13. Perspectives of nano-carrier drug delivery systems to overcome cancer drug resistance in the clinics.
  14. Recent trends of bioconjugated nanomedicines through nose-to-brain delivery for neurological disorders.
  15. Light-triggered Photodynamic Nanomedicines for Overcoming Localized Therapeutic Efficacy in Cancer Treatment.
  16. Anti-inflammatory and analgesic properties of Moroccan medicinal plants: Phytochemistry, in vitro and in vivo investigations, mechanism insights, clinical evidences and perspectives.
  17. Dermal Delivery of Lipid Nanoparticles: Effects on Skin and Assessment of Absorption and Safety.
  18. Preparation, characterization and evaluation of anti-tyrosinase activity of solid lipid nanoparticles (SLNs) containing Undecylenoyl phenylalanine (Sepiwhite®).
  19. Delivery of curcumin by fucoidan-coated mesoporous silica nanoparticles: Fabrication, characterization, and in vitro release performance.
  20. Antimicrobial benefits of flavonoids and their nanoformulations.
  21. Emerging RAS-directed therapies for cancer.
  22. Chondroitin sulfate-based prodrug nanoparticles enhance photodynamic immunotherapy via Golgi apparatus targeting.
  23. Evaluation of anti-proliferative activity of Eryngium caucasicum on melanoma cancer cells.
  24. Fully Natural Lecithin Encapsulated Nano-Resveratrol for Anti-Cancer Therapy.
  25. Trends in the Design and Evaluation of Polymeric Nanocarriers: The In Vitro Nano-Bio Interactions.
  26. Chemotherapeutic Role of Polyphenols Present in Ocimum Sanctum.
  27. Olaparib and Doxorubicin Co-Loaded Polypeptide Nanogel for Enhanced Breast Cancer Therapy.
  28. Recent Developments and Potential for Clinical Use of Casein as a Drug Carrier.
  29. Cyclic arginine-glycine-aspartic acid-modified red blood cells for drug delivery: Synthesis and in vitro evaluation.
  30. Prolonged blood circulation outperforms active targeting for nanocarriers-mediated enhanced hepatocellular carcinoma therapy in vivo.
  31. Development and Evaluation of Biotin Functionalized Fullerenes for the Delivery of Irinotecan to Colon Tumors.
  32. A core-shell liquid metal-Cu nanoparticle with glutathione consumption via an in situ replacement strategy for tumor combination treatment of chemodynamic, microwave dynamic and microwave thermal therapy.
  33. Intravesical combination therapies for non-muscle invasive bladder cancer: Recent advances and future directions.
  34. Molecular Mechanism of Curcumin and Its Analogs as Multifunctional Compounds against Pancreatic Cancer.
  35. Tumor acidity-responsive polymeric nanoparticles to promote intracellular delivery of zoledronic acid by PEG detachment and positive charge exposure for enhanced antitumor potency.
  36. Inhibition of Glutamine Cellular Uptake Contributes to the Cytotoxic Effect of Xanthohumol in Triple-Negative Breast Cancer Cells.
  37. Iron delivery systems for controlled release of iron and enhancement of iron absorption and bioavailability.
  38. Melatonin as an adjuvant treatment modality with doxorubicin.
  39. NIR Responsive Injectable Nanocomposite Thermogel System Against Osteosarcoma Recurrence.
  40. pH-responsive nanoparticles for multidimensional combined chemo-immunotherapy of cancer.
  41. Drug repurposing: An emerging strategy in alleviating skin cancer.
  42. Targeting Microenvironment of Melanoma and Head and Neck Cancers in Photodynamic Therapy.
  43. Curcumin: reclaiming the lost ground against cancer resistance.
  44. Formulation and Statistical Evaluation of Tablets Containing Pitavastatin- Self Nano Emulsifying Drug Delivery Systems.
  45. Impact of fenofibrate on NAFLD/NASH: A genetic perspective.
  46. The Origins, Evolution, and Future of Dietary Methionine Restriction.
  47. Reversing breast cancer bone metastasis by metal organic framework-capped nanotherapeutics via suppressing osteoclastogenesis.
  48. Smart pH-responsive nanomedicines for disease therapy.
  49. The Cross-Talk between Polyphenols and the Target Enzymes Related to Oxidative Stress-Induced Thyroid Cancer.
  50. Molecular Mechanisms of Vitamin D-Mediated Immunomodulation.
  51. Surface Engineering of Nanomaterials with Polymers, Biomolecules, and Small Ligands for Nanomedicine.
  52. Curcumae rhizoma and its major constituents against hepatobiliary disease: Pharmacotherapeutic properties and potential clinical applications.
  53. Development of a novel pomegranate polysaccharide nanoemulsion formulation with anti-inflammatory, antioxidant and antitumor properties.
  54. Brain-targeting drug delivery systems.
  55. Challenges and opportunities on vegetable oils derived systems for biomedical applications.
  56. Red ginseng polysaccharide exhibits anticancer activity through GPX4 downregulation-induced ferroptosis.
  57. Mitochondrial targeted drug delivery combined with Manganese Catalyzed Fenton reaction for the treatment of breast cancer.
  58. Fabrication of human serum albumin-imprinted photothermal nanoparticles for enhanced immunotherapy.
  59. Editorial: Metabolic Abnormalities and Breast Cancer: Challenges From Bench to Bedside.
  60. Traditional uses, phytochemistry, transformation of ingredients and pharmacology of the dried seeds of Raphanus sativus L. (Raphani Semen), A comprehensive review.
  61. Liposome co-encapsulation of anti-cancer agents for pharmacological optimization of nanomedicine-based combination chemotherapy.
  62. 20(s)-ginsenoside Rh2 promotes TRAIL-induced apoptosis by upregulating DR5 in human hepatocellular carcinoma cells.
  63. Low-Intensity Focused Ultrasound Targeted Microbubble Destruction Enhanced Paclitaxel Sensitivity by Decreasing Autophagy in Paclitaxel-Resistant Ovarian Cancer.
  64. Evolving era of "sponges": Nanosponges as a versatile nanocarrier for the effective skin delivery of drugs.
  65. Nanoparticle combination for precise stroma modulation and improved delivery for pancreatic cancer.
  66. Impact of the amount of PEG on prodrug nanoassemblies for efficient cancer therapy.
  67. Impact of curcumin, quercetin, or resveratrol on the pathophysiology of endometriosis: A systematic review.
  68. Dietary exosome-like nanoparticles: An updated review on their pharmacological and drug delivery applications.
  69. A Recent Advancement In Nanotechnology Approaches For The Treatment Of Cervical Cancer.
  70. Synthesis and Potential Antidiabetic Properties of Curcumin-Based Derivatives: An In Vitro and In Silico Study of α-Glucosidase and α-Amylase Inhibition.
  71. Applications of Chitosan and its Derivatives in Skin and Soft Tissue Diseases.
  72. Mechanisms by Which Traditional Chinese Medicines Influence the Intestinal Flora and Intestinal Barrier.
  73. Natural products as a means of overcoming cisplatin chemoresistance in bladder cancer.
  74. Dietary Flavonoids with Catechol Moiety Inhibit Anticancer Action of Bortezomib: What about the other Boronic Acid-Based Drugs?
  75. Diallyl disulfide and diallyl trisulfide in garlic as novel therapeutic agents to overcome drug resistance in breast cancer.
  76. The Synthesis of Urolithins and Their Derivatives and the Modes of Antitumor Action.
  77. Polyserotonin as a versatile coating with pH-responsive degradation for anti-tumor therapy.
  78. Correction: Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia.
  79. A deep tumor penetration nanoplatform for glycolysis inhibition and antimetastasis of breast cancer.
  80. Reflected stemness as a potential driver of the tumour microenvironment.
  81. Metabolic reprogramming as an emerging mechanism of resistance to endocrine therapies in prostate cancer.
  82. Comparing palliative treatment options for cholangiocarcinoma: photodynamic therapy vs. radiofrequency ablation.
  1. Biomaterials. 2022 May 07. pii: S0142-9612(22)00205-8. [Epub ahead of print]286 121565
    Advanced nanomedicines for the regulation of cancer metabolism.
    Jiaying Yang, Yu Zhao, Yanyan Zhou, Xiaolu Wei, Hongjie Wang, Nan Si, Jian Yang, Qinghe Zhao, Baolin Bian, Haiyu Zhao.
      Cancer cells can reprogram metabolic pathways to facilitate proliferation, metastasis, biosynthesis, and chemoresistance. Metabolic reprogramming is currently considered as a hallmark of tumors and is recognized as a promising therapeutic strategy. The recent progress in nanomedicine has greatly improved the therapeutic effect of conventional therapeutic modalities such as surgical treatment, radiotherapy, chemical drug therapy. However, nanomedicine engineering still fails to achieve satisfactory therapeutic effects due to the metabolic reprogramming of tumor cells. The targeted delivery and development of precise therapeutic strategies are the latest focus in tumor metabolism to design nanomedicines according to the characteristics of cancer metabolic reprogramming. Therefore, this review focuses mainly on metabolic pathways of tumors. Pathways such as glycolysis, aerobic respiration, lipid metabolism, nucleotide metabolism, and glutathione metabolism are reviewed in detail. The latest advances are summarized in the design and combined treatment of smart nanomedicines that can regulate cancer metabolism to provide an emerging cancer therapeutic model. The challenges and future developments of this cancer therapeutic model are discussed in detail to understand as much as possible the prospects of this field. Designing nanomedicine therapy strategies by targeting tumor metabolic characteristics will provide a novel approach for the application of personalized biomedicine of tumors.
    Keywords:  Metabolic reprogramming; Metabolism regulation; Nanomedicine; Synergistic therapy; Tumors metabolism
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121565
  2. Acta Biomater. 2022 May 14. pii: S1742-7061(22)00285-9. [Epub ahead of print]
    Nanodrug-Loaded Bifidobacterium bifidum Conjugated with Anti-Death Receptor Antibody for Tumor-Targeted Photodynamic and Sonodynamic Synergistic Therapy.
    Wenhao Li, Zefei Zhang, Jie Liu, Bo Wang, Guangjin Pu, Ji Li, Yuqiao Huang, Maoquan Chu.
      Using bacteria for tumor-targeted therapy has attracted much attention in recent years. However, how to improve the targeted delivery and cancer therapy efficacy is an important but challenging scientific issue. Herein, a drug delivery system using a probiotic as a carrier was developed for tumor-targeted photodynamic and sonodynamic synergistic therapy. In this system, chlorin e6 (Ce6) nanoparticles (NPs) were prepared and incorporated into B. bifidum, followed by the conjugation of anti-death receptor 5 antibody (anti-DR5 Ab). Interestingly, B. bifidum under 671 nm laser or ultrasound (US) irradiation could generate reactive oxygen species (ROS), and Ce6-B. bifidum-anti-DR5 Ab obtained could target hypoxic regions in tumor with high efficiency after intravenous injection. The ROS level generated by Ce6-B. bifidum-anti-DR5 Ab under both laser and US irradiation was much higher than the combined ROS generated separately using a laser and US for the same probiotics. The cytotoxicity and laryngeal tumor growth-inhibiting efficiency of Ce6-B. bifidum-anti-DR5 Ab under both laser and US irradiation were significant higher than the values obtained using laser or US irradiation alone, which demonstrated the synergistic effect on tumor growth. B. bifidum could be eliminated from the body without exerting harmful effects on mouse health. This strategy is a platform that can be extended to treat other solid tumors. STATEMENT OF SIGNIFICANCE: Using bacteria as drug delivery carriers will show unique advantages. However, how to improve the targeted delivery efficiency and tumor inhibiting capacity is a challenging scientific issue. Herein, a novel delivery system using a probiotic as carrier was developed for tumor-targeted therapy. In this delivery system, chlorin e6 nanoparticles were prepared and then incorporated into living Bifidobacterium bifidum (B.bifidum), followed by the conjugation of anti-death receptor 5 antibody. This delivery system could efficiently target to mouse tumors, accumulate the hypoxic areas and inhibit the tumor growth through the photodynamic and sonodynamic synergistic effect. Our results will provide a platform for B.bifidum-mediated tumor targeted therapy.
    Keywords:  B. bifidum; anti-death receptor antibody; photodynamic and sonodynamic effects; synergistic therapy; tumor targeting
    DOI:  https://doi.org/10.1016/j.actbio.2022.05.016
  3. J Hepatol. 2022 May 17. pii: S0168-8278(22)00314-2. [Epub ahead of print]
    Metabolic Reprogramming in Cholangiocarcinoma.
    Chiara Raggi, Maria Letizia Taddei, Colin Rae, Chiara Braconi, Fabio Marra.
      Metabolic reprogramming is a hallmark of cancer and allows tumor cells to meet the increased energy demands required for rapid proliferation, invasion, and metastasis. Indeed, many tumor cells acquire distinctive metabolic and bioenergetic features to survive under conditions of limited resources, mainly using alternative nutrients. Several recent studies have explored the metabolic plasticity of cancer cells with the aim to identify new druggable targets, and therapeutic strategies aimed to limit the access to nutrients have been successfully applied to the treatment of some tumors. Cholangiocarcinoma (CCA), a highly heterogeneous tumor, is the second most common form of primary liver cancer. It is characterized by resistance to chemotherapy and poor prognosis, with 5-year survival lower than 20%. Deregulation of metabolic pathways has been described during the onset and progression of CCA. Increased aerobic glycolysis and glutamine anaplerosis provide CCA cells with the ability to generate biosynthetic intermediates. Other metabolic alterations involving carbohydrates, amino acids and lipids have been shown to sustain cancer cell growth and dissemination. In this review, we discuss the complex metabolic rewiring taking place during CCA development, leading to unique nutrient addiction. The possible role of therapeutic interventions based on metabolic changes is also thoroughly discussed.
    Keywords:  CD36; IDH1/2; PGC1α; cancer stem cells; fatty acids; fatty-acid synthase; glutamine; glycolysis; mTOR; methionine adenosyltransferases; mitochondria; oxidative metabolism
    DOI:  https://doi.org/10.1016/j.jhep.2022.04.038
  4. Cancer Drug Resist. 2020 ;3(3): 302-333
    Exploring near-infrared absorbing nanocarriers to overcome cancer drug resistance.
    Siwei Chu, Ursula Stochaj.
      One of the major obstacles of successful cancer therapy is cancer drug resistance. The unique tools and applications developed by nanomedicine provide new approaches to surmount this common limitation of current treatment regimens. Nanocarriers that absorb light in the near-infrared spectrum are particularly suitable for this purpose. These nanocarriers can produce heat, release drugs or stimulate the production of physiologically relevant compounds when illuminated with near-infrared light. The current review summarizes the causes contributing to cancer multidrug resistance. The major types of nanocarriers that have been developed in recent years to overcome these hurdles are described. We focus on nanoparticles that are responsive to near-infrared light and suitable to surmount cancer multidrug resistance. Our review concludes with the bottlenecks that currently restrict the use of nanocarriers in the clinic and an outlook on future directions.
    Keywords:  Cancer drug resistance; chemotherapy; combination therapy; controlled drug release; nanomedicine; near-infrared light; photodynamic therapy; photothermal therapy
    DOI:  https://doi.org/10.20517/cdr.2020.20
  5. Cancer Drug Resist. 2020 ;3(4): 930-946
    Albumin-based nanoparticles: a promising strategy to overcome cancer drug resistance.
    Islam Hassanin, Ahmed Elzoghby.
      Circumvention of cancer drug resistance is one of the major investigations in nanomedicine. In this regard, nanotechnology-based drug delivery has offered various implications. However, protein-based nanocarriers have been a versatile choice compared to other nanomaterials, provided by their favorable characteristics and safety profiles. Specifically, albumin-based nanoparticles have been demonstrated to be an effective drug delivery system, owing to the inherent targeting modalities of albumin, through gp60- and SPARC-mediated receptor endocytosis. Furthermore, surface functionalization was exploited for active targeting, due to albumin's abundance of carboxylic and amino groups. Stimuli-responsive drug release has also been pertained to albumin nano-systems. Therefore, albumin-based nanocarriers could potentially overcome cancer drug resistance through bypassing drug efflux, enhancing drug uptake, and improving tumor accumulation. Moreover, albumin nanocarriers improve the stability of various therapeutic cargos, for instance, nucleic acids, which allows their systemic administration. This review highlights the recent applications of albumin nanoparticles to overcome cancer drug resistance, the nano-fabrication techniques, as well as future perspectives and challenges.
    Keywords:  Albumin; active targeting; cancer therapy; drug delivery; multi-drug resistance; nanoparticles; nucleic acid therapy; stimuli- response release
    DOI:  https://doi.org/10.20517/cdr.2020.68
  6. ACS Nano. 2022 May 15.
    Inhalable Biomimetic Protein Corona-Mediated Nanoreactor for Self-Amplified Lung Adenocarcinoma Ferroptosis Therapy.
    Wenhao Wang, Fangqin Fu, Zhengwei Huang, Wenhua Wang, Minglong Chen, Xiao Yue, Jintao Fu, Xiaoqian Feng, Ying Huang, Chuanbin Wu, Xin Pan.
      Ferroptosis therapy by catalyzing the Fenton reaction has emerged as a promising tumor elimination strategy for lung adenocarcinoma (ADC). However, the unsatisfactory Fenton reaction efficiency, strong intracellular antioxidant system, and insufficient lung drug accumulation limits the ferroptosis therapeutic effect. To address these issues, an inhalable nanoreactor was proposed by spontaneously adsorbing biomimetic protein corona (PC) composed of matrix metalloproteinase 2 responsive gelatin and glutamate (Glu) on the surface of cationic nanostructured lipid carriers (NLC) core loaded with ferrocene (Fc) and fluvastatin. The prepared Fc-NLC(F)@PC could be nebulized into lung lesions with 2.6 times higher drug accumulation and boost lipid peroxide production by 3.2 times to enhance ferroptosis therapy. Mechanically, fluvastatin was proved to inhibit monocarboxylic acid transporter 4 mediated lactate efflux, inducing tumor acidosis to boost Fc-catalyzing reactive oxygen species production, while the extracellular elevating Glu concentration was found to inhibit xCT (system Xc-) functions and further collapse the tumor antioxidant system by glutathione synthesis suppression. Mitochondrial dysfunction and cell membrane damage were involved in the nanoreactor-driven ferroptotic cell death process. The enhanced antitumor effects by combination of tumor acidosis and antioxidant system collapse were confirmed in an orthotopic lung ADC tumor model. Overall, the proposed nanoreactor highlights the pulmonary delivery approach for local lung ADC treatment and underscores the great potential of ferroptosis therapy.
