Cell-homing exosomes as a drug delivery carrier to overcome multiple drug resistance

摘要 化疗药物的多药耐药(MDR)仍然是影响疗效的主要障碍 癌症的治疗。外排转运体，主要负责多药耐药，从癌症中泵出药物 用于后续消除和无目标分配的细胞。因此，药物沉积不足 这些细胞导致治疗失败。作为功能性和细胞外纳米囊泡的来源 从细胞上看，外切体在细胞间的交流中起着至关重要的作用。新出现的结果已经 表明内源性外切体为治疗药物的输送提供了显著的优势。 与传统的纳米载体相比，具有细胞归巢选择性和低免疫原性。我们最近的研究 现已确定，来自耐药细胞的外切体显著增加了药物 对亲本细胞的反应。数据还表明，外小体增加的能力 传递的抗癌药物对耐药细胞的细胞毒性可能不仅来自能量驱动 内吞作用途径还包括特定的表面蛋白介导的归巢选择性。在这个项目中， 我们计划(1)鉴定耐药癌细胞分泌的外切体，(2)确定 分离的外切体对耐药癌细胞的归巢选择性机制。与 完成上述主动研究，我们期待着exosome特别克服 自体耐药癌细胞中的药物耐药性。这项研究还将改善 了解癌细胞分泌的外切体在耐药中的作用。结果将是 发现生物工程外切体作为递送平台，并导致基于外切体的策略 克服抗药性，这是癌症治疗中最艰难和最具挑战性的障碍。

Abstract Multiple drug resistance (MDR) to chemotherapeutic drugs remains the major obstacle for the effective treatment of cancers. Efflux transporters, mainly responsible for MDR, pump drugs from the cancer cells for subsequent elimination and untargeted distribution. As a result, insufficient drug deposition in the cells leads to the failure of treatment. As functional and extracellular nanovesicles derived from cells, exosomes play an essential role in the cell-cell communication. Emerging results have indicated that endogenous exosomes offer significant advantages for the delivery of therapeutic agents over traditional nanocarriers with cell-homing selectivity and low immunogenicity. Our recent studies have now defined that exosomes derived from drug-resistant cells significantly increased drug response to parental cells. The data also demonstrate that the ability of exosomes to increase the cytotoxicity of delivered anticancer drugs to resistant cells may obtain from not only energy-driven endocytosis pathways but also specific surface proteins-mediated homing selectivity. In this project, we plan to (1) characterize exosomes secreted by drug-resistant cancer cells and (2) determine the mechanism of homing selectivity of the isolated exosomes to drug-resistant cancer cells. With the completion of above initiative research, we expect that exosomes especially overcome pharmacoresistance in autologous drug-resistant cancer cells. The study will also improve the understanding of cancer cell-secreted exosomes in the role of drug resistance. The outcome will discover bioengineered exosomes as delivery platforms and lead to exosome-based strategies to overcome drug resistance, the toughest and most challenging hurdle in cancer therapy.