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.
Multiple drug resistance (MDR) is a major cause of the chemotherapy failure. One of the most developed mechanisms of MDR involves reducing drug accumulation by enhancing effluxes in cancer cells. This study is proposed to use drug-resistant cells-secreted and autologous-homing exosome nanovesicles as drug carriers to deliver anticancer drugs to the cells. Using inherent interaction with parental cells, exosomes are able to convey more chemotherapeutics and restore effective drug levels in the resistant cells over traditional nanocarriers. With the completion of proposed research, we expect that optimized novel and natural exosome nanocarrier will overcome MDR and selectively deliver therapeutics to cancer cells, resulting in more effective chemotherapy with fewer side effects.