    Keywords:  fenton reaction; ferroptosis therapy; lung adenocarcinoma; nanostructured lipid carriers; pulmonary delivery
    DOI:  https://doi.org/10.1021/acsnano.2c02634
  7. Int J Biol Macromol. 2022 May 16. pii: S0141-8130(22)01057-1. [Epub ahead of print]
    A review on plant polysaccharide based on drug delivery system for construction and application, with emphasis on traditional Chinese medicine polysaccharide.
    Hexin Gong, Weinan Li, Jialin Sun, Li Jia, Qingxia Guan, Yuyan Guo, Yanhong Wang.
      Carbohydrate polymers with unique chemical composition, molecular weight and functional chemical groups show multiple potentials in drug delivery. Most carbohydrate polymers such as plant polysaccharides exhibit advantages of biodegradability, ease of modification, low immunogenicity and low toxicity. They can be conjugated, cross-linked or functionally modified, and then used as nanocarrier materials. Polysaccharide drug delivery system can avoid the phagocytosis of the reticuloendothelial system, prevent the degradation of biomolecules, and increase the bioavailability of small molecules, thus exerting effective therapeutic effects. Therefore, they have been fully explored. In this paper, we reviewed the construction methods of drug delivery systems based on carbohydrate polymers (astragalus polysaccharide, angelica polysaccharide, lycium barbarum polysaccharide, ganoderma lucidum polysaccharide, bletilla polysaccharide, glycyrrhiza polysaccharide, and epimedium polysaccharides, etc). The application of polysaccharide drug delivery systems to deliver small molecule chemotherapeutic drugs, gene drugs, and metal ion drugs was also briefly introduced. At the same time, the role of the polysaccharide drug delivery system in tumor treatment, targeted therapy, and wound healing was discussed. In addition, the research of polysaccharide delivery systems based on the therapeutic efficacy of traditional Chinese medicine was also summarized and prospected.
    Keywords:  Application; Carbohydrate polymers; Drug delivery system; Structural modification; Traditional Chinese medicine polysaccharide
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.05.087
  8. J Nanobiotechnology. 2022 May 14. 20(1): 230
    A nanoreactor boosts chemodynamic therapy and ferroptosis for synergistic cancer therapy using molecular amplifier dihydroartemisinin.
    Xiao-Xin Yang, Xiang Xu, Mei-Fang Wang, Hua-Zhen Xu, Xing-Chun Peng, Ning Han, Ting-Ting Yu, Liu-Gen Li, Qi-Rui Li, Xiao Chen, Yu Wen, Tong-Fei Li.
      BACKGROUND: Chemodynamic therapy (CDT) relying on intracellular iron ions and H2O2 is a promising therapeutic strategy due to its tumor selectivity, which is limited by the not enough metal ions or H2O2 supply of tumor microenvironment. Herein, we presented an efficient CDT strategy based on Chinese herbal monomer-dihydroartemisinin (DHA) as a substitute for the H2O2 and recruiter of iron ions to amplify greatly the reactive oxygen species (ROS) generation for synergetic CDT-ferroptosis therapy.RESULTS: The DHA@MIL-101 nanoreactor was prepared and characterized firstly. This nanoreactor degraded under the acid tumor microenvironment, thereby releasing DHA and iron ions. Subsequent experiments demonstrated DHA@MIL-101 significantly increased intracellular iron ions through collapsed nanoreactor and recruitment effect of DHA, further generating ROS thereupon. Meanwhile, ROS production introduced ferroptosis by depleting glutathione (GSH), inactivating glutathione peroxidase 4 (GPX4), leading to lipid peroxide (LPO) accumulation. Furthermore, DHA also acted as an efficient ferroptosis molecular amplifier by direct inhibiting GPX4. The resulting ROS and LPO caused DNA and mitochondria damage to induce apoptosis of malignant cells. Finally, in vivo outcomes evidenced that DHA@MIL-101 nanoreactor exhibited prominent anti-cancer efficacy with minimal systemic toxicity.
    CONCLUSION: In summary, DHA@MIL-101 nanoreactor boosts CDT and ferroptosis for synergistic cancer therapy by molecular amplifier DHA. This work provides a novel and effective approach for synergistic CDT-ferroptosis with Chinese herbal monomer-DHA and Nanomedicine.
    Keywords:  Chemodynamic therapy (CDT); Dihydroartemisinin (DHA); Ferroptosis; Nanoreactor; Nanoscale metal–organic framework (nMOF)
    DOI:  https://doi.org/10.1186/s12951-022-01455-0
  9. J Food Biochem. 2022 May 17. e14228
    Therapeutic potentials of genistein: New insights and perspectives.
    Sumbal Rasheed, Kanwal Rehman, Momina Shahid, Shaleem Suhail, Muhammad Sajid Hamid Akash.
      Genistein, a polyphenolic isoflavone compound found abundantly in soy or soy-based products, is widely consumed in the Asian population. Genistein has poor bioavailability, to overcome this problem many advanced nano-drug delivery carrier systems are designed to enhance its water solubility and stability. However, further research is required to develop more efficient bioavailability improvement strategies. Genistein is a phytoestrogen which has been associated with reducing the risk of cancer, cardiovascular disorders, and diabetes mellitus. This plant-based bioactive compound possesses numerous biological activities such as anti-oxidant, anti-inflammatory, anti-obesity, anti-cancer, cardioprotective, and anti-diabetic activities to treat various disease states. Genistein has been used as an active therapeutic agent in many medications. Moreover, several clinical trials are in the ongoing stage to develop more efficient treatment therapies, especially for cancer treatment. This article highlights the protective and therapeutic benefits of genistein in the treatment of different ailments, and more specifically elaborates on the anti-cancer potential of genistein regarding various types of cancers. PRACTICAL APPLICATIONS: Genistein possesses versatile biological activities, including anti-diabetic, anti-inflammatory, anti-oxidant, anti-obesity, and anti-angiogenic. The most studied activity is anti-cancer. Currently, a number of pre-clinical and clinical trials are being carried out on anti-neoplastic and cytotoxic activities of genistein to develop novel therapeutic agents with excellent anti-cancer potential for the treatment of various kinds of cancer. Moreover, many bioavailability enhancement strategies have been developed to improve the bioavailability of genistein. Genistein shows significant hypoglycemic effects alone or in combination with other anti-diabetic agents. Genistein in combination with other chemotherapeutic agents is used for the treatment of prostate, bone, colorectal, glioma, breast, and bladder cancer.
    Keywords:  anti-cancer potential; bioavailability; clinical trials; genistein
    DOI:  https://doi.org/10.1111/jfbc.14228
  10. Evid Based Complement Alternat Med. 2022 ;2022 4071489
    Anisi Stellati Fructus, a Significant Traditional Chinese Medicine (TCM) Herb and Its Bioactivity against Gastric Cancer.
    Maryam Khan, Saba Shamim.
      Anisi stellati fructus (ASF) is the fruit of Illicium verum Hook F. (Chinese star anise), which is native to many countries, and is a significant Chinese medicinal herb. Gastric cancer (GC) is one of the major fatal types of cancers with multiple stages and a poor prognosis. The present review aims to discuss the bioactive properties of ASF and its phytocompounds against GC, with a particular insight into the molecular mechanisms and signaling pathways involved in its anti-GC mechanism. Furthermore, it highlights the potential mechanism of action of major phytocompounds of ASF against GC. Clinical studies (in vitro and in vivo) regarding the action of ASF and its major bioactive compounds such as quercetin, luteolin, kaempferol, d-limonene, and honokiol against GC were reviewed. For this review, search of literature was performed in Science, PubMed, Google Scholar, Web of Science, and Scopus related to ASF and its phytocompounds, from which only relevant studies were chosen. Major bioactive compounds of ASF and their extracts have proven to be effective against GC due to the mechanistic action of these compounds involving signaling pathways that target cancer cell apoptosis, proliferation, and tumor metastasis in GC cells. Existing reports of these compounds and their combinatory effects with other modern anticancer agents have also been reviewed. From its traditional use to its role as an anticancer agent, ASF and its bioactive phytocompounds have been observed to be effective in modern research, specifically against GC. However, further studies are required for the identification of molecular targets and pharmacokinetic potential and for the formulation of anti-GC drugs.
    DOI:  https://doi.org/10.1155/2022/4071489
  11. ACS Macro Lett. 2022 Apr 19. 11(4): 543-548
    Glutathione-Triggered Mitochondria-Targeting Reassembly from Polymeric Micelles to Nanofibers for a Synergistic Anticancer Effect.
    Jingbo Wang, Qinghao Zhou, Xiang Li, Debabrata Dutta, Zhishen Ge.
      Nanofibers self-assembled from peptides have attracted much attention to inhibit cancer cells. However, there are still some disadvantages, including high concentration for self-assembly and incapability to load drugs, which limit their applications. In this report, we rationally integrate self-assembled peptides, glutathione-sensitive disulfide bonds, and mitochondrial targeting moieties into the amphiphilic block copolymer to construct the nanocarriers, which can be used to load anticancer drug doxorubicin (DOX). After cellular internalization, the nanocarriers can reassemble from micelles to nanofibers under the trigger by glutathione and locate in mitochondria. The released DOX and nanofibers induce mitochondrial dysfunction and activate the apoptosis pathway to synergistically inhibit tumor cells. This organelle-specific drug delivery system with reassembly capability from micelles to nanofibers shows great potential for effectively killing cancer cells.
    DOI:  https://doi.org/10.1021/acsmacrolett.2c00059
  12. Reprod Sci. 2022 May 18.
    Current Update on Nanotechnology-Based Approaches in Ovarian Cancer Therapy.
    Boddapati Kalyani Bhardwaj, Sanu Thankachan, Priyanila Magesh, Thejaswini Venkatesh, Rie Tsutsumi, Padmanaban S Suresh.
      Ovarian cancer is one of the leading causes of cancer-related deaths among women. The drawbacks of conventional therapeutic strategies encourage researchers to look for alternative strategies, including nanotechnology. Nanotechnology is one of the upcoming domains of science that is rechanneled towards targeted cancer therapy and diagnosis. Nanocarriers such as dendrimers, liposomes, polymer micelles, and polymer nanoparticles present distinct surface characteristics in morphology, surface chemistry, and mode of action that help differentiate normal and malignant cells, which paves the way for target-specific drug delivery. Similarly, nanoparticles have been strategically utilized as efficacious vehicles to deliver drugs that alter the epigenetic modifications in epigenetic therapy. Some studies suggest that the use of specialized target-modified nanoparticles in siRNA-based nanotherapy prevents internalization and improves the antitumor activity of siRNA by ensuring unrestrained entry of siRNA into the tumor vasculature and efficient intracellular delivery of siRNA. Moreover, research findings highlight the significance of utilizing nanoparticles as depots for photosensitive drugs in photodynamic therapy. The applicability of nanoparticles is further extended to medical imaging. They serve as contrast agents in combination with conventional imaging modalities such as MRI, CT, and fluorescence-based imaging to produce vivid and enhanced images of tumors. Therefore, this review aims to explore and delve deeper into the advent of various nanotechnology-based therapeutic and imaging techniques that provide non-invasive and effective means to tackle ovarian cancers.
    Keywords:  Dendrimers; Liposomes; Ovarian cancer; Polymer nanoparticles
    DOI:  https://doi.org/10.1007/s43032-022-00968-1
  13. Cancer Drug Resist. 2021 ;4(1): 44-68
    Perspectives of nano-carrier drug delivery systems to overcome cancer drug resistance in the clinics.
    Anna Ulldemolins, Joaquin Seras-Franzoso, Fernanda Andrade, Diana Rafael, Ibane Abasolo, Petra Gener, Simo Schwartz.
      Advanced cancer is still considered an incurable disease because of its metastatic spread to distal organs and progressive gain of chemoresistance. Even though considerable treatment progress and more effective therapies have been achieved over the past years, recurrence in the long-term and undesired side effects are still the main drawbacks of current clinical protocols. Moreover, a majority of chemotherapeutic drugs are highly hydrophobic and need to be diluted in organic solvents, which cause high toxicity, in order to reach effective therapeutic dose. These limitations of conventional cancer therapies prompted the use of nanomedicine, the medical application of nanotechnology, to provide more effective and safer cancer treatment. Potential of nanomedicines to overcome resistance, ameliorate solubility, improve pharmacological profile, and reduce adverse effects of chemotherapeutical drugs is thus highly regarded. Their use in the clinical setting has increased over the last decade. Among the various existing nanosystems, nanoparticles have the ability to transform conventional medicine by reducing the adverse effects and providing a controlled release of therapeutic agents. Also, their small size facilitates the intracellular uptake. Here, we provide a closer review of clinical prospects and mechanisms of action of nanomedicines to overcome drug resistance. The significance of specific targeting towards cancer cells is debated as well.
    Keywords:  Drug delivery systems; cancer treatment; nanomedicine; resistance
    DOI:  https://doi.org/10.20517/cdr.2020.59
  14. Drug Deliv Transl Res. 2022 May 15.
    Recent trends of bioconjugated nanomedicines through nose-to-brain delivery for neurological disorders.
    Tejas Girish Agnihotri, Govinda Shivaji Jadhav, Bichismita Sahu, Aakanchha Jain.
      The global burden of neurological disorders has been increasing day by day which calls for immediate attention to the solutions. Novel drug delivery systems are one of the alternatives that we count on to counteract these disorders. As the blood-brain barrier creates a significant hindrance to the delivery of drugs across the endothelium lining of the brain, nose-to-brain delivery has been the favorite option to administer such drugs. In recent times, bioconjugation has been viewed as a rapidly growing area in the field of pharmaceuticals. The pharmaceutical industry and academic research are investing significantly in bioconjugated structures as an attractive and advantageous potential aid to nanoparticulate delivery systems, with all of its flexible benefits in terms of tailor grafting and custom design as well as overcoming the majority of their drawbacks. This review discusses drug delivery via the intranasal route and gives insight into bioconjugation systems for drug molecules, their chemistry, and benefits over other systems. Conjugation of drugs/macromolecules with peptides, carbohydrates, ligands, and nucleic acids has also been discussed in detail. The figure represents few types of novel drug delivery systems and molecules that have been attempted by researchers for nose-to-brain delivery through nasal (mucosal) route for the effective management of epilepsy, Alzheimer's disease, brain cancer, and other brain disorders.
    Keywords:  Antibody conjugates; Bioconjugation strategies; Imaging; Nanoparticles (NPs); Nose-to-brain delivery; Theranostics applications
    DOI:  https://doi.org/10.1007/s13346-022-01173-y
  15. Adv Drug Deliv Rev. 2022 May 14. pii: S0169-409X(22)00234-4. [Epub ahead of print] 114344
    Light-triggered Photodynamic Nanomedicines for Overcoming Localized Therapeutic Efficacy in Cancer Treatment.
    Jiwoong Choi, In-Cheol Sun, Hee Sook Hwang, Hong Yeol Yoon, Kwangmeyung Kim.
      Photodynamic nanomedicines have significantly enhanced the therapeutic efficacy of photosensitizers (PSs) by overcoming critical limitations of PSs such as poor water solubility and low tumor accumulation. Furthermore, functional photodynamic nanomedicines have enabled overcoming oxygen depletion during photodynamic therapy (PDT) and tissue light penetration limitation by supplying oxygen or upconverting light in targeted tumor tissues, resulting in providing the potential to overcome biological therapeutic barriers of PDT. Nevertheless, their localized therapeutic effects still remain a huddle for the effective treatment of metastatic- or recurrent tumors. Recently, newly designed photodynamic nanomedicines and their combination chemo- or immune checkpoint inhibitor therapy enable the systemic treatment of various metastatic tumors by eliciting antitumor immune responses via immunogenic cell death (ICD). This review introduces recent advances in photodynamic nanomedicines and their applications, focusing on overcoming current limitations. Finally, the challenges and future perspectives of the clinical translation of photodynamic nanomedicines in cancer PDT are discussed.
    Keywords:  Light-triggered nanomedicine; photodynamic imaging; photodynamic immunotherapy; photodynamic therapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.addr.2022.114344
  16. J Pharm Anal. 2022 Feb;12(1): 35-57
    Anti-inflammatory and analgesic properties of Moroccan medicinal plants: Phytochemistry, in vitro and in vivo investigations, mechanism insights, clinical evidences and perspectives.
    Abdelhakim Bouyahya, Fatima-Ezzahrae Guaouguaou, Nasreddine El Omari, Naoual El Menyiy, Abdelaali Balahbib, Mohamed El-Shazly, Youssef Bakri.
      Moroccan medicinal plants exhibit several pharmacological properties such as antimicrobial, anticancer, antidiabetic, analgesic, and anti-inflammatory effects, which are related to the presence of numerous bioactive compounds, including phenolic acids, flavonoids, and terpenoids. In the present review, we systematically evaluate previously published reports on the anti-inflammatory and analgesic effects of Moroccan medicinal plants. The in vitro investigations revealed that Moroccan medicinal plants inhibit several enzymes related to inflammatory processes, whereas in vivo studies noted significant anti-inflammatory and analgesic effects as demonstrated using different experimental models. Various bioactive compounds exhibiting in vitro and in vivo anti-inflammatory and analgesic effects, with diverse mechanisms of action, have been identified. Some plants and their bioactive compounds reveal specific secondary metabolites that possess important anti-inflammatory effects in clinical investigations. Our review proposes the potential applications of Moroccan medicinal plants as sources of anti-inflammatory and analgesic agents.
    Keywords:  Analgesic; Anti-inflammatory; Bioactive compounds; Inflammation; Medicinal plants
    DOI:  https://doi.org/10.1016/j.jpha.2021.07.004
  17. Adv Exp Med Biol. 2022 ;1357 83-114
    Dermal Delivery of Lipid Nanoparticles: Effects on Skin and Assessment of Absorption and Safety.
    Fátima Pinto, Luis P Fonseca, Dragana P C de Barros.
