A review on the use of extracellular vesicles for the delivery of drugs and biological therapeutics.

INTRODUCTION: Exosomes, a type of extracellular vesicles, are effective tools for delivering small-molecule drugs and biological therapeutics into cells and tissues. Surface modifications with targeting ligands ensure precise delivery to specific cells, minimizing accumulation in healthy organs and reducing the side effects. This is a rapidly growing area in drug delivery research and this review aims to comprehensively discuss the recent advances in the field. AREA COVERED: Recent studies have presented compelling evidence supporting the application of exosomes as efficient delivery vehicles that escape endosome trapping, achieving effective in vivo delivery in animal models. This review provides a systemic discussion on the exosome-based delivery technology, with topics covering exosome purification, surface modification, and targeted delivery of various cargos ranging from siRNAs, miRNAs, and proteins, to small molecule drugs. EXPERT OPINION: Exosome-based gene and drug delivery has low toxicity and low immunogenicity. Surface modifications of the exosomes can effectively avoid endosome trapping and increase delivery efficiency. This exciting technology can be applied to improve the treatments for a wide variety of diseases.

Dietary phytochemical and metabolic disease prevention: Focus on plant proteins.

Plant-based functional foods have attracted increasing research interest to validate their use in preventing metabolic disease. Since it is increasingly recognized that inflammation, oxidative stress, and circadian rhythm play vital roles in various metabolic diseases, including diabetes, obesity and non-alcoholic liver disease, plant proteins, protein hydrolysates, and food extracts that intervene in these biological processes are promising dietary supplements to prevent metabolic diseases. Here, we reviewed the recent research on plant-based foods used for metabolic disease prevention and provided new perspectives regarding the current study gaps and future directions in this field.

Neratinib causes non-recoverable gut injury and reduces intestinal cytochrome P450 3A enzyme in mice.

Neratinib is a pan-HER tyrosine kinase inhibitor newly approved by FDA in 2017 to treat HER2-positive breast cancer, but the phase III trial of neratinib showed that 96% of the patients taking neratinib experienced diarrhea. So far very few mechanistic studies explore neratinib-induced gastrointestinal (GI) toxicity. Hereby, we performed toxicity studies in mice to characterize the potential mechanism underlying this adverse effect. C57BL/6 J mice were separated into three groups A, B, C. Group A received vehicle; group B was orally dosed with 100 mg/kg neratinib once daily for 18 days. Group C was dosed with 100 mg/kg neratinib for 12 days and switched to vehicle for 6 days. Intestine and liver were collected for further analysis. Human intestine-derived cells were treated with neratinib in vitro. Our results showed that 12 days treatment of neratinib caused persistent histological damage in mouse GI tract. Both gene expression and activity of Cyp3a11, the major enzyme metabolizing neratinib in mice was reduced in small intestine. The gene expression of proinflammatory cytokines increased throughout the GI tract. Such damages were not recovered after 6 days without neratinib treatment. In addition, in vitro data showed that neratinib was potent in killing human intestine-derived cell lines. Based on such findings, we hypothesized that neratinib downregulates intestinal CYP3A enzyme to cause excessive drug disposition, eventually leading to gut injury.

Irinotecan decreases intestinal UDP-glucuronosyltransferase (UGT) 1A1 via TLR4/MyD88 pathway prior to the onset of diarrhea.

Irinotecan is a first-line treatment for colorectal cancer and the prodrug of 7-ethyl-10-hydroxy-camptothecin (SN-38). However, its fatal gastrointestinal (GI) toxicity raises serious concern. In liver, irinotecan generates its inactive metabolite, SN-38G via UDP-glucuronosyltransferase (UGT)1A1. Subsequently, SN-38G is excreted into GI tract where it is reactivated by microbiome to yield the toxic metabolite, SN-38. Activation of toll-like receptor (TLR)/myeloid differentiation primary response 88 (MyD88) by bacterial endotoxin decreases drug-metabolizing enzymes. In this study, we treated C57BL6/J mice with 50 mg/kg irinotecan once daily until observing grade 4 diarrhea. Mice were sacrificed on day0, day2 and day8. Based on the finding in C57BL6/J mice, we repeated the treatment in Tlr2-/-, Tlr4-/- and Myd88-/- mice to determine the impact of inflammation on UGT metabolism. Our toxicity study in C57BL6/J mice showed that mice started bloody diarrhea after 6 days' injection of irinotecan. Ugt1a1 expression in GI tract started decreasing after 24h since first dose, before the onset of diarrhea. In Tlr4-/- and Myd88-/- mice, no Ugt1a1 reduction was observed in distal GI tract after irinotecan injection. In Tlr2-/- mice, intestinal Ugt1a1 expression was down-regulated. Our results indicate that after two doses of irinotecan, mice started losing capability of detoxifying SN-38. TLR4 plays more important role in Ugt1a1 reduction than TLR2, despite that TLR2 and TLR4 share MyD88 as common adaptor protein. We concluded that irinotecan reduced intestinal Ugt1a1 via TLR4/MyD88 pathway, which eventually triggers the onset of diarrhea. Our finding unveils a novel mechanism underlying irinotecan-induced diarrhea and provides a new direction to prevent chemotherapy side effect.