Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA.
Department of Bionanotechnology and Bioconvergence Engineering, Jeonbuk National University, Jeonju 54896, South Korea.
J Control Release. 2024 Jan;365:286-300. doi: 10.1016/j.jconrel.2023.11.031. Epub 2023 Nov 25.
Multidrug resistance (MDR) is an inevitable clinical problem in chemotherapy due to the activation of abundant P-glycoprotein (P-gp) that can efflux drugs. Limitations of current cancer therapy highlight the need for the development of a comprehensive cancer treatment strategy, including drug-resistant cancers. Small extracellular vesicles (sEVs) possess significant potential in surmounting drug resistance as they can effectively evade the efflux mechanism and transport small molecules directly to MDR cancer cells. One mechanism mediating MDR in cancer cells is sustaining increased levels of reactive oxygen species (ROS) and maintenance of the redox balance with antioxidants, including glutathione (GSH). Herein, we developed GSH-depleting benzoyloxy dibenzyl carbonate (B2C)-encapsulated sEVs (BsEVs), which overcome the efflux system to exert highly potent anticancer activity against human MDR ovarian cancer cells (OVCAR-8/MDR) by depleting GSH to induce oxidative stress and, in turn, apoptotic cell death in both OVCAR-8/MDR and OVCAR-8 cancer cells. BsEVs restore drug responsiveness by inhibiting ATP production through the oxidation of nicotinamide adenine dinucleotide with hydrogen (NADH) and inducing mitochondrial dysfunction, leading to the dysfunction of efflux pumps responsible for drug resistance. In vivo studies showed that BsEV treatment significantly inhibited the growth of OVCAR-8/MDR and OVCAR-8 tumors. Additionally, OVCAR-8/MDR tumors showed a trend towards a greater sensitivity to BsEVs compared to OVCAR tumors. In summary, this study demonstrates that BsEVs hold tremendous potential for cancer treatment, especially against MDR cancer cells.
多药耐药性（MDR）是化疗中不可避免的临床问题，这是由于大量 P-糖蛋白（P-gp）的激活，它可以将药物排出细胞外。当前癌症治疗的局限性突出了开发全面癌症治疗策略的必要性，包括耐药性癌症。小细胞外囊泡（sEVs）具有克服耐药性的巨大潜力，因为它们可以有效地逃避外排机制，并将小分子直接输送到耐药性癌细胞。一种介导癌细胞 MDR 的机制是维持活性氧（ROS）水平的增加，并通过抗氧化剂（包括谷胱甘肽（GSH））维持氧化还原平衡。在此，我们开发了耗尽 GSH 的苯甲酰氧基二苄基碳酸酯（B2C）包封的 sEVs（BsEVs），通过耗尽 GSH 来诱导氧化应激，并在人耐药性卵巢癌细胞（OVCAR-8/MDR）中诱导细胞凋亡，从而克服外排系统，发挥对 OVCAR-8/MDR 和 OVCAR-8 癌细胞的高效抗癌活性。BsEVs 通过氧化烟酰胺腺嘌呤二核苷酸（NADH）并诱导线粒体功能障碍来抑制 ATP 产生，从而抑制负责耐药性的外排泵的功能，恢复药物反应性，导致外排泵功能障碍。体内研究表明，BsEV 治疗显著抑制了 OVCAR-8/MDR 和 OVCAR-8 肿瘤的生长。此外，与 OVCAR 肿瘤相比，OVCAR-8/MDR 肿瘤对 BsEVs 的敏感性呈增加趋势。总之，这项研究表明 BsEVs 在癌症治疗方面具有巨大的潜力，特别是对耐药性癌症细胞。