      During the recent decades, dermal delivery has achieved visible popularity mainly due to the increase of chronic skin diseases and the demand for targeted delivery and patient compliance. Dermal delivery provides an attractive alternative to oral drug delivery, promoting the drug application directly at the site of action, resulting in higher localized drug concentration with reduced systemic drug exposure. Among several types of drug delivery systems used in dermal delivery are the lipid nanoparticles, which include solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). These lipid nanocarriers have attracted great interest and have been intensively studied for their use in dermal applications. Lipid nanoparticles increase the transport of active compounds through the skin by improving drug solubilization in the formulation, drug partitioning into the skin, and fluidizing skin lipids. Moreover, these nanocarriers are composed of biologically active and biodegradable lipids that show less toxicity and offer many favorable attributes such as adhesiveness, occlusion, skin hydration, lubrication, smoothness, skin penetration enhancement, modified release, improvement of formulation appearance providing a whitening effect, and offering protection of actives against degradation.This chapter focuses on the effects of lipid nanoparticles in dermal delivery, on the types of active compounds that are used in their formulation and application, some aspects related to their possible toxicity, and a description of the most commonly used techniques for the evaluation of drug absorption on the skin.
    Keywords:  Dermal absorption; Dermal delivery; Nanostructured lipid carriers; Occlusion; Retinoids; Solid lipid nanoparticles; Vegetable oils
    DOI:  https://doi.org/10.1007/978-3-030-88071-2_4
  18. J Cosmet Dermatol. 2022 May 20.
    Preparation, characterization and evaluation of anti-tyrosinase activity of solid lipid nanoparticles (SLNs) containing Undecylenoyl phenylalanine (Sepiwhite®).
    Homa Kabiri, Zahra Tayarani-Najaran, Pouria Rahmanian-Devin, Mohadeseh Sadat Vaziri, Samira Nasirizadeh, Shiva Golmohammadzadeh, Hossein Kamali.
      BACKGROUND: Hyperpigmentation is darkened patches or spots on the skin occurred by increased melanin. Undecylenoyl phenylalanine (Sepiwhite®), as a commercial lipophilic derivative of phenylalanine, is a powerful new brightener that can be used in the treatment of skin pigmentation disorders.AIMS: Solid lipid nanoparticles (SLNs) increase the efficiency of hydrophobic drugs. The current study aimed to prepare and characterize SLNs containing Sepiwhite (SEPI-SLN).
    METHODS: In this study, an optimized SEPI-SLN formulation was selected by applying the response surface method. In vitro drug loading content, the release profile of SEPI, and cell viability were investigated. The permeation rate of SEPI-SLN was also compared to conventional cream containing Sepiwhite (SEPI-CREAM). Furthermore, the anti-tyrosinase activity of Sepiwhite was also evaluated.
    RESULTS: The optimized formulation showed a spherical morphology with particle size and entrapment efficiency of 218.6 ± 11.1 nm and % 87.31±0.65, respectively. Differential scanning calorimetry (DSC) analysis confirmed SEPI-loaded SLN formulation with no drug-lipid incompatibility. The in vitro permeation experiment revealed the enhanced cutaneous uptake of SEPI-SLN. The results also showed that Sepiwhite could stop melanogenesis with inhibition of the tyrosinase enzyme.
    CONCLUSION: Our findings confirm that SLNs could be a proper nanocarrier for the relevant usage of Sepiwhite as a powerful brightener agent.
    Keywords:  Anti-tyrosinase, melania; Brightener; Hyperpigmentation; Sepiwhite; Solid lipid nanoparticles (SLNs)
    DOI:  https://doi.org/10.1111/jocd.15102
  19. Int J Biol Macromol. 2022 May 14. pii: S0141-8130(22)01056-X. [Epub ahead of print]211 368-379
    Delivery of curcumin by fucoidan-coated mesoporous silica nanoparticles: Fabrication, characterization, and in vitro release performance.
    Xu Zhang, Yanfei Zhu, Lihong Fan, Junhong Ling, Li-Ye Yang, Nan Wang, Xiao-Kun Ouyang.
      Mesoporous silica nanoparticles (MSN) are effective drug delivery carriers because of their adjustable large pore size and high porosity. In this study, complex nanoparticles containing disulfide bonds (SS) were designed and prepared as curcumin (Cur) carriers by using fucoidan (FUC) and MSN as the polymer matrix. The product was characterized using scanning electron microscopy, transmission electron microscopy, dynamic light scattering, Fourier-transform infrared spectroscopy, and an N2 adsorption and desorption test. When the mass ratio of MSN to FUC was 2:1, the nanospheres particle size was the smallest (295.6 ± 0.98 nm, -35.2 ± 0.8 mV). Furthermore, the curcumin encapsulation rate by MSN-Cur-SS-FUC was over 90%, and the cumulative release rate in 24 h was over 80% due to the combined effect of weak acidity and high glutathione concentration in the tumor site microenvironment. When the Cur concentration was 50 μg/mL, the cell viability of free Cur was 63.8%, the cell viability of MSN-Cur-SS-FUC was 14.5%, and the cell viability of MSN-SS-FUC at the same concentration remained above 74.6%. MSN-SS-FUC composite nanoparticles showed a good delivery of Cur, a lipid-soluble active compound, and provides a new delivery route for other lipid-soluble and poorly bioavailable active compounds.
    Keywords:  Curcumin; Fucoidan; Mesoporous silica
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.05.086
  20. Curr Pharm Des. 2022 May 09.
    Antimicrobial benefits of flavonoids and their nanoformulations.
    Sara Salatin, Ahad Bazmani, Shahriar Shahi, Behrooz Naghili, Mohammad Yousef Memar, Solmaz Maleki Dizaj.
      Nowadays, there is an urgent need to discover and develop long-term and effective antimicrobial and biofilm-inhibiting compounds. Employing combination therapies using novel drug delivery systems and also natural antimicrobial substances is a promising strategy in this field. Nanoparticles (NPs)-based materials have become well appreciated in recent times due to serve as antimicrobial agents or the carriers for promoting the bioavailability and effectiveness of antibiotics. Flavonoids belong to the promising groups of bioactive compounds abundantly found in fruits, vegetables, spices, and medicinal plants with strong antimicrobial features. Flavonoids and NPs have potential as alternatives to the conventional antimicrobial agents, both on their own as well as in combination. Different classes of flavonoid NPs may be particularly advantageous in handling microbial infections. The most important antimicrobial mechanisms of flavonoid NPs include oxidative stress induction, non-oxidative mechanisms, and metal ion release. However, the efficacy of flavonoid NPs against pathogens and drug-resistant pathogens changes according to their physicochemical characteristics as well as the particular structure of microbial cell wall and enzymatic composition. In this review, we provide an outlook on the antimicrobial mechanism of flavonoid-based NPs and the crucial factors that are involved.
    Keywords:  Flavonoids; antibacterial; antimicrobial; infection; multidrug-resistant bacteria; nanoparticles; pathogens
    DOI:  https://doi.org/10.2174/1381612828666220509151407
  21. Cancer Drug Resist. 2021 ;4(3): 543-558
    Emerging RAS-directed therapies for cancer.
    Michael Conroy, Darren Cowzer, Walter Kolch, Austin G Duffy.
      RAS oncogenes are the most commonly mutated oncogenes in human cancer, and RAS-mutant cancers represent a major burden of human disease. Though these oncogenes were discovered decades ago, recent years have seen major advances in understanding of their structure and function, including the therapeutic and prognostic significance of diverse isoforms. Targeting of these mutations has proven difficult, despite some successes with inhibition of RAS effector signalling. More recently, direct RAS inhibition has been achieved in a trial setting. While this has yet to be translated to everyday clinical practice, this development carries much promise. This review summarizes the diverse approaches that have been taken to RAS inhibition and then focuses on the most recent developments in direct inhibition of KRAS(G12C).
    Keywords:  Ras; erk; inhibition; isoform; pancreatic; signalling; targeted
    DOI:  https://doi.org/10.20517/cdr.2021.07
  22. Acta Biomater. 2022 May 14. pii: S1742-7061(22)00283-5. [Epub ahead of print]
    Chondroitin sulfate-based prodrug nanoparticles enhance photodynamic immunotherapy via Golgi apparatus targeting.
    Haohuan Li, Caifeng Deng, Yulu Tan, Jianxia Dong, Yuanhao Zhao, Xiaorong Wang, Xingyue Yang, Jingwen Luo, Huile Gao, Yuan Huang, Zhi-Rong Zhang, Tao Gong.
      Photodynamic therapy (PDT) is an emerging therapeutic approach that can inhibit tumor growth by destroying local tumors and activating systemic antitumor immune responses. However, PDT can be ineffective because of photosensitizer aggregation, tumor-induced dendritic cells (DCS) dysfunction and PDT-mediated immunosuppression. Therefore, we designed chondroitin sulfate-based prodrug nanoparticles for the co-delivery of the photosensitizer chlorin e6 (Ce6) and retinoic acid (RA), which can reduce PDT-mediated immunosuppression by disrupting the Golgi apparatus and blocking the production of immunosuppressive cytokines. Moreover, CpG oligodeoxynucleotide was combined as immunoadjuvant to promote the maturation of DCs. As expected, the strategy of Golgi apparatus targeting immunotherapy combined PDT was confirmed to relieve PDT-induced immunosuppression, showed excellent PDT antitumor efficacy in B16F10-subcutaneous bearing mice model. Thus, our finding offers a promising approach for photodynamic immunotherapy of advanced cancers. STATEMENT OF SIGNIFICANCE: Golgi apparatus has been shown to be a potential target of immunosuppression for producing several immunosuppressive cytokines. In this work, a Golgi apparatus-targeted prodrug nanoparticle was developed to enhance the immune response in photodynamic immunotherapy. The nanoparticle can target and disrupt the Golgi apparatus in tumor cells, which reduced PDT-mediated immunosuppression by blocking the production of immunosuppressive cytokines. This work provides an effective strategy of PDT in combination with the Golgi apparatus-targeted nanovesicle for enhanced cancer therapy.
    Keywords:  Cancer; Golgi apparatus; Immunosuppression; Photodynamic therapy; Prodrug
    DOI:  https://doi.org/10.1016/j.actbio.2022.05.014
  23. BMC Complement Med Ther. 2022 May 14. 22(1): 134
    Evaluation of anti-proliferative activity of Eryngium caucasicum on melanoma cancer cells.
    Haleh Forouhandeh, Zahra Rezaei Param, Ommoleila Molavi, Parina Asgharian, Vahideh Tarhriz.
      BACKGROUND: The genus Eryngium is a member of the Apiaceae family that has shown different pharmacological effects mainly including anti-inflammatory, analgesic, anti-cancer, hepatoprotective, and anti-oxidant. Previous research on the anti-cancer activity of Eryngium in some cancer cell lines has led us to explore the anti-proliferative activity of E. caucasicum in the B16F10 cell line.OBJECTIVE: In this study, the antiproliferative activity of E. caucasicum on melanoma cancer cells (B16F10) and non-cancerous cells (HFFF2) were evaluated in vitro.
    METHODS: The dried plant sample of E. caucasicum was extracted by Soxhlet apparatus with n-Hexane, dichloromethane, and methanol solvents. The effects of cytotoxicity of the extracts by the MTT method on melanoma cancer cells (B16F10) and noncancerous cells (HFFF2) was investigated for 24 and 48 hours. Then, the cytotoxicity of different fractions of the strong extract against normal and cancer cells was evaluated by this method. Annexin V/PI assay was used to study the induction apoptosis via the fractions in cancer cells.
    FINDINGS: According to the results of the MTT test, n-Hexane extract is the most effective extract against the B16F10 cell line and is a candidate for fractionation with VLC. Among the fractions, 40 and 60% VLC fractions of n-Hexan extract inhibited the growth of B16F10 cells at 24 and 48 hours while, these fractions at IC50 concentration had no cytotoxic effects on normal cells. Treatment of cancer cells with effective extract caused apoptosis and necrosis and 40 and 60% more fractions induced apoptosis in these cells.
    CONCLUSION: The n-Hexane extract of E. caucasicum and its 40 and 60% fractions showed the highest cytotoxic effect against the B16F10 cell line compared to other extracts and control groups. This inhibition was made through induction of apoptosis.
    Keywords:  Apoptosis; Cytotoxicity; Eryngium caucasicum; Melanoma
    DOI:  https://doi.org/10.1186/s12906-022-03618-w
  24. Int J Nanomedicine. 2022 ;17 2069-2078
    Fully Natural Lecithin Encapsulated Nano-Resveratrol for Anti-Cancer Therapy.
    Meiyi Liang, Mingyan Guo, Phei Er Saw, Yandan Yao.
      Introduction: Chemotherapeutics are known to have undesirable side effects (i.e. nausea, weight loss, hair loss, weakened immune system, etc.) due to the non-specificity of the drugs. Encapsulation of these chemotherapeutics inside nanoparticles significantly improves the bioavailability and half-life of drugs, while increasing their tumor penetration and localization. However, most, if not all, nanoparticles in clinics or research are synthetic, with no long-term studies on the effect of these nanoparticles in vivo. Herein, we developed a synergistic resveratrol nanoparticle system by using lecithin encapsulation. Lecithin, being a fully natural phospholipid derived from soybean, possesses inherent anti-tumor activity.Methods: Lec(RSV) was successfully prepared using the nanoprecipitation method, and characterized by particle size and zeta potential analysis, and transmission electron microscopy (TEM). The in vitro cellular uptake and cytotoxic effects of Lec(RSV) were investigated in human breast cancer cell line BT474. Finally, the in vivo tumoral uptake of Lec(RSV) was carried out in the BT474 orthotopic model.
    Results: Lec(RSV) showed a uniform distribution of ~120 nm, with prolonged stability. Lec(RSV) showed high cellular uptake and anti-cancer properties in vitro. Time-dependent uptake in the BT474 xenograft model indicated an increased tumoral uptake and apoptosis rate at 4 hours after tail vein injection of Lec(RSV).
    Conclusion: Taken together, we successfully developed a fully natural Lec(RSV) that possesses potent anti-cancer activity in vitro, with good tumoral uptake in vivo. We hypothesize that Lec(RSV) could be a safe anti-cancer therapeutic that could be easily translated into clinical application.
    Keywords:  anti-tumor properties; fully natural nanoparticle; lecithin; resveratrol
    DOI:  https://doi.org/10.2147/IJN.S362418
  25. Adv Exp Med Biol. 2022 ;1357 19-41
    Trends in the Design and Evaluation of Polymeric Nanocarriers: The In Vitro Nano-Bio Interactions.
    Ana Bettencourt, Lídia M Gonçalves.
      Different types of natural and synthetic polymeric nanocarriers are being tested for diverse biomedical applications ranging from drug/gene delivery vehicles to imaging probes. The development of such innovative nanoparticulate systems (NPs) should include in the very beginning of their conception a comprehensive evaluation of the nano-bio interactions. Specifically, intrinsic physicochemical properties as size, surface charge and shape may have an impact on cellular uptake, intracellular trafficking, exocytosis and cyto- or genocompatibility. Those properties can be tuned for effectiveness purposes such as targeting intracellular organelles, but at the same time inducing unforeseen adverse nanotoxicological effects. Further, those properties may change due to the adsorption of biological components (e.g. proteins) with a tremendous impact on the cellular response. The evaluation of these NPs is highly challenging and has produced some controversial results. Future research work should focus on the standardization of analytical or computational methodologies, aiming the identification of toxicity trends and the generation of a useful meta-analysis database on polymeric nanocarriers.This chapter covers all the aforementioned aspects, emphasizing the importance of the in vitro cellular studies in the first stages of polymeric nanocarriers development.
    Keywords:  In vitro tests; Nanotoxicology; Physicochemical properties; Polymeric-nanostructures; Safe-by-design
    DOI:  https://doi.org/10.1007/978-3-030-88071-2_2
  26. Anticancer Agents Med Chem. 2022 May 16.
    Chemotherapeutic Role of Polyphenols Present in Ocimum Sanctum.
    Saima Khatoon, Nida Kalam, Vinod Rmt Balasubramaniam, Mohd Farooq Shaikh, Mohammad Tahir Ansari.
      Ocimum sanctum is a sacred herb of India and is commonly known as 'Tulsi' or 'Holy Basil' in regional languages of the country. Various parts of O. sanctum are recognised to have remarkable therapeutic efficacy, and are therefore used in Indian traditional medicine system, Ayurveda. Scientific studies have shown that O. sanctum has a range of pharmacological activities. The presence of a substantial amount of polyphenols in O. sanctum could be the reason for its excellent bioactivity. Polyphenols are used to prevent or treat oncologic diseases due to their anti-cancer effects, which are related to activation of apoptotic signaling, cell cycle arrest, binding ability with membrane receptors, and potential effects on immunomodulation and epigenetic mechanisms. The poor bioavailability of polyphenols restricts their clinical use. The application of nanonization has been implemented to improve their bioavailability, penetrability, and prolong their anticancer action. The present review analyses the recent preclinical studies related to the chemo-preventive and therapeutic potential of polyphenols present in O. sanctum. Moreover, the current article also examines in-depth the biochemical and molecular mechanisms involved in the antineoplastic actions of the considered polyphenols.
    Keywords:  Ocimum sanctum; apigenin; cancer; eugenol; ferulic acid; quercetin
    DOI:  https://doi.org/10.2174/1871520622666220516142839
  27. Front Bioeng Biotechnol. 2022 ;10 904344
    Olaparib and Doxorubicin Co-Loaded Polypeptide Nanogel for Enhanced Breast Cancer Therapy.
    Yanhong Liu, Meiyan Wang, Wanru Liu, Jili Jing, Hongshuang Ma.
      Although great progress has been made in improving the efficacy of cancer treatment through combination treatment using drug agents, there are still challenges in improving the efficiency of drug delivery. In this study, olaparib and doxorubicin were co-loaded on disulfide bond cross-linked polypeptide nanogels for the treatment of breast cancer in mouse models. Under stimulation of a high glutathione environment in cancer cells, the drug is quickly released from the nanogel to target cancer cells. In addition, compared with free drugs and single-drug-loaded nanogels, dual-drug- co-loaded nanogels exhibit the best anti-cancer effect and demonstrated excellent biological safety. Therefore, the co-delivery of olaparib and doxorubicin through polypeptide nanogels presents good prospects for application as anti-cancer treatment.
    Keywords:  co-delivery; molecular targeted therapy; olaparib; polypeptide; reduction-responsive
    DOI:  https://doi.org/10.3389/fbioe.2022.904344
  28. Curr Drug Deliv. 2022 May 13.
    Recent Developments and Potential for Clinical Use of Casein as a Drug Carrier.
    Ravindra Semwal, Sunil Kumar Joshi, Ruchi Badoni Semwal, Deepak Kumar Semwal.
      BACKGROUND: The development of drug delivery carriers is the key area of research in the field of novel drug delivery systems. To date, a long list of carriers has been identified for this purpose but the deliveries of poorly water-soluble active substances are still facing challenges and hence, such substances are pharmacologically unsafe and economically incompetent.OBJECTIVE: This article aims to review the applications of casein as a drug carrier and its potential for clinical use.
    METHODS: The relevant literature on the casein protein was collected from authentic online scientific databases like PubMed, Scopus and Google Scholar using different keywords including "casein", "drug delivery system", "drug carrier" and "bioavailability". The articles and books accessed online were thoroughly reviewed and the most relevant reports on casein as a drug carrier were only included in the present study.
    RESULTS: Casein, a milk protein, has many structural and physicochemical properties which facilitate its functionality in delivery systems. Moreover, its amphiphilic nature makes it the most suitable carrier for both hydrophobic and hydrophilic drugs without showing any toxic effects. The carriers obtained from natural sources are trustworthy over synthetic carriers and in the demand of the market due to their easy availability, low-cost factor, bio-friendly and nontoxic nature.
    CONCLUSION: Casein was found an effective natural drug carrier in various delivery systems due to its unique applications in improving the bioavailability and efficacy of a drug.
    Keywords:  Casein; bioavailability; drug delivery system; hydrogel; micelles; nanoparticles
    DOI:  https://doi.org/10.2174/1567201819666220513085552
  29. J Pharm Anal. 2022 Apr;12(2): 324-331
    Cyclic arginine-glycine-aspartic acid-modified red blood cells for drug delivery: Synthesis and in vitro evaluation.
    Chen Wang, Min Wang, Yan Zhang, Hongxin Jia, Binbin Chen.
      Red blood cells (RBCs) are an excellent choice for cell preparation research because of their biocompatibility, high drug loading, and long half-life. In this study, doxorubicin (DOX) was encapsulated with RBCs as the carrier. The biotin-avidin system binding principle was used to modify biotinylated cyclic arginine-glycine-aspartic acid (cRGD) onto RBC surfaces for accurate targeting, high drug loading, and sustained drug release. The RBC drug delivery system (DDS) was characterized, and the concentration of surface sulfur in the energy spectrum was 6.330%. The physical and chemical properties of RBC DDS were as follows: drug content, 0.857 mg/mL; particle size, 3339 nm; potential value, -12.5 mV; and cumulative release rate, 81.35%. There was no significant change in RBC morphology for up to seven days. The results of the targeting and cytotoxicity studies of RBC DDS showed that many RBCs covered the surfaces of U251 cells, and the fluorescence intensity was higher than that of MCF-7 cells. The IC50 value of unmodified drug-loaded RBCs was 2.5 times higher than that of targeted modified drug-loaded RBCs, indicating that the targeting of cancer cells produced satisfactory inhibition. This study confirms that the RBC DDS has the characteristics of accurate targeting, high drug loading, and slow drug release, which increases its likelihood of becoming a clinical cancer treatment in the future.
    Keywords:  Cytotoxicity; Drug delivery; Red blood cells; Targeting
    DOI:  https://doi.org/10.1016/j.jpha.2021.06.003
  30. J Control Release. 2022 May 13. pii: S0168-3659(22)00287-5. [Epub ahead of print]
    Prolonged blood circulation outperforms active targeting for nanocarriers-mediated enhanced hepatocellular carcinoma therapy in vivo.
    Yue-Qing Wang, Cong Huang, Peng-Ju Ye, Jin-Rong Long, Cheng-Hu Xu, Ying Liu, Xiao-Li Ling, Shao-Yang Lv, Dong-Xiu He, Hua Wei, Cui-Yun Yu.
      Successful hepatocellular carcinoma (HCC) therapy in vivo remains a significant challenge due to the down-regulated expression of the receptors on the surface of tumor cells for compromised active targeting efficiency and cellular uptake of nanoparticles (NPs)-based drug delivery systems (DDSs) and "accelerated blood clearance" and premature unpackaging of NPs in vivo induced by the poly(ethylene glycol)ylation (PEGylation). Inspired by the repeatedly highlighted prolonged blood circulation property of RBCm-camouflaged NPs, we hypothesis that the prolonged blood circulation property resulting from RBCm coating outperforms the active targeting mechanisms of various targeting ligands for enhanced HCC therapy in vivo. Clarification of this hypothesis is therefore of great significance and urgency to break the afore mentioned bottlenecks that hamper the efficient HCC treatment in vivo. For this purpose, we reported in this study the first identification of a determining factor of nanocarriers for enhanced HCC therapy in vivo by the use of the previously fabricated pectin-doxorubicin nanoparticles (PDC-NPs) as a typical example, i.e., the natural RBCm was used as a stealth coating of PDC-NPs for the fabrication of biomimetic DDSs, PDC@RBC-NPs via hypotonic dialysis and mechanical co-extrusion methods. Comprehensive in vitro and in vivo evaluation and comparison of the properties and performance of PDC@RBC-NPs and PDC-NPs were performed in terms of colloidal stability, biosafety, drug release profiles, macrophage escape, anti-HCC effect. The resulting PDC@RBC-NPs outperformed PDC-NPs for HCC therapy in vitro and in vivo. Notably, PDC@RBC-NPs-treated BALB/c nude mice showed a significantly smaller final average tumor volume of 613mm3 after 16 days than the PDC-NPs-treated group with an average value of 957mm3. Therefore, the PDC@RBC-NPs developed herein showed great potential for clinical transformations due to the facile preparation and superior therapeutic efficiency against HCC. Most importantly, prolonged blood circulation was identified as a determining factor of nanocarriers instead of active targeting for enhanced HCC therapy in vivo, which could be used to direct the future design and development of advanced DDSs with greater therapeutic efficiency for HCC.
    Keywords:  Biomimetic nanoparticle; Erythrocyte membrane; Hepatocellular carcinoma; Long circulation; Macrophage escape
    DOI:  https://doi.org/10.1016/j.jconrel.2022.05.024
  31. Curr Drug Deliv. 2022 May 16.
    Development and Evaluation of Biotin Functionalized Fullerenes for the Delivery of Irinotecan to Colon Tumors.
    Shikha Dhiman, Amardeep Kaur, G L Gupta, Manu Sharma.
      BACKGROUND: Irinotecan is a promising antitumor agent approved by FDA for intravenoususe in colon cancer treatment either alone or in combination. It is a topoisomerase inhibitor and by blocking the topoisomerase-I enzyme, it causes DNA damage and results in cell death. However, it lacks selectivity and specificity for tumor cells, resulting in systemic toxicity. Thus, it is essential to reduce its side effects and improve therapeutic efficacy.OBJECTIVE: The study was aimed to improve the therapeutic efficacy and to minimize the toxic effects of irinotecan by developing a fullerene functionalized biotin drug delivery system and adsorbing irinotecan on the surface of the functionalized fullerene-biotin complex.
    METHODS: Fullerene (C60) has been observed as a potential drug delivery agent and the amine- functionalized C60-NH2 was synthesized by functionalizing ethylenediamine on the surface of C60. The PEI functionalized C60 was further synthesized by polymerization of aziridine on the surface of C60-NH2. Biotin was attached by an amide linkage to C60-PEI and the anti-colon cancer drug irinotecan (IRI) was encapsulated (C60-PEI-Biotin/IRI). The C60-PEI-Biotin/IRI was characterized and evaluated for in vivo anti-colon cancer activity in rats and the results were compared with the parent drug irinotecan.
    RESULTS: The results showed that C60-PEI-Biotin/IRI conjugatehad acontrolled release profile according to in vitroHPLC studies. Moreover in vivo anti-tumor studies suggested that the conjugate proved to be less toxic to vital organs and had high efficacy towards tumor cells. Statistical studies confirmed less tumor index and tumor burden in the case of conjugate when compared to irinotecan.
    CONCLUSION: It is hypothesized that the conjugate (C60-PEI-Biotin/IRI) could cross the cell membrane easily through overexpressed biotin receptors on the cell surface of colon cancer cells and showed better efficacy and less toxicity in comparison to IRI in the colon cancer rat model.
    Keywords:  Irinotecan; biotin; cell membrane.; colon cancer; drug delivery; fullerenes; nanoparticles
    DOI:  https://doi.org/10.2174/1567201819666220516153010
  32. Biomater Sci. 2022 May 20.
    A core-shell liquid metal-Cu nanoparticle with glutathione consumption via an in situ replacement strategy for tumor combination treatment of chemodynamic, microwave dynamic and microwave thermal therapy.
    Yongnian Yu, Qiong Wu, Meng Niu, Li Gou, Longfei Tan, Changhui Fu, Xiangling Ren, Jun Ren, Yongfa Zheng, Xianwei Meng.
      The presence of high content glutathione (GSH) provides an effective "protective shield" for tumor cells, which undoubtedly is a huge impediment to reactive oxygen species (ROS)-based treatment. Fortunately, divalent copper (Cu2+) can not only consume GSH, destroying the protection mechanism of GSH, but also can be reduced to Cu+ with excellent Fenton-like reaction activity. Hence, capitalizing on the properties of liquid metals, we introduced Cu with three different valances via an in situ replacement reaction. A stable core-shell liquid-metal based "Cu storage pool" was obtained. It can effectively deplete GSH within the cells, and simultaneously produce ·OH through a Fenton-like reaction, further improving the effect of chemodynamic therapy (CDT). Under microwave irradiation, it is also capable of producing a large amount of ROS to promote tumor treatment. In addition, the loading of ionic liquid endows LZC@IL nanoparticles with certain microwave heating performance, which is able to augment microwave thermal therapy (MWTT). With the combination of CDT, microwave dynamic therapy (MDT) and MWTT, LZC@IL has an excellent effect on tumor elimination. This work offers a new idea for the application of liquid metals and the combined treatment of tumors, which has potential application value.
    DOI:  https://doi.org/10.1039/d2bm00435f
  33. Eur J Pharmacol. 2022 May 14. pii: S0014-2999(22)00285-0. [Epub ahead of print] 175024
    Intravesical combination therapies for non-muscle invasive bladder cancer: Recent advances and future directions.
    You Li, Shams F Youssef, Asma Bm Buanz.
      Bladder cancer is the 10th most frequently diagnosed cancer worldwide with 5-year survival rate around 70%. The current first-line treatment for non-muscle invasive bladder cancer is transurethral resection of bladder tumours followed by intravesical Mycobacterium Bovis Bacillus Calmette-Guérin (BCG) immunotherapy. However, tumor recurrence rate is still high ranging from 31% to 78% within five years. To avoid radical cystectomy, intravesical combination therapies have been developed as salvage treatments to overcome BCG failure. Recent advances in diagnostics thanks to tumor molecular profiling and in treatment such as development of immunotherapies provides more treatment options beyond BCG treatment. This also goes hand-in hand with formulation advances to deliver these new therapies where traditional drug delivery systems might not be suitable, which in turn is completed by challenges to deliver drugs via the intravesical route. In this article the aim was to provide an in-depth analysis of the current developments of intravesical combination therapies, ranging from relatively simple combinations of mixing existed intravesical therapeutic agents (immunotherapies and chemotherapies) to the combined formulations containing advanced gene therapies and targeted therapies, with special focus on therapies that have made it to the clinical trial stage. In addition, recent attempts to utilize device-assisted treatments and novel drug delivery platforms are included. This review also highlights the limitations that still need to be overcome such as the inadequate studies on newly explored drug carriers and proposes potential directions for future work to overcome BCG-failure.
    Keywords:  BCG; Bladder cancer; Combination therapies; Formulation; Intravesical drug delivery; Non-muscle invasive bladder cancer
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175024
  34. Nutr Cancer. 2022 May 18. 1-13
    Molecular Mechanism of Curcumin and Its Analogs as Multifunctional Compounds against Pancreatic Cancer.
    Qun Huang, Ya Zhang, Yanlin Zheng, Hongjing Yang, Yang Yang, Ya Mo, Liuying Li, Hong Zhang.
      Pancreatic cancer (PC) is one of the most common malignant tumors with a poor prognosis and high mortality. Surgical resection is the most effective treatment for PC; however, only a minority of patients have resectable tumors. Chemotherapy is the primary treatment for PC. Curcumin is a natural chemical substance obtained from plants with a wide range of pharmacological activities. Research evidence suggests that curcumin can influence PC development through multiple molecular mechanisms. The synthesis of novel curcumin analogs and preparation of curcumin nano-formulations are effective strategies to overcome the low bioavailability of curcumin in the treatment of PC. This review aims to summarize the mechanisms of action of curcumin in preclinical and clinical studies on PC and research progress in enhancing its bioavailability.
    DOI:  https://doi.org/10.1080/01635581.2022.2071451
  35. J Mater Chem B. 2022 May 19.
    Tumor acidity-responsive polymeric nanoparticles to promote intracellular delivery of zoledronic acid by PEG detachment and positive charge exposure for enhanced antitumor potency.
    Ya-Hsuan Chou, Yu-Ling Liu, Tsai-Ching Hsu, Jia-Le Yow, Bor-Show Tzang, Wen-Hsuan Chiang.
      Zoledronic acid (ZA), a third-generation bisphosphonate, has been extensively used to treat osteoporosis and cancer bone metastasis and demonstrated to suppress proliferation of varied cancer cells and selectively kill tumor-associated microphages (TAMs). However, the clinical applications of ZA in extraskeletal tumor treatment are largely restricted due to its rapid renal clearance and binding to bones. In this study, to promote intracellular delivery of ZA for amplified antitumor efficacy, tumor acidity-responsive polymeric nanoparticles with high ZA payload (ca. 12.3 wt%) and low premature ZA leakage were designed. As a pivotal material for surface coating, the acidity-sensitive and amphiphilic methoxy poly(ethylene glycol) (mPEG)-benzoic imine-octadecane (C18) (mPEG-b-C18) was synthesized by conjugation of mPEG-CHO with 1-octadecylamine upon Schiff base reaction. Through tailor-made co-assembly of the hydrophobic poly(lactic-co-glycolic acid) (PLGA), amphiphilic tocopheryl polyethylene glycol succinate (TPGS) and mPEG-b-C18 to encapsulate ionic complexes composed of ZA molecules and branched poly(ethylenimine) (PEI) segments, the attained therapeutic polymeric nanoparticles, characterized to have a hydrophobic PLGA/ZA/PEI-constituted core covered with mPEG-b-C18 and TPGS, were able to not only detach mPEG shielding upon acidity-triggered hydrolysis of benzoic imine bonds but also expose surface positive charges of protonated PEI segments. The in vitro cellular uptake and cytotoxicity studies demonstrated that the internalization of acidity-sensitive ZA-encapsulated nanoparticles by TRAMP-C1 mouse prostate cancer cells and murine macrophages RAW 264.7 was considerably promoted upon acidity-elicited PEG detachment and surface charge conversion, thus remarkably boosting intracellular ZA delivery and anticancer potency. Compared to PEG non-detachable ZA-loaded nanoparticles with poor tumor deposition and antitumor effect, the PEG-detachable ZA-carrying nanoparticles markedly accumulated in TRAMP-C1 solid tumors in vivo and inhibited tumor growth, thereby increasing the survival rate of the treated mice. The collective data suggest the great promise of tumor acidity-sensitive ZA-carrying hybrid nanoparticles in the treatment of extraskeletal solid tumors.
    DOI:  https://doi.org/10.1039/d2tb00695b
  36. Nutr Cancer. 2022 May 20. 1-18
    Inhibition of Glutamine Cellular Uptake Contributes to the Cytotoxic Effect of Xanthohumol in Triple-Negative Breast Cancer Cells.
    F Carmo, C Silva, F Martel.
      Breast cancer constitutes the most incident cancer and one of the most common causes of cancer-related death. "Glutamine addiction", an important metabolic feature of cancer cells, is dependent on supply of this amino acid from external sources. In this study, the effect of several polyphenols (catechin, epicatechin, EGCG, catechin:lysine, naringenin, hesperidin, malvidin, delphinidin, kaempferol, quercetin, rutin, myricetin, resveratrol, xanthohumol, and chrysin) upon glutamine (3H-GLN) uptake by human breast epithelial adenocarcinoma cell lines with distinct characteristics (MCF-7 and MDA-MB-231) was assessed.Several polyphenols interfere with 3H-GLN uptake by both cell lines. Xanthohumol markedly decreases total and Na+-dependent 3H-GLN uptake and showed a cytotoxic and anti-proliferative effect in MDA-MB-231 cells. Xanthohumol is as an uncompetitive inhibitor of Na+-dependent 3H-GLN uptake and inhibits GPNA (L-γ-glutamyl-p-nitroanilide)-sensitive, both ASCT2 (alanine, serine, cysteine transporter 2)-mediated and non-ASCT2-mediated 3H-GLN uptake. Xanthohumol does not interfere with the transcription rates of ASCT2. The cytotoxic effect of xanthohumol, but not its anti-proliferative effect, is GPNA-sensitive and related to ASCT2 inhibition. Combination of xanthohumol with the breast cancer chemotherapeutic agent doxorubicin results in an additive anti-proliferative, but not cytotoxic effect.We conclude that targeting glutamine uptake might constitute a potential interesting strategy for triple-negative breast cancer.
    DOI:  https://doi.org/10.1080/01635581.2022.2076889
  37. Crit Rev Food Sci Nutr. 2022 May 19. 1-20
    Iron delivery systems for controlled release of iron and enhancement of iron absorption and bioavailability.
    Shengjie Hu, Songyi Lin, Xueqing He, Na Sun.
      Iron deficiency is a global nutritional problem, and adding iron salts directly to food will have certain side effects on the human body. Therefore, there is growing interest in food-grade iron delivery systems. This review provides an overview of iron delivery systems, with emphasis on the controlled release of iron during gastrointestinal digestion, as well as the enhancement of iron absorption and bioavailability. Iron-bearing proteins are easily degraded by digestive enzymes and absorbed through receptor-mediated endocytosis. Instead, protein aggregates are slowly degraded in the stomach, which delays iron release and serves as a potential iron supplement. Amino acids, peptides and polysaccharides can bind iron through iron binding sites, but the formed compounds are prone to dissociation in the stomach. Moreover, peptides and polysaccharides can deliver iron by mediating the formation of ferric oxyhydroxide which is absorbed through endocytosis or bivalent transporter 1. In addition, liposomes are unstable during gastric digestion and iron is released in large quantities. Complexes formed by polysaccharides and proteins, and microcapsules formed by polysaccharides can delay the release of iron in the gastric environment and prolong iron release in the intestinal environment. This review is conducive to the development of iron functional ingredients and dietary supplements.
    Keywords:  Gastrointestinal digestion; iron absorption; iron bioavailability; iron delivery system; iron release
    DOI:  https://doi.org/10.1080/10408398.2022.2076652
  38. Biochimie. 2022 May 12. pii: S0300-9084(22)00126-2. [Epub ahead of print]
    Melatonin as an adjuvant treatment modality with doxorubicin.
    Parisa Maleki Dana, Fatemeh Sadoughi, Russel J Reiter, Sotoudeh Mohammadi, Zahra Heidar, Masoumeh Mirzamoradi, Zatollah Asemi.
      Combination chemotherapy seems to be a beneficial choice for some cancer patients particularly when the drugs target different processes of oncogenesis; patients treated with combination therapies sometimes have a better prognosis than those treated with single drug chemotherapy. However, research has shown that this is not always the case, and this approach may only increase toxicity without having a significant effect in augmenting the antitumor actions of the drugs. Doxorubicin (Dox) is one of the most common chemotherapy drugs used to treat many types of cancer, but it also has serious side effects, such as cardiotoxicity, skin necrosis, testicular toxicity, and nephrotoxicity. Many studies have examined the efficiacy of melatonin (MLT) as an anticancer agent. In fact, MLT is an anti-cancer agent that has various functions in inhibiting cancer cell proliferation, inducing apoptosis, and suppressing metastasis. Herein, we provide a comprehensive evaluation of the literature concerned with the role of MLT as an adjuvant in Dox-based chemotherapies and discuss how MLT may enhance the antitumor effects of Dox (e.g., by inducing apoptosis and suppressing metastasis) while rescuring other organs from its adverse effects, such as cardio- and nephrotoxicity.
    Keywords:  Chemotherapy; Doxorubicin; Melatonin; Toxicity
    DOI:  https://doi.org/10.1016/j.biochi.2022.05.005
  39. Macromol Rapid Commun. 2022 May 19. e2200255
    NIR Responsive Injectable Nanocomposite Thermogel System Against Osteosarcoma Recurrence.
    Ranran Guo, Peng Zhang, Jianing Liu, Ruihong Xie, Leyu Wang, Liu Cai, Xiaozhong Qiu, Hongxun Sang.
      Compared to traditional postoperative radiation and chemotherapy, immune checkpoint blockade (ICB) therapy demonstrates superiority by provoking own immune system to cure cancer completely even for some terminally ill patients. However, systemic administration of ICB is liable to cause severe immunity inflammation or immune storm. Here we propose an injectable, near infrared (NIR) responsive, multifunctional nanocomposite thermogel as a local ICB delivery system for cancer postsurgical therapy. By copolymerization of thermosensitive and zwitterionic monomer, the injectable thermogel with adjustable sol-gel transition temperature is obtained. Afterwards, combined with functional mesoporous nanoparticles, the platform could absorb NIR light and transfer it into heat. The generated heat will promote retro Diels-Alder reaction to degrade coating layer on nanoparticle, achieving NIR controlled ICB release. Furthermore, the local ICB delivery system is applied on an osteosarcoma postsurgical recurrence model and results indicate the platform with favorable biocompatibility could avoid early leakage of cargos and greatly increase drug content at tumor site. Besides, long-term controlled ICB release of the system effectively improve the amount of active T cells, resulting in excellent anti-tumor recurrence effect. Overall, this work suggests the local injectable nanocomposite thermogel is expected to be a promising tool for cancer postoperative therapy. This article is protected by copyright. All rights reserved.
    Keywords:  cancer recurrence; injectable thermogel; nanocomposite; near infrared
    DOI:  https://doi.org/10.1002/marc.202200255
  40. J Pharm Sci. 2022 May 14. pii: S0022-3549(22)00200-3. [Epub ahead of print]
    pH-responsive nanoparticles for multidimensional combined chemo-immunotherapy of cancer.
    Kavya Sree Maravajjala, K Laxmi Swetha, Aniruddha Roy.
      Current research has demonstrated that tumor development and progression are dependent on a multi-cellular interactome, which forms the tumor microenvironment. Multiple components of this multi-cellular ecosystem need to be targeted simultaneously for successful cancer therapy. The objective of this study was to develop a multidimensional combined chemo-immunotherapeutic modality for effective breast cancer treatment. TLR 7/8 agonist resiquimod was identified as a potent macrophage stimulant in an initial screening. To deliver paclitaxel as a chemotherapeutic drug and resiquimod as an immune activator in a tumor-targeted fashion, two different pH-sensitive nanoparticles were synthesized using two different polymers, a linear PLGA and a multi-arm, star-shaped PLGA. The star-PLGA pH-responsive nanoparticles exhibited improved pH-dependent drug release and increased penetration in a complex breast cancer spheroid model (breast cancer cell + macrophage cell). Treatment with paclitaxel and resiquimod encapsulated in the pH-responsive nanoparticles resulted in increased cancer cell death and macrophage activation, as tested in an in-vitro breast cancer spheroid model. Altogether, the current study suggests that the paclitaxel and resiquimod combination has potent chemo-immunotherapeutic activity, and delivery using a pH-sensitive nanoparticle further improves its efficacy.
    Keywords:  Combined chemo-immunotherapy; Paclitaxel; Resiquimod; Tumor targeting; pH-responsive nanoparticles
    DOI:  https://doi.org/10.1016/j.xphs.2022.05.008
  41. Eur J Pharmacol. 2022 May 14. pii: S0014-2999(22)00292-8. [Epub ahead of print] 175031
    Drug repurposing: An emerging strategy in alleviating skin cancer.
    Popat Kumbhar, Kapil Kole, Tejashree Yadav, Ashwini Bhavar, Pramod Waghmare, Rajdeep Bhokare, Arehalli Manjappa, Niraj Kumar Jha, Dinesh Kumar Chellappan, Sunita Shinde, Sachin Kumar Singh, Kamal Dua, Ahmad Salawi, John Disouza, Vandana Patravale.
      Skin cancer is one of the most common forms of cancer. Several million people are estimated to have affected with this condition worldwide. Skin cancer generally includes melanoma and non-melanoma with the former being the most dangerous. Chemotherapy has been one of the key therapeutic strategies employed in the treatment of skin cancer, especially in advanced stages of the disease. It could be also used as an adjuvant with other treatment modalities depending on the type of skin cancer. However, there are several shortfalls associated with the use of chemotherapy such as non-selectivity, tumour resistance, life-threatening toxicities, and the exorbitant cost of medicines. Furthermore, new drug discovery is a lengthy and costly process with minimal likelihood of success. Thus, drug repurposing (DR) has emerged as a new avenue where the drug approved formerly for the treatment of one disease can be used for the treatment of another disease like cancer. This approach is greatly beneficial over the de novo approach in terms of time and cost. Moreover, there is minimal risk of failure of repurposed therapeutics in clinical trials. There are a considerable number of studies that have reported on drugs repurposed for the treatment of skin cancer. Thus, the present manuscript offers a comprehensive overview of drugs that have been investigated as repurposing candidates for the efficient treatment of skin cancers mainly melanoma and its oncogenic subtypes, and non-melanoma. The prospects of repurposing phytochemicals against skin cancer are also discussed. Furthermore, repurposed drug delivery via topical route and repurposed drugs in clinical trials are briefed. Based on the findings from the reported studies discussed in this manuscript, drug repurposing emerges to be a promising approach and thus is expected to offer efficient treatment at a reasonable cost in devitalizing skin cancer.
    Keywords:  Clinical trials; Drug repurposing; Molecular mechanisms; Pharmacology; Phytochemicals; Skin cancer
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175031
  42. Curr Med Chem. 2022 ;29(18): 3261-3299
    Targeting Microenvironment of Melanoma and Head and Neck Cancers in Photodynamic Therapy.
    Ivana Ratkaj, Martina Mušković, Nela Malatesti.
      BACKGROUND: Photodynamic therapy (PDT), in comparison to other skin cancers, is still far less effective for melanoma, due to the strong absorbance and the role of melanin in cytoprotection. The tumour microenvironment (TME) has a significant role in tumour progression, and the hypoxic TME is one of the main reasons for melanoma progression to metastasis and its resistance to PDT. Hypoxia is also a feature of solid tumours in the head and neck region that indicates negative prognosis.OBJECTIVE: The aim of this study was to individuate and describe systematically the main strategies in targeting the TME, especially hypoxia, in PDT against melanoma and head and neck cancers (HNC), and assess the current success in their application.
    METHODS: PubMed was used for searching, in MEDLINE and other databases, for the most recent publications on PDT against melanoma and HNC in combination with the TME targeting and hypoxia.
    RESULTS: In PDT for melanoma and HNC, it is very important to control hypoxia levels, and amongst the different approaches, oxygen self-supply systems are often applied. Vascular targeting is promising, but to improve it, optimal drug-light interval, and formulation to increase the accumulation of the photosensitiser in the tumour vasculature, have to be established. On the other side, the use of angiogenesis inhibitors, such as those interfering with VEGF signalling, is somewhat less successful than expected and needs to be further investigated.
    CONCLUSION: The combination of PDT with immunotherapy by using multifunctional nanoparticles continues to develop and seems to be the most promising for achieving a complete and lasting antitumour effect.
    Keywords:  Photodynamic therapy; head and neck cancer; hypoxia; melanoma; photosensitisers; tumour microenvironment
    DOI:  https://doi.org/10.2174/0929867328666210709113032
  43. Cancer Drug Resist. 2021 ;4(2): 298-320
    Curcumin: reclaiming the lost ground against cancer resistance.
    Siraj Shaikh, Javed Shaikh, Yusufi Sadia Naba, Kailas Doke, Khursheed Ahmed, Mujahid Yusufi.
      Curcumin, a polyphenol, has a wide range of biological properties such as anticancer, antibacterial, antitubercular, cardioprotective and neuroprotective. Moreover, the anti-proliferative activities of Curcumin have been widely studied against several types of cancers due to its ability to target multiple pathways in cancer. Although Curcumin exhibited potent anticancer activity, its clinical use is limited due to its poor water solubility and faster metabolism. Hence, there is an immense interest among researchers to develop potent, water-soluble, and metabolically stable Curcumin analogs for cancer treatment. While drug resistance remains a major problem in cancer therapy that renders current chemotherapy ineffective, curcumin has shown promise to overcome the resistance and re-sensitize cancer to chemotherapeutic drugs in many studies. In the present review, we are summarizing the role of curcumin in controlling the proliferation of drug-resistant cancers and development of curcumin-based therapeutic applications from cell culture studies up to clinical trials.
    Keywords:  Curcumin; clinical trials; drug-resistant cancer; signaling pathways
    DOI:  https://doi.org/10.20517/cdr.2020.92
  44. Curr Drug Deliv. 2022 May 17.
    Formulation and Statistical Evaluation of Tablets Containing Pitavastatin- Self Nano Emulsifying Drug Delivery Systems.
    Sridevi Gowripattapu, D SathisKumar, S Selvamuthukumar.
      PURPOSE: To formulate and characterize tablets containing Pitavastatin that has been loaded with a self-nano emulsifying drug delivery system (SNEDDS).METHODS: Pitavastatin SNEDDS were prepared with a variety of oils, surfactants, co-surfactants, and solvents to improve the dissolution rate and bioavailability of the HMG-CoA reductase inhibitor. The SNEDDS components were preliminarily investigated for drug solubility in various vehicles, excipient miscibility, emulsification rate, and ternary phase diagrams. The tablets were made using a porous carrier made of Aerosil 200 and then loaded with SNEDDS using a simple absorption method. Physical parameters such as tablet hardness, weight variation, disintegration, drug content, and in-vitro drug release were then measured on the tablets.
    RESULTS: Labrafac Lipophilewl1349 (Oil), Tween 80 (Surfactant) and Egg lecithin (Co-surfactant) were selected for the preparation of SNEDDS. Tablets with high porosity suitable for loading with SNEDDS and containing the super-disintegrants, achieved complete dissolution of Pitavastatin from the tablets. In vitro release of Pitavastatin from SNEDDS and the tablets was similar (p < 0.05).
    CONCLUSION: SNEDDS of Pitavastatin is a promising approach to achieving a solid dosage form of the liquid-loaded drug delivery systems for enhancing the solubility and dissolution rate of the drug, and hence also its bioavailability.
    Keywords:  Pitavastatin; SNEDDS; co-surfactant; drug carrier; drug release; self-nanoemulsifying; solubility; surfactant
    DOI:  https://doi.org/10.2174/1567201819666220517113012
  45. Drug Discov Today. 2022 May 17. pii: S1359-6446(22)00194-5. [Epub ahead of print]
    Impact of fenofibrate on NAFLD/NASH: A genetic perspective.
    Ali Mahmoudi, Tannaz Jamialahmadi, Thomas P Johnston, Amirhossein Sahebkar.
      Nonalcoholic fatty liver disease (NAFLD), caused by an accumulation of fat deposits in hepatocytes, prevalently affects at least one-third of the world's population. The progression of this disorder can potentially include a spectrum of consecutive stages, specifically: steatosis, steatohepatitis and cirrhosis. Fenofibrate exhibits potential therapeutic efficacy for NAFLD owing to several properties, which include antioxidant, apoptotic, anti-inflammatory and antifibrotic activity. In the present review, we discuss the direct or indirect impact of fenofibrate on genes involved at various stages in the progression of NAFLD. Moreover, we have reviewed studies that compare fenofibrate with other drugs in treating NAFLD, as well as recent clinical trials, in an attempt to identify reliable scientific and clinical evidence concerning the therapeutic effects and benefits of fenofibrate on NAFLD. Teaser.
    Keywords:  Animal models; Clinical; Co-assembly; Fenofibrate; Genes; Microcirculation
    DOI:  https://doi.org/10.1016/j.drudis.2022.05.007
  46. Annu Rev Nutr. 2022 May 19.
    The Origins, Evolution, and Future of Dietary Methionine Restriction.
    Han Fang, Kirsten P Stone, Desiree Wanders, Laura A Forney, Thomas W Gettys.
      The original description of dietary methionine restriction (MR) used semipurified diets to limit methionine intake to 20% of normal levels, and this reduction in dietary methionine increased longevity by ∼30% in rats. The MR diet also produces paradoxical increases in energy intake and expenditure and limits fat deposition while reducing tissue and circulating lipids and enhancing overall insulin sensitivity. In the years following the original 1993 report, a comprehensive effort has been made to understand the nutrient sensing and signaling systems linking reduced dietary methionine to the behavioral, physiological, biochemical, and transcriptional components of the response. Recent work has shown that transcriptional activation of hepatic fibroblast growth factor 21 (FGF21) is a key event linking the MR diet to many but not all components of its metabolic phenotype. These findings raise the interesting possibility of developing therapeutic, MR-based diets that produce the beneficial effects of FGF21 by nutritionally modulating its transcription and release. Expected final online publication date for the Annual Review of Nutrition, Volume 42 is August 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-nutr-062320-111849
  47. Biomaterials. 2022 May 03. pii: S0142-9612(22)00189-2. [Epub ahead of print]285 121549
    Reversing breast cancer bone metastasis by metal organic framework-capped nanotherapeutics via suppressing osteoclastogenesis.
    Binhua Zou, Zushuang Xiong, Lizhen He, Tianfeng Chen.
      Bone metastasis is the major cause of cancer-related morbidity and mortality. To avoid further osteolysis, current treatment ideas focus on tumor cell and the inhibition of osteoclast. Herein, zeolitic imidazolate framework-8-capped Cu2-XSe composite nanoplatform (ICG@Cu2-XSe-ZIF-8) is developed for chemodynamic therapy (CDT) and photothermal therapy (PTT) treatment of malignant breast cancer bone tumors. The rational design of ZIF-8 encapsulation greatly reduces the accumulation of Cu2-XSe to damage the normal cells. Under acidic microenvironment in tumor, ZIF-8 is cleaved to release Cu2-XSe, which can subsequently degrade into Cu (+) and Cu (2+) ions to initiate a Fenton-like reaction inducing CDT. Meanwhile, Cu2-XSe is used to be an effective photothermal transduction agent for exerting the PTT effect. What's more, the selenium element in Cu2-XSe can regulates selenoprotein to inhibit tumor cells and osteoclasts. Of note, the hyperthermia induced by PTT can further enhance the CDT effect in tumor, achieving a synergistic PTT/CDT effect. Based on these advantages, ICG@Cu2-XSe-ZIF-8 effectively suppresses the tumor cells in bone tissue, and reduces the erosion of bone tissue via suppressing osteoclastogenesis. In conclusion, this study demonstrates the potential action mechanism of ZIF-8-capped nanomedicine against osteolysis in bone metastasis.
    Keywords:  Chemo-photothermal therapy; Malignant bone tumor; Nanoparticles; Osteoclast; PTT
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121549
  48. J Pharm Investig. 2022 May 09. 1-15
    Smart pH-responsive nanomedicines for disease therapy.
    Jongyoon Shinn, Nuri Kwon, Seon Ah Lee, Yonghyun Lee.
      Background: Currently nanomedicines are the focus of attention from researchers and clinicians because of the successes of lipid-nanoparticles-based COVID-19 vaccines. Nanoparticles improve existing treatments by providing a number of advantages including protection of cargo molecules from external stresses, delivery of drugs to target tissues, and sustained drug release. To prevent premature release-related side effects, stable drug loading in nanoformulations is required, but the increased stability of the formulation could also lead to a poor drug-release profile at the target sites. Thus, researchers have exploited differences in a range of properties (e.g., enzyme levels, pH, levels of reduced glutathione, and reactive oxygen species) between non-target and target sites for site-specific release of drugs. Among these environmental stimuli, pH gradients have been widely used to design novel, responsive nanoparticles.Area covered: In this review, we assess drug delivery based on pH-responsive nanoparticles at the levels of tissues (tumor microenvironment, pH ~ 6.5) and of intracellular compartments (endosome and lysosome, pH 4.5-6.5). Upon exposure to these pH stimuli, pH-responsive nanoparticles respond with physicochemical changes to their material structure and surface characteristics. These changes include swelling, dissociation, or surface charge switching, in a manner that favors drug release at the target site (the tumor microenvironment region and the cytosol followed by endosomal escape) rather than the surrounding tissues.
    Expert opinion: Lastly, we consider the challenges involved in the development of pH-responsive nanomedicines.
    Keywords:  Endosomal escape; Nanomedicines; Tumor microenvironment; pH-responsiveness
    DOI:  https://doi.org/10.1007/s40005-022-00573-z
  49. Oxid Med Cell Longev. 2022 ;2022 2724324
    The Cross-Talk between Polyphenols and the Target Enzymes Related to Oxidative Stress-Induced Thyroid Cancer.
    Shabnam Heydarzadeh, Sima Kheradmand Kia, Maryam Zarkesh, Safura Pakizehkar, Samaneh Hosseinzadeh, Mehdi Hedayati.
      The most serious hallmark step of carcinogenesis is oxidative stress, which induces cell DNA damage. Although in normal conditions ROS are important second messengers, in pathological conditions such as cancer, due to imbalanced redox enzyme expression, oxidative stress can occur. Recent studies with firmly established evidence suggest an interdependence between oxidative stress and thyroid cancer based on thyroid hormone synthesis. Indeed, a reduced antioxidant defense system might play a part in several steps of progression in thyroid cancer. Based on studies that have been conducted previously, future drug designs for targeting enzymatic ROS sources, as a single agent or in combination, have to be tested. Polyphenols represent the potential for modulating biological events in thyroid cancer, including antioxidative activity. Targeting enzymatic ROS sources, without affecting the physiological redox state, might be an important purpose. As regards the underlying chemopreventive mechanisms of natural compounds that have been discussed in other cancer models, the confirmation of the influence of polyphenols on thyroid cancer is inconclusive and rarely available. Therefore, there is a need for further scientific investigations into the features of the antioxidative effects of polyphenols on thyroid cancer. The current review illustrates the association between some polyphenols and the key enzymes that take place in oxidation reactions in developing thyroid cancer cells. This review gives the main points of the enzymatic ROS sources act and redox signaling in normal physiological or pathological contexts and supplies a survey of the currently available modulators of TPO, LOX, NOX, DUOX, Nrf2, and LPO derived from polyphenols.
    DOI:  https://doi.org/10.1155/2022/2724324
  50. Galen Med J. 2021 ;10 e2097
    Molecular Mechanisms of Vitamin D-Mediated Immunomodulation.
    Farhan Khashim Alswailmi, Syed Imran Ali Shah, Haleema Nawaz, Ghassab Mohammad Al-Mazaideh.
      Ever since discovering the fat-soluble secosteroid vitamin D, an abundance of research has been conducted on the molecular mechanisms for the multiple health benefits of this nutrient. Studies on the beneficial effects of vitamin D supplementation have found appreciable evidence suggesting that it may play a more prime role than initially presumed. Though it has largely been implicated in bone pathophysiology, novel research on vitamin D indicates its fundamental involvement in a wide range of disease processes through its multiple systemic effects, including but not limited to metabolic, cardiovascular, anti-inflammatory, antineoplastic, antioxidant, neuroprotective, and immune actions. Recent work has yielded important mechanistic insights into the functions of vitamin D in mediating immunity. The present work sheds light on the metabolism and immune response mechanisms of vitamin D. Current review is based on a thorough search of the available relevant research findings of the metabolic transformations of vitamin D and the molecular basis of its role in immunity. Apart from its classical mechanistic control of mineral homeostasis, vitamin D has immunomodulatory effects through various mechanisms at both systemic and cellular levels. Disruption of vitamin D reliant molecular pathways in the regulation of immune response can potentially result in the development and/or progression of autoimmune and infective processes.
    Keywords:  Adaptive Immunity; Immunomodulation; Innate Immunity; Vitamin D
    DOI:  https://doi.org/10.31661/gmj.v10i0.2097
  51. Materials (Basel). 2022 Apr 30. pii: 3251. [Epub ahead of print]15(9):
    Surface Engineering of Nanomaterials with Polymers, Biomolecules, and Small Ligands for Nanomedicine.
    Ana M Díez-Pascual.
      Nanomedicine is a speedily growing area of medical research that is focused on developing nanomaterials for the prevention, diagnosis, and treatment of diseases. Nanomaterials with unique physicochemical properties have recently attracted a lot of attention since they offer a lot of potential in biomedical research. Novel generations of engineered nanostructures, also known as designed and functionalized nanomaterials, have opened up new possibilities in the applications of biomedical approaches such as biological imaging, biomolecular sensing, medical devices, drug delivery, and therapy. Polymers, natural biomolecules, or synthetic ligands can interact physically or chemically with nanomaterials to functionalize them for targeted uses. This paper reviews current research in nanotechnology, with a focus on nanomaterial functionalization for medical applications. Firstly, a brief overview of the different types of nanomaterials and the strategies for their surface functionalization is offered. Secondly, different types of functionalized nanomaterials are reviewed. Then, their potential cytotoxicity and cost-effectiveness are discussed. Finally, their use in diverse fields is examined in detail, including cancer treatment, tissue engineering, drug/gene delivery, and medical implants.
    Keywords:  cancer therapy; drug delivery; functional nanomaterials; medical implants; nanomedicine; polymers; tissue engineering
    DOI:  https://doi.org/10.3390/ma15093251
  52. Phytomedicine. 2022 Mar 31. pii: S0944-7113(22)00168-4. [Epub ahead of print]102 154090
    Curcumae rhizoma and its major constituents against hepatobiliary disease: Pharmacotherapeutic properties and potential clinical applications.
    Tian-Hui Gao, Wan Liao, Li-Ting Lin, Zong-Ping Zhu, Mei-Gui Lu, Chao-Mei Fu, Tian Xie.
      BACKGROUND: Hepatobiliary disease currently serves as an urgent health issue in public due to health-modulating factors such as extension of life expectancy, increasingly sedentary lifestyles and over-nutrition. A definite treatment remains lacking owing to different stages of the disease itself and its intricate pathogenesis. Traditional Chinese medicine (TCM) has been gradually popularized in clinic with the satisfactory efficacy and good safety. Curcumae Rhizoma (called E Zhu, EZ in Chinese) is a representative herb, which has been used to treat hepatobiliary disease for thousands of years.PURPOSE: To systematically summarize the recent research advances on the pharmacological activities of EZ and its constituents, explain the underlying mechanisms of preventing and treating hepatobiliary diseases, and assess the shortcomings of existing work. Besides, ethnopharmacology, phytochemicals, and toxicology of EZ have been researched.
    METHODS: The information about EZ was collected from various sources including classic books about Chinese herbal medicine, and scientific databases including Web of Science, PubMed, ScienceDirect, Springer, ACS, SCOPUS, CNKI, CSTJ, and WANFANG using keywords given below and terms like pharmacological and phytochemical details of this plant.
    RESULTS: The chemical constituents isolated and identified from EZ, such as terpenoids including β-elemene, furanodiene, germacrone, etc. and curcuminoids including curcumin, demethoxycurcumin, bisdemethoxycurcumin, etc. prove to have hepatoprotective effect, anti-liver fibrotic effect, anti-fatty liver effect, anti-liver neoplastic effect, and cholagogic effect through TGF-β1/Smad, JNK1/2-ROS, NF-κB and other anti-inflammatory and antioxidant signaling pathways. Also, EZ is often combined with other Chinese herbs in the treatment of hepatobiliary diseases with good clinical efficacy and no obvious adverse reactions.
    CONCLUSION: It provides a preclinical basis for the efficacy of EZ as an effective therapeutic agent for the prevention and treatment of hepatobiliary diseases. Even so, the further studies still needed to alleviate hepatotoxicity and expand clinical application.
    Keywords:  Chemical components; Clinical trials; Curcumae Rhizoma; Ethnopharmacology; Hepatobiliary disease; Toxicology
    DOI:  https://doi.org/10.1016/j.phymed.2022.154090
  53. Curr Drug Deliv. 2022 May 09.
    Development of a novel pomegranate polysaccharide nanoemulsion formulation with anti-inflammatory, antioxidant and antitumor properties.
    Samah S Hoseny, Amel M Soliman, Sohair R Fahmy, Shimaa A Sadek.
      BACKGROUND: Colorectal cancer is one of the most serious gastrointestinal cancers in Africa and its prevention is a pronounced challenge in contemporary medicine worldwide.OBJECTIVE: The present study aimed to develop a nanoemulsion drug delivery system using pomegranate polysaccharides (PGPs) as alternative cancer remedy, then evaluated its biological activities.
    METHODS: The PGPs yield and chemical composition were evaluated, then a PGPs nanoemulsion (PGPs-NE) was prepared using the self-emulsification technique with an oil phase. The physicochemical characterization of PGPs-NE was then analyzed. The in vitro antioxidant, anti-inflammatory activities, and antitumor potency of PGPs and PGPs-NE were also evaluated.
    RESULTS: The PGPs yield was 10%. The total sugar and protein content of PGPs was 44.66 mg/dl and 19.83µg/ml, respectively. PGPs was mainly composed of five monosaccharides including fructose, glucose, galactose, rhamnose, and arabinose. Concerning physiochemical characterization, the formulated PGPs-NE had three optical absorption bands at 202, 204 and 207nm and a transmittance of 80%. Its average hydrodynamic particle size was 9.5nm, with a PDI of less than 0.2 and a negative zeta potential (-30.6 mV). The spherical shape of PGPs-NE was confirmed by a transmission electron microscope study, with an average size of less than 50 nm. Additionally, the method used to prepare the PGPs-NE formulation provided a high entrapment efficiency (92.82%). The current study disclosed that PGPs-NE exhibited strong antioxidant, anti-inflammatory, and antitumor agent potency compared to that of free PGPs.
    CONCLUSION: These promising current findings provide evidence for the possible efficacy of novel PGPs-NE as an alternative treatment for CRC.
    Keywords:  Colorectal cancer; anti-inflammatory; antioxidant; drug delivery system; nanoemulsion; pomegranate polysaccharides
    DOI:  https://doi.org/10.2174/1567201819666220509161548
  54. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 May 20. e1818
    Brain-targeting drug delivery systems.
    Peixin Liu, Chen Jiang.
      Brain diseases, including neurodegenerative diseases, acute ischemic stroke and brain tumors, have become a major health problem and a huge burden on society with high morbidity and mortality. However, most of the current therapeutic drugs can only relieve the symptoms of brain diseases, and it is difficult to achieve satisfactory therapeutic effects fundamentally. Extensive studies have shown that the therapeutic effects of brain diseases are mainly affected by two factors: the conservation of the blood-brain barrier (BBB) and the complexity of the brain micro-environment. Brain-targeting drug delivery systems provide new possibilities for overcoming these barriers with versatility. In this review, it provides an overview of BBB alteration and discusses targeting delivery strategies for brain diseases therapy. Furthermore, delivery systems which are designed to modulate the brain micro-environment with synergistic effects were also highlighted. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies.
    Keywords:  blood-brain barrier; brain diseases; brain microenvironment; synergistic effects
    DOI:  https://doi.org/10.1002/wnan.1818
  55. Mater Sci Eng C Mater Biol Appl. 2022 Feb 23. pii: S0928-4931(22)00080-7. [Epub ahead of print] 112720
    Challenges and opportunities on vegetable oils derived systems for biomedical applications.
    Ana R Ribeiro, Simone S Silva, Rui L Reis.
      Vegetable oils have been suggested in polymer science as an environmentally friendly feedstock existing in abundance in nature, with worldwide availability and low cost. Although they have been widely explored as building blocks for polymers synthesis, their functional roles as owners of potent biomolecules are less unexplored. Their ancient biomolecules support natural biological roles such as antioxidant, antibacterial, anti-inflammatory, and anti-tumor properties, which are considered a great promise for biomedical proposes. This comprehensive review provides an overview of grape, soybean, castor, sesame, olive vegetable oils where their native anti-inflammatory, anti-tumor, antioxidant, and antibacterial biological compounds bring health benefits that can be translated to the biomedical field. These plant oils are considered the most relevant for the molecular design of functional and high-performance biomaterials that can contribute to the reduction of carbon footprint. The representative examples of vegetable oil-derived biomaterials, their main composition, shape, and the processing technology will be covered and innovative strategies toward the development of new multifunctional polymeric materials for pharmacological patches, wound healing devices, drug carriers, and scaffolds for tissue engineering applications will be discussed.
    Keywords:  Biomaterials; Biomedical applications; Polymers; Vegetable oils
    DOI:  https://doi.org/10.1016/j.msec.2022.112720
  56. Pharm Biol. 2022 Dec;60(1): 909-914
    Red ginseng polysaccharide exhibits anticancer activity through GPX4 downregulation-induced ferroptosis.
    Feng-Guo Zhai, Qi-Chao Liang, Yi-Yan Wu, Jia-Qi Liu, Jia-Wei Liu.
      CONTEXT: Red ginseng polysaccharide (RGP) is an active component of the widely used medicinal plant Panax ginseng C. A. Meyer (Araliaceae), which has displayed promising activities against cancer cells. However, the detailed molecular mechanism of RGP in ferroptosis is still unknown.OBJECTIVE: This study evaluates the effects of RGP in cancer cells.
    MATERIALS AND METHODS: A549 and MDA-MB-231 cells were used. Cell proliferation was measured by CCK-8 assay after being treated with RGP at concentrations of 0, 50, 100, 200, 400, 800 and 1600 μg/mL at 0, 12, 24 and 48 h. Lipid reactive oxygen species (ROS) levels were assessed by C11-BODIPY assay. The control group was treated with PBS.
    RESULTS: RGP inhibited human A549 (IC50: 376.2 μg/mL) or MDA-MB-231(IC50: 311.3 μg/mL) proliferation and induced lactate dehydrogenase (LDH) release, promoted ferroptosis and suppressed the expression of GPX4. Moreover, the effects of RGP were enhanced by the ferroptosis inducer erastin, while abolished by ferroptosis inhibitor ferrostatin-1.
    DISCUSSION AND CONCLUSIONS: Our study is the first to demonstrate (1) the anticancer activity of RGP in human lung cancer and breast cancer. (2) RGP presented the anti-ferroptosis effects in lung and breast cancer cells via targeting GPX4.
    Keywords:  Lung cancer; breast cancer; traditional Chinese medicine
    DOI:  https://doi.org/10.1080/13880209.2022.2066139
  57. Int J Pharm. 2022 May 14. pii: S0378-5173(22)00365-9. [Epub ahead of print] 121810
    Mitochondrial targeted drug delivery combined with Manganese Catalyzed Fenton reaction for the treatment of breast cancer.
    Xincheng Zhong, Xiaoyan Bao, Haiqing Zhong, Yi Zhou, Zhentao Zhang, Yiying Lu, Qi Dai, Qiyao Yang, Peng Ke, Yiyi Xia, Linjie Wu, Zaiyun Sui, Yan Lu, Min Han, WenHong Xu, Jianqing Gao.
      In previous studies, we found that triphenylphosphine-modified doxorubicin (TPP-DOX) can effectively kill drug-resistant tumor cells, but its effect on sensitive tumor cells is weakened. In this research, with albumin from Bovine Serum (BSA) as a carrier, TPP-DOX@MnBSA (TD@MB) nanoparticles were prepared by co-loading TPP-DOX and manganese which can realize the combination of chemotherapy and chemodynamic therapy (CDT). The uniform and stable nano-spherical nanoparticle can promote drug uptake, achieve mitochondrial-targeted drug delivery, increase intracellular reactive oxygen species (ROS) and catalyze the production of highly toxic oxidative hydroxyl radicals (OH·), further inhibiting the growth of both sensitive and drug-resistant MCF-7 cells. Besides, TD@MB can down-regulate the stemness-related proteins and the metastasis-related proteins, potentially decreasing the tumor stemness and metastasis. In vivo experiment indicated that TD@MB was able to exert desired antitumor effect, good tumor targeting and biocompatibility.
    Keywords:  Breast cancer; doxorubicin; drug resistance; mitochondrial target
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121810
  58. J Mater Chem B. 2022 May 17.
    Fabrication of human serum albumin-imprinted photothermal nanoparticles for enhanced immunotherapy.
    Jizhuang Ma, Yao Zhang, Hongyi Sun, Pingtian Ding, Dawei Chen.
      Photothermal nanoparticles have been confirmed to induce an antitumor immune response and turn "cold tumor" into "hot tumor". However, their delivery efficacy to tumors is limited by the elimination from the reticalendothel system. Herein, human serum albumin (HSA)-imprinted polymer coated Fe3O4 nanoparticles (Fe3O4@MIPs) are fabricated by oxidative polymerization of dopamine in the presence of HSA on the polydopamine pre-modified Fe3O4 nanoparticle surface, followed by the removal of HSA. The Fe3O4@MIPs exhibit rapid and specific reabsorption toward HSA. The molecularly imprinted sites on the Fe3O4@MIPs endow it with an albumin-rich protein corona in the blood and result in less elimination from the reticalendothel system than non-albumin-imprinted particles (Fe3O4@NIPs). Moreover, the molecularly imprinted polymer, which consists of polydopamine, also improves the photothermal effect of Fe3O4 nanoparticles. In vivo, the albumin camouflage in Fe3O4@MIPs produces a 2.6-fold improvement in tumor accumulation in comparison to Fe3O4@NIPs, and more heat is produced upon 808 nm laser irradiation, which further triggers an efficient immunogenic cell death (ICD) progress. Thus, the combination of Fe3O4@MIPs and PD-L1 antibody can not only inhibit the growth of primary tumors but also eliminates lung metastasis by eliciting immunological effect.
    DOI:  https://doi.org/10.1039/d2tb00396a
  59. Front Oncol. 2022 ;12 890810
    Editorial: Metabolic Abnormalities and Breast Cancer: Challenges From Bench to Bedside.
    Zheng Wang, Pu Li, Mark Daniel Pegram, Xiaosong Chen.
      
    Keywords:  breast cancer; metabolic reprogramming; metabolism abnormalities; obesity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.890810
  60. J Ethnopharmacol. 2022 May 14. pii: S0378-8741(22)00426-3. [Epub ahead of print] 115387
    Traditional uses, phytochemistry, transformation of ingredients and pharmacology of the dried seeds of Raphanus sativus L. (Raphani Semen), A comprehensive review.
    Lei Gao, Huan Li, Bingqian Li, Huili Shao, Xinyue Yu, Zhuang Miao, Lizhen Zhang, Liqiao Zhu, Huagang Sheng.
      ETHNOPHARMACOLOGICAL RELEVANCE: Raphani Semen (Lai Fu-zi in Chinese, RS), the dried seeds of Raphanus sativus L., is a traditional Chinese herbal medicine. RS has long been used for eliminating bloating and digestion, antitussive, expectorant and anti-asthmatic in clinical treatment of traditional Chinese medicine.AIM OF THE STUDY: This review provides a critical and comprehensive summary of traditional uses, phytochemistry, transformation of ingredients and pharmacology of RS based on research data that have been reported, aiming at providing a basis for further study on RS.
    MATERIALS AND METHODS: The search terms "Raphani Semen", "the seeds of Raphanus sativus L." and "radish seed" were used to obtain the information from electronic databases such as Web of Science, China National Knowledge Infrastructure, PubMed and other web search instruments. Traditional uses, phytochemistry, transformation of ingredients and pharmacology of RS were summarized.
    RESULTS: RS has been traditionally used to treat food dyspeptic retention, distending pain in the epigastrium and abdomen, constipation, diarrhea and dysentery, panting, and cough with phlegm congestion in the clinical practice. The chemical constituents of RS include glucosinolates and sulfur-containing derivatives, phenylpropanoid sucrosides, small organic acids and derivatives, flavone glycosides, alkaloids, terpenoids, steroids, oligosaccharides and others. Among them, glucosinolates can be transformated to isothiocyanates by plant myrosinase or the intestinal flora, which display a variety of activities, such as anti-tumor, anti-inflammatory, antioxidant, antibacterial, treatment of metabolic diseases, central nervous system protection, anti-osteoporosis. RS has a variety of pharmacological activities, including treatment of metabolic diseases, anti-inflammatory, anti-tumor, antioxidant, antibacterial, antihypertensive, central nervous system protection, anti-osteoporosis, etc. This review will provide useful insight for exploration, further study and precise medication of RS in the future.
    CONCLUSIONS: According to its traditional uses, phytochemistry, transformation of ingredients and pharmacology, RS is regarded as a promising medical plant with various chemical compounds and numerous pharmacological activities. However, the material bases and mechanisms of traditional effect of RS need further study.
    Keywords:  Pharmacology; Phytochemistry; Raphani semen; Traditional uses; Transformation of ingredients
    DOI:  https://doi.org/10.1016/j.jep.2022.115387
  61. Cancer Drug Resist. 2021 ;4(2): 463-484
    Liposome co-encapsulation of anti-cancer agents for pharmacological optimization of nanomedicine-based combination chemotherapy.
    Alberto Gabizon, Patricia Ohana, Yasmine Amitay, Jenny Gorin, Dina Tzemach, Lidia Mak, Hilary Shmeeda.
      Aim: Co-encapsulation of anti-cancer agents in pegylated liposomes may provide an effective tool to maximize efficacy of combined drug therapy by taking advantage of the long circulation time, passive targeting, and reduced toxicity of liposome formulations. Methods: We have developed several liposome formulations of co-encapsulated drugs using various permutations of three active agents: doxorubicin (Dox), mitomycin-C lipidic prodrug (MLP), and alendronate (Ald). Dox and MLP are available in single drug liposomal formulations: pegylated liposomal Dox (PLD, Doxil®), clinically approved, and pegylated liposomal MLP (PL-MLP, Promitil®), in phase 1-2 clinical testing. We have previously shown that co-encapsulation of Dox and Ald in pegylated liposomes (PLAD) results in a formulation with valuable immuno-pharmacologic properties and superior antitumor properties over PLD in immunocompetent animal models. Building on the PLAD and PL-MLP platforms, we developed a new pegylated liposomal formulation of co-entrapped Dox and MLP (PLAD-MLP), with the former localized in the liposome water phase via remote loading with an ammonium alendronate and the latter passively loaded into the liposome lipid bilayer. An alternative formulation of co-entrapped MLP and Dox in which ammonium Ald was replaced with ammonium sulfate (PLD-MLP) was also tested for comparative purposes. Results: PLAD-MLP displays high loading efficiency of Dox and MLP nearing 100%, and a mean vesicle diameter of 110 nm. Cryo-transmission electron microscopy (cryo-TEM) of PLAD-MLP reveals round vesicles with an intra-vesicle Dox-alendronate precipitate. PLAD-MLP was tested in an in vitro MLP activation assay with the reducing agent dithiothreitol and found to be significantly less susceptible to thiolytic activation than PL-MLP. Alongside thiolytic activation of MLP, a significant fraction of encapsulated Dox was released from liposomes. PLAD-MLP is stable upon in vitro incubation in human plasma with nearly 100% drug retention. In mouse pharmacokinetic studies, PLAD-MLP extended MLP half-life in circulation when compared to that of MLP delivered as PL-MLP. In addition, the MLP levels in tissues were greater than those obtained with PL-MLP, indicating that PLAD-MLP slows down the cleavage of the prodrug MLP to MMC, thus resulting in a more sustained and prolonged exposure. The circulation half-life of Dox in PLAD-MLP was similar to the PLD Dox half-life. The pattern of tissue distribution was similar for the co-encapsulated drugs, although Dox levels were generally higher than those of MLP, as expected from cleavage of MLP to its active metabolite MMC. In mouse tumor models, the therapeutic activity of PLAD-MLP was superior to PL-MLP and PLD with a convenient safety dose window. The Ald-free formulation, PLD-MLP, displayed similar pharmacokinetic properties to PLAD-MLP, but its therapeutic activity was lower. Conclusion: PLAD-MLP is a novel multi-drug liposome formulation with attractive pharmacological properties and powerful antitumor activity and is a promising therapeutic tool for combination cancer chemotherapy.
    Keywords:  Doxorubicin; bisphoshonate; drug carrier; drug delivery; mitomycin c; nanoparticle; prodrug; remote loading
    DOI:  https://doi.org/10.20517/cdr.2020.87
  62. Med Oncol. 2022 May 15. 39(5): 70
    20(s)-ginsenoside Rh2 promotes TRAIL-induced apoptosis by upregulating DR5 in human hepatocellular carcinoma cells.
    Wenmo Liu, Siqi Wang, Qinchuan Yang, Xinyao Feng, Bin Yu, Xianghui Yu.
      Tumor necrosis factor-related apoptosis-inducing ligand is a potential therapeutic anti-cancer drug with selective cytotoxicity in cancer cells. However, in multiple clinical trials, the therapeutic effect of TRAIL is limited owing to tumor resistance. The combination of small molecules or other drugs may represent a suitable strategy to overcome TRAIL resistance. This study found that 20(s)-ginsenoside Rh2 sensitized non-sensitive human hepatocellular carcinoma cells to TRAIL-induced apoptosis. The combination of TRAIL and Rh2 decreased cell viability and increased caspase cascade-induced apoptosis in several liver cancer cell lines. Moreover, we found that Rh2 reduced the apoptosis-related protein XIAP and Survivin, a negative regulator of the apoptosis pathway. At the same time, Rh2 can further enhance TRAIL-induced apoptosis by upregulating the death receptor 5, thereby significantly enhancing its anti-tumor effect. Furthermore, Rh2 enhanced the therapeutic efficacy of TRAIL in mouse xenograft models, suggesting that Rh2 also sensitizes TRAIL in vivo. Taken together, our study indicates that Rh2 may act as a sensitizer in combination with TRAIL to increase the efficacy of its anti-tumor activity.
    Keywords:  20(s)-ginsenoside Rh2; Apoptosis; Cancer therapy; DR5; TRAIL
    DOI:  https://doi.org/10.1007/s12032-022-01663-6
  63. Front Oncol. 2022 ;12 823956
    Low-Intensity Focused Ultrasound Targeted Microbubble Destruction Enhanced Paclitaxel Sensitivity by Decreasing Autophagy in Paclitaxel-Resistant Ovarian Cancer.
    Gonglin Fan, Jiale Qin, Xiaofeng Fu, Xing Si, Liqiang Li, Keji Yang, Beibei Wang, Haiya Lou, Jiang Zhu.
      Ultrasound targeted microbubble destruction (UTMD) was introduced as a promising method to improve anti-tumor therapeutic efficacy, while minimizing side effects to healthy tissues. Nevertheless, the acoustical phenomenon behind the UTMD as well as the exact mechanisms of autophagy action involved in the increased anti-cancer response are still not fully understood. Therefore, we examined the drug resistance-reversing effects of low-intensity focused ultrasound with microbubble (LIFU+MB) in paclitaxel (PTX)-resistant ovarian cancer cells. Cell viability was evaluated using CCK8 (Cell Counting Kit-8), apoptosis was detected by flow cytometry, quantitative real-time PCR and Western blot were used to detect the expressions of mRNA and protein, and autophagy was observed by transmission electron microscopy (TEM). We revealed that the level of autophagy was increased (p < 0.05) in PTX-resistant ovarian cancer cells. Treatment of LIFU+MB combined with PTX can notably inhibit proliferation as well as increase apoptosis (p < 0.01) in drug-resistant cells. We proposed that LIFU+MB might affect the sensitivity of ovarian cancer cells to PTX by modulating autophagy. To verify the hypothesis, we analyzed the autophagy level of drug-resistant cells after the treatment of LIFU+MB and found that autophagy was significantly inhibited. Altogether, our findings demonstrated that LIFU+MB could reverse PTX resistance in ovarian cancer via inhibiting autophagy, which provides a novel strategy to improve chemosensitivity in ovarian cancer.
    Keywords:  autophagy; low-intensity focused ultrasound; microbubble; ovarian cancer; paclitaxel; resistance
    DOI:  https://doi.org/10.3389/fonc.2022.823956
  64. Curr Pharm Des. 2022 May 18.
    Evolving era of "sponges": Nanosponges as a versatile nanocarrier for the effective skin delivery of drugs.
    Prashansha Mullick, Aswathi R Hegde, Divya Gopalan, Abhijeet Pandey, Krishnadas Nandakumar, Sanyog Jain, Gowthamarajan Kuppusamy, Srinivas Mutalik.
      BACKGROUND: Nanosponge, as a carrier for skin delivery system for drugs, plays a vital role. It not only serves to administer the drug to the targeted layer of skin but also increases the drug retention and deposition on the skin.OBJECTIVE: In this review, we aim to highlight the effects of several process and formulation variables prompting the characteristics of various nanosponges for the delivery of drugs into/ across the skin.
    METHOD: In the present review article, over-all introduction of nanosponges, its preparation, characterstics features, advanatges, disadvantages, factors affecting their preparation are covered. Furthermore, an elaborative description of nanosponges for skin delivery and its toxicological perspective with some referential examples of nanosponge drugs have also been deliberated here.
    RESULTS: Factors associated with the formation of nanosponges can directly or indirectly affect its efficacy in skin delivery of drugs. These nanoforms are efficient in delivering the drugs which possess lower aqueous solubility, therefore, the aqueous solubility of drugs possessing a narrow therapeutic window can easily be enhanced. It also helps in achieving targeted drug delivery, controlled release of drugs, increases bioavailability, reduces drug toxicity, decreases drug degradation, and many more.
    CONCLUSION: Nanosponges have been identified as a potential drug delivery carriers into as well as across skin. Delivery of biologics such as vaccines, enzymes, peptides, proteins, and antibodies, is also gaining attention in the recent past.
    Keywords:  Controlled release; Nanosponges; Skin delivery; Sustained Release; Targeted delivery; Transdermal
    DOI:  https://doi.org/10.2174/1381612828666220518090431
  65. J Control Release. 2022 May 12. pii: S0168-3659(22)00281-4. [Epub ahead of print]
    Nanoparticle combination for precise stroma modulation and improved delivery for pancreatic cancer.
    Mubin Tarannum, Katherine Holtzman, Didier Dréau, Pinku Mukherjee, Juan L Vivero-Escoto.
      Therapeutic success in the treatment of pancreatic ductal adenocarcinoma (PDAC) is hindered by the extensive stroma associated to this disease. Stroma is composed of cellular and non-cellular components supporting and evolving with the tumor growth. One of the most studied mediators of cancer cell-stroma crosstalk is sonic hedgehog (SHh) pathway leading to the intense desmoplasia observed in PDAC tumors. Herein, we demonstrate that the use of mesoporous silica nanoparticles (MSNs) containing an SHh inhibitor, cyclopamine (CyP), and the combination of chemotherapeutic drugs (Gemcitabine (Gem)/cisplatin (cisPt)) as the main delivery system for the sequential treatment led to reduction in the tumor stroma along with an improvement in the treatment of PDAC. We synthesized two versions of the MSN-based platform containing the SHh inhibitor (CyP-MSNs) and the drug combination (PEG-Gem-cisPt-MSNs). In vitro and in vivo protein analysis show that CyP-MSNs effectively inhibited the SHh pathway. In addition, the sequential combination of CyP-MSNs followed by PEG-Gem-cisPt-MSNs led to effective stromal modulation, increased access of secondary PEG-Gem-cisPt-MSNs at the tumor site, and improved therapeutic performance in HPAF II xenograft mice. Taken together, our findings support the potential of drug delivery using MSN nanoparticles for stroma modulation and to prevent pancreatic cancer progression.
    Keywords:  Combination therapy; Mesoporous silica nanoparticles; Pancreatic cancer; SHh inhibitor; Tumor stroma
    DOI:  https://doi.org/10.1016/j.jconrel.2022.05.019
  66. Asian J Pharm Sci. 2022 Mar;17(2): 241-252
    Impact of the amount of PEG on prodrug nanoassemblies for efficient cancer therapy.
    Yaqiao Li, Lingxiao Li, Qianhui Jin, Tian Liu, Jin Sun, Yongjun Wang, Zhijun Yang, Zhonggui He, Bingjun Sun.
      PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles (prodrug-SANPs). However, the impacts of the amount of PEG on the self-assemble stability, cellular uptake, pharmacokinetics, and antitumor efficacy of prodrug-SANPs are still unknown. Herein, selenoether bond bridged docetaxel dimeric prodrug was synthesized as the model prodrug. Five prodrug-SANPs were designed by using different mass ratios of prodrugs to PEG (Wprodrug/WDSPE-mPEG2000 = 10:0, 9:1, 8:2, 7:3 and 6:4), and defined as Pure drug NPs, 9:1NPs, 8:2NPs, 7:3 NPs and 6:4 NPs, respectively. Interestingly, 8:2 NPs formed the most compact nanostructure, thus improving the self-assemble stability and pharmacokinetics behavior. In addition, the difference of these prodrug-SANPs in cellular uptake was investigated, and the influence of PEG on cytotoxicity and antitumor efficacy was also clarified in details. The 8:2 NPs exhibited much better antitumor efficacy than other prodrug-SANPs and even commercial product. Our findings demonstrated the pivotal role of the amount of PEG on prodrug-SANPs.
    Keywords:  Docetaxel; Oxidation responsive; PEGylation; Prodrug; Self-assembly nanoparticles
    DOI:  https://doi.org/10.1016/j.ajps.2022.02.002
  67. Phytother Res. 2022 May 18.
    Impact of curcumin, quercetin, or resveratrol on the pathophysiology of endometriosis: A systematic review.
    Mariana Hipólito-Reis, Ana Catarina Neto, Delminda Neves.
      Endometriosis, a gynecological disease that affects reproductive age women is difficultly controlled in the long term by currently available treatments, prompting patients to adopt self-controlled interventions including dietary changes. The aim of this review is to provide evidence of how curcumin, quercetin, and resveratrol can act as natural interventions to control endometriosis. The review followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A comprehensive search was carried out in PubMed, Scopus, and Web of Science to gather together all the articles that study the specific actions of curcumin, resveratrol, or quercetin in endometriosis pathophysiology. All types of study designs including experimental data were considered. Thirty articles, including a clinical trial, were included. For the assessment of the quality of the selected studies that globally have "good quality", the GRADE (Grading of Recommendations Assessment, Development and Evaluation) and the SYRCLE ROB tool criteria were used. By acting on mechanisms of inflammation, oxidative stress, cell proliferation, invasion and adhesion, apoptosis, angiogenesis and glucose and lipid metabolism, curcumin, quercetin, and resveratrol showed to have beneficial effects, evidencing their potential application in the endometriosis treatment. However, future clinical studies are necessary to determine the real efficacy of these compounds in human endometriosis.
    Keywords:  curcumin; endometriosis; inflammation; nutrition; quercetin; resveratrol
    DOI:  https://doi.org/10.1002/ptr.7464
  68. Mol Nutr Food Res. 2022 May 20. e2200142
    Dietary exosome-like nanoparticles: An updated review on their pharmacological and drug delivery applications.
    Rajitha Anusha, Sulochana Priya.
      Exosomes are lipid bilayer membrane-bound extracellular vesicular structures (30-150 nm) mainly released by eukaryotic cells of animal origin. Exosome-like nanoparticles (ELNs) are the vesicular structures originating from plant sources with features similar to eukaryotic animal cell derived exosomes. ELNs derived from dietary sources (dietary ELNs) have exceptional pharmacological potential in alleviating many diseases and are good in maintaining intestinal health through the manipulation of the gut microbiome. The dietary ELNs being highly biocompatible find their application in targeted therapy as well. They are being established as promising drug delivery agents and can also be developed into dietary supplements. This review highlights the ELNs derived from various dietary sources, their diversity in molecular compositions, potential health benefits and drug delivery applications. Few clinical trials are attempted with dietary ELNs which are also described in the review along with their properties that can be exploited for the food and pharma industries in the future. This article is protected by copyright. All rights reserved.
    Keywords:  Dietary exosome-like nanoparticles; drug delivery; gut microbiota; miRNA; pharmacology
    DOI:  https://doi.org/10.1002/mnfr.202200142
  69. Anticancer Agents Med Chem. 2022 May 13.
    A Recent Advancement In Nanotechnology Approaches For The Treatment Of Cervical Cancer.
    Yashoda Mariappa Hegde, Panneerselvam Theivendren, Geetha S, Monashilpa P, Nivetha S, Selvaraj Kunjiappan, Sivakumar Vellaichamy, Murugananthan Gopal, Senthil Rajan Dharmalingam.
      BACKGROUND: Cervical cancer is one of the leading causes of female death, with a mortality rate of over 200,000 per year in developing countries. . Despite a decrease in cervical cancer occurrences in developed countries over the last decade, the frequency of the disease in developing nations continues to climb at an alarming rate, particularly when it is linked to the human papillomavirus (HPV). With just a few and highly invasive conventional therapies available, there is a clear need for novel treatment options such as nanotechnology-based chemotherapeutic drug delivery. Current limitations: Traditional anticancer therapy is limited by poor drug potency, non-specificity, unwanted side effects, and the development of multiple drug resistance (MDR), leading in a decrease in long-term anticancer therapeutic efficacy. An ideal cancer therapy requires a personalized and specialized medication delivery method capable of eradicating even the last cancer cell responsible for disease recurrence.PURPOSE: Nanotechnology provides effective drug delivery mechanisms, allowing it to serve both therapeutic and diagnostic purposes. Nanotechnology-based formulations are widely used to accurately target the target organ, maintain drug load bioactivity, preferentially accumulate the drug at the target location, and reduce cytotoxicity.
    FUTURE PERSPECTIVES: The key benefits of this drug delivery are that it improves pharmacological activity, solubility, bioavailability, and reduces toxicity in the target tissue by targeting ligands, allowing for new innovative treatment methods in an area that is desperately required. The goal of this review is to highlight possible research on nanotechnology-based delivery systems for cancer detection and treatment.
    Keywords:  Cervical cancer; diagnosis; drug delivery; human papillomavirus; nanotechnology; treatment methods
    DOI:  https://doi.org/10.2174/1871520622666220513160706
  70. Med Chem. 2022 May 09.
    Synthesis and Potential Antidiabetic Properties of Curcumin-Based Derivatives: An In Vitro and In Silico Study of α-Glucosidase and α-Amylase Inhibition.
    Mohammad Ezati, Fahimeh Ghavamipour, Narges Khosravi, Reza H Sajedi, Maryam Chalabi, Alireza Farokhi, Hadi Adibi, Reza Khodarahmi.
      BACKGROUND: Over the past twenty years, the prevalence of diabetes as one of the most common metabolic diseases has become a public health problem worldwide. Blood glucose control is an important factor in delaying the onset and progression of diabetes-related complications. α-Glycosidase (α-Glu) and α-amylase (α-Amy) are important enzymes in glucose metabolism. Diabetic control through the inhibition of carbohydrate hydrolyzing enzymes is established as an effective strategy.METHODS: In this study, curcumin-based benzaldehyde derivatives with high stability, bioavailability, and favorable efficiency were synthesized.
    RESULTS: The results showed that L13, L8, and L11 derivatives have the highest inhibitory effect on α-Glu with IC50 values of 18.65, 20.6, and 31.7 µM and, also L11, L13, and L8 derivatives have the highest inhibitory effect on α-Amy with IC50 value of 14.8, 21.8, and 44.9 µM respectively. Furthermore, enzyme inhibitory kinetic characterization was also performed to understand the mechanism of enzyme inhibition.
    CONCLUSION: L13 compared to the other compounds, exhibited acceptable inhibitory activity against both enzymes. Considering antioxidant properties of the synthesized compounds, the L13 derivative could be an appropriate candidate for further study through the rational drug design to the exploration of a new class of powerful anti-diabetic drugs, not only to reduce glycemic index but also to limit the activity of the major reactive oxygen species (ROS) producing pathways.
    Keywords:  Curcumin derivatives; antidiabetic agents; antioxidant activity; α-amylase; α-glucosidase.
    DOI:  https://doi.org/10.2174/1573406418666220509101854
  71. Front Bioeng Biotechnol. 2022 ;10 894667
    Applications of Chitosan and its Derivatives in Skin and Soft Tissue Diseases.
    Yidan Xia, Dongxu Wang, Da Liu, Jiayang Su, Ye Jin, Duo Wang, Beibei Han, Ziping Jiang, Bin Liu.
      Chitosan and its derivatives are bioactive molecules that have recently been used in various fields, especially in the medical field. The antibacterial, antitumor, and immunomodulatory properties of chitosan have been extensively studied. Chitosan can be used as a drug-delivery carrier in the form of hydrogels, sponges, microspheres, nanoparticles, and thin films to treat diseases, especially those of the skin and soft tissue such as injuries and lesions of the skin, muscles, blood vessels, and nerves. Chitosan can prevent and also treat soft tissue diseases by exerting diverse biological effects such as antibacterial, antitumor, antioxidant, and tissue regeneration effects. Owing to its antitumor properties, chitosan can be used as a targeted therapy to treat soft tissue tumors. Moreover, owing to its antibacterial and antioxidant properties, chitosan can be used in the prevention and treatment of soft tissue infections. Chitosan can stop the bleeding of open wounds by promoting platelet agglutination. It can also promote the regeneration of soft tissues such as the skin, muscles, and nerves. Drug-delivery carriers containing chitosan can be used as wound dressings to promote wound healing. This review summarizes the structure and biological characteristics of chitosan and its derivatives. The recent breakthroughs and future trends of chitosan and its derivatives in therapeutic effects and drug delivery functions including anti-infection, promotion of wound healing, tissue regeneration and anticancer on soft tissue diseases are elaborated.
    Keywords:  biological property; chitosan; drug-delivery carrier; regenerative medicine; soft tissue disease
    DOI:  https://doi.org/10.3389/fbioe.2022.894667
  72. Front Cell Infect Microbiol. 2022 ;12 863779
    Mechanisms by Which Traditional Chinese Medicines Influence the Intestinal Flora and Intestinal Barrier.
    Qingya Che, Tingting Luo, Junhua Shi, Yihuai He, De-Lin Xu.
      The effect of a drug on the intestinal flora and the intestinal barrier is an important evaluation index for drug safety and efficacy. Chemical synthetic drugs are widely used due to their advantages of fast efficacy and low doses, but they are prone to cause drug resistance and inhibit proton pumps, which may harm intestinal health. Traditional Chinese medicine (TCM) has been applied clinically for thousands of years, and how TCMs regulate intestinal health to achieve their effects of disease treatment has become a hot research topic that needs to be resolved. This paper reviews the recent research on the effects of TCMs on intestinal microorganisms and the intestinal mucosal barrier after entering the intestine, discusses the interaction mechanisms between TCMs and intestinal flora, and details the repair effect of TCMs on the intestinal mucosal barrier to provide a reference for the development, utilization, and modernization of TCM.
    Keywords:  effect mechanism; intestinal flora; intestinal mucosal barrier; review; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fcimb.2022.863779
  73. Cancer Drug Resist. 2021 ;4(1): 69-84
    Natural products as a means of overcoming cisplatin chemoresistance in bladder cancer.
    Ganeshkumar Rajendran, John A Taylor, Benjamin L Woolbright.
      Cisplatin remains an integral part of the treatment for muscle invasive bladder cancer. A large number of patients do not respond to cisplatin-based chemotherapy and efficacious salvage regimens are limited. Immunotherapy has offered a second line of treatment; however, only approximately 20% of patients respond, and molecular subtyping of tumors indicates there may be significant overlap in those patients that respond to cisplatin and those patients that respond to immunotherapy. As such, restoring sensitivity to cisplatin remains a major hurdle to improving patient care. One potential source of compounds for enhancing cisplatin is naturally derived bioactive products such as phytochemicals, flavonoids and others. These compounds can activate a diverse array of different pathways, many of which can directly promote or inhibit cisplatin sensitivity. The purpose of this review is to understand current drug development in the area of natural products and to assess how these compounds may enhance cisplatin treatment in bladder cancer patients.
    Keywords:  Cisplatin; apoptosis; bladder cancer; natural products
    DOI:  https://doi.org/10.20517/cdr.2020.69
  74. Curr Cancer Drug Targets. 2022 May 16.
    Dietary Flavonoids with Catechol Moiety Inhibit Anticancer Action of Bortezomib: What about the other Boronic Acid-Based Drugs?
    Katrin Sak.
      Approval of the first boronic acid group-containing drug, bortezomib, in 2003 for the treatment of multiple myeloma sparked an increased interest of medicinal chemists in boronic acid-based therapeutics. As a result, another boronic acid moiety-harboring medication, ixazomib, was approved in 2015 as a second-generation proteasome inhibitor for multiple myeloma; and dutogliptin is under clinical investigation in combination therapy against myocardial infarction. Moreover, a large number of novel agents with boronic acid element in their structure are currently in intensive preclinical studies, allowing to suppose that at least some of them enter clinical trials in the near future. On the other hand, only some years after bortezomib approval, direct interactions between its boronic acid group and catechol moiety of green tea catechins as well as some other common dietary flavonoids like quercetin and myricetin were discovered, leading to the formation of stable cyclic boronate esters and abolishing the anticancer activities. Although highly relevant, to date, no reports on possible co-effects of catechol group-containing flavonoids with new-generation boronic acid-based drugs can be found. However, this issue cannot be ignored, especially considering the abundance of catechol moiety-harboring flavonoids in both plant-derived food items as well as over-the-counter dietary supplements and herbal products. Therefore, in parallel with the intensified development of boronic acid-based drugs, their possible interactions with catechol groups of plant-derived flavonoids must also be clarified to provide dietary recommendations to patients for maximizing therapeutic benefits. If concurrently consumed flavonoids can indeed antagonize drug efficacy, it may pose a real risk to clinical outcomes.
    Keywords:  Flavonoids; anticancer activity; boronic acid drugs; catechol; dietary counselling.; nutritional oncology; proteasome inhibition
    DOI:  https://doi.org/10.2174/1568009622666220516102235
  75. J Pharm Anal. 2022 Apr;12(2): 221-231
    Diallyl disulfide and diallyl trisulfide in garlic as novel therapeutic agents to overcome drug resistance in breast cancer.
    RamaRao Malla, Rakshmitha Marni, Anindita Chakraborty, Mohammad Amjad Kamal.
      Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. It is a cancer that originates from the mammary ducts and involves mutations in multiple genes. Recently, the treatment of breast cancer has become increasingly challenging owing to the increase in tumor heterogeneity and aggressiveness, which gives rise to therapeutic resistance. Epidemiological, population-based, and hospital-based case-control studies have demonstrated an association between high intake of certain Allium vegetables and a reduced risk in the development of breast cancer. Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are the main allyl sulfur compounds present in garlic, and are known to exhibit anticancer activity as they interfere with breast cancer cell proliferation, tumor metastasis, and angiogenesis. The present review highlights multidrug resistance mechanisms and their signaling pathways in breast cancer. This review discusses the potential anticancer activities of DADS and DATS, with emphasis on drug resistance in triple-negative breast cancer (TNBC). Understanding the anticancer activities of DADS and DATS provides insights into their potential in targeting drug resistance mechanisms of TNBC, especially in clinical studies.
    Keywords:  Breast cancer; Diallyl disulfide; Diallyl trisulfide; Drug resistance; Metastasis
    DOI:  https://doi.org/10.1016/j.jpha.2021.11.004
  76. Mini Rev Med Chem. 2022 May 16.
    The Synthesis of Urolithins and Their Derivatives and the Modes of Antitumor Action.
    Xiangrong Xu, Zhuanhong Liu, Lei Yao.
      Urolithins are microbial metabolites derived from berries and pomegranate fruits, which display anti-inflammatory, anti-oxidative, and anti-aging activities. There are eight natural urolithins (urolithin A-E, M5, M6 and M7) isolated by now. Structurally, urolithins are phenolic compounds and belong to 6H-dibenzo[b,d]pyran-6-one. They have drawn considerable attention because of their vast range of biological activities and health benefits. Recent studies also suggest that they possess anti-SARS-CoV-2 and anticancer effects. In this article, the recent advances on the synthesis of urolithins and their derivatives from 2015 to 2021 are reviewed. To improve or overcome the solubility and metabolism stability issues, the modifications of urolithins are mainly centered on the hydroxy group and lactone group, and some compounds are showing promising results and potential for further study. The possible modes of antitumor action of urolithin are also discussed. Several signaling pathways, including PI3K-Akt, Wnt/β-catenin pathways, and multiple receptors (aryl hydrocarbon receptor, estrogen and androgen receptors) and enzymes (tyrosinase and lactate dehydrogenase) are involved in the antitumor activity of urolithins.
    Keywords:  Urolithin; antitumor; derivatives; mode of action; modification; synthesis
    DOI:  https://doi.org/10.2174/1389557522666220516125500
  77. Chem Commun (Camb). 2022 May 20.
    Polyserotonin as a versatile coating with pH-responsive degradation for anti-tumor therapy.
    Yingcai Meng, Jiaojiao Zhu, Jinsong Ding, Wenhu Zhou.
      Through self-polymerization of serotonin monomer, polyserotonin (PST) can coat on arbitrary surfaces with pH-responsive degradation, which was employed for nanoparticle coating and controlled drug release, achieving a robust anti-tumor effect when combined with its intrinsic photothermal effect.
    DOI:  https://doi.org/10.1039/d2cc00083k
  78. Biomark Res. 2022 May 19. 10(1): 33
    Correction: Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia.
    Yi Xu, Christopher Hino, David J Baylink, Jeffrey Xiao, Mark E Reeves, Jiang F Zhong, Saied Mirshahidi, Huynh Cao.
      
    DOI:  https://doi.org/10.1186/s40364-022-00379-z
  79. J Mater Chem B. 2022 May 19.
    A deep tumor penetration nanoplatform for glycolysis inhibition and antimetastasis of breast cancer.
    Jie Zhou, Qianwen Yin, Shengnan Li, Ruhe Yang, Rui Lou, Yiwen Sun, Bin Du.
      The poor penetration into deep tumor tissues of nanomedicines could not inhibit the production of lactic acid by deep tumor glycolysis, which leads to the accumulation of lactic acid and promotes tumor metastasis. In order to increase tumor penetration, it remains challenging to avoid tumor metastasis by the direct degradation of the extracellular matrix (ECM). Herein, in order to increase tumor penetration, a nano-platform, which can reduce extracellular matrix (ECM) production, and inhibit the glycolysis of deep tumors by releasing ethylenediaminetetraacetic acid (EDTA) is reported. In this design, EDTA and indocyanine green (ICG) are encapsulated in the liposome by a thin-film hydration method, and folic acid (FA) and the polyethyleneimine polymer (FA-PEI) are applied to coat the surface of liposomes through electrostatic interactions, and the FA-EDTA/ICG-Lip nanoparticles are obtained. FA-EDTA/ICG-Lip NPs can release EDTA and ICG in lysosomes (pH 4.5) to reduce ECM production by down-regulating transforming growth factor β (TGF-β) and activating an immune response by inducing tumor cell immunogenic cell death (ICD), respectively. Simultaneously, EDTA inhibits glycolysis of deep tumors by chelating Mg2+. By avoiding tumor metastasis, the strategy of indirectly reducing ECM production is demonstrated to enhance tumor penetration and inhibit deep tumor glycolysis.
    DOI:  https://doi.org/10.1039/d1tb01759d
  80. Trends Cell Biol. 2022 May 16. pii: S0962-8924(22)00108-8. [Epub ahead of print]
    Reflected stemness as a potential driver of the tumour microenvironment.
    Felipe S Rodrigues, Francesca D Ciccarelli, Ilaria Malanchi.
      A fundamental requirement for cancer initiation is the activation of developmental programmes by mutant cells. Oncogenic signals often confer an undifferentiated, stem cell-like phenotype that supports the long-term proliferative potential of cancer cells. Although cancer is a genetically driven disease, mutations in cancer-driver genes alone are insufficient for tumour formation, and the proliferation of cells harbouring oncogenic mutations depends on their microenvironment. In this Opinion article we discuss how the reprogrammed status of cancer cells not only represents the essence of their tumorigenicity but triggers 'reflected stemness' in their surrounding normal counterparts. We propose that this reciprocal interaction underpins the establishment of the tumour microenvironment (TME).
    Keywords:  cancer drivers; metastasis; stem cells; tissue regeneration; tumour microenvironment
    DOI:  https://doi.org/10.1016/j.tcb.2022.04.007
  81. Cancer Drug Resist. 2021 ;4(1): 143-162
    Metabolic reprogramming as an emerging mechanism of resistance to endocrine therapies in prostate cancer.
    Paolo Chetta, Giorgia Zadra.
      Prostate cancer (PCa) is the second leading cause of cancer-related death in the US. Androgen receptor (AR) signaling is the driver of both PCa development and progression and, thus, the major target of current in-use therapies. However, despite the survival benefit of second-generation inhibitors of AR signaling in the metastatic setting, resistance mechanisms inevitably occur. Thus, novel strategies are required to circumvent resistance occurrence and thereby to improve PCa survival. Among the key cellular processes that are regulated by androgens, metabolic reprogramming stands out because of its intricate links with cancer cell biology. In this review, we discuss how cancer metabolism and lipid metabolism in particular are regulated by androgens and contribute to the acquisition of resistance to endocrine therapy. We describe the interplay between genetic alterations, metabolic vulnerabilities and castration resistance. Since PCa cells adapt their metabolism to excess nutrient supply to promote cancer progression, we review our current knowledge on the association between diet/obesity and resistance to anti-androgen therapies. We briefly describe the metabolic symbiosis between PCa cells and tumor microenvironment and how this crosstalk might contribute to PCa progression. We discuss how tackling PCa metabolic vulnerabilities represents a potential approach of synthetic lethality to endocrine therapies. Finally, we describe how the continuous advances in analytical technologies and metabolic imaging have led to the identification of potential new prognostic and predictive biomarkers, and non-invasive approaches to monitor therapy response.
    Keywords:  Metabolic reprogramming; castration resistance; endocrine therapies; metabolic imaging; metabolomics; prostate cancer; therapy respo nse
    DOI:  https://doi.org/10.20517/cdr.2020.54
  82. Clin Endosc. 2022 May 17.
    Comparing palliative treatment options for cholangiocarcinoma: photodynamic therapy vs. radiofrequency ablation.
    Tayyaba Mohammad, Michel Kahaleh.
      Referral to an endoscopist is often done once curative resection is no longer an option for cholangiocarcinoma management. In such cases, palliation has become the main objective of the treatment. Photodynamic therapy and radiofrequency ablation can be performed to achieve palliation, with both procedures associated with improved stent patency and survival. Despite the greatly increased cost and association with photosensitivity, photodynamic therapy allows transmission to the entire biliary tree. In contrast, radiofrequency ablation is cheaper and faster to apply but requires intraductal contact. This paper reviews both modalities and compares their efficacy and safety for bile duct cancer palliation.
    Keywords:  Ablation treatment; Bile duct neoplasms; Cholangiocarcinoma; Photodynamic therapy
    DOI:  https://doi.org/10.5946/ce.2021.274
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