Journal
THERANOSTICS
Volume 9, Issue 20, Pages 5755-5768Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.36163
Keywords
multidrug resistance; stimuli-responsive; drug-inhibitor conjugate; self-assembly; nanodrug
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Funding
- National Natural Science Foundation of China [21702097, 21504055, 91527304, 81672587]
- National key research and development plan of P. R. China [2016YFA0201500]
- Postdoctoral Science Foundation of China [2018T110389, 2017M611543]
- Shanghai Jiao Tong University & Affiliated Sixth People's Hospital South Campus [2017B003]
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Severe multidrug resistance (MDR) often develops in the process of chemotherapy for most small molecule anticancer drugs, which results in clinical chemotherapy failures. Methods: Here, a nanodrug is constructed through the self-assembly of amphiphilic drug-inhibitor conjugates (ADIC) containing a redox-responsive linkage for reversing the multidrug resistance (MDR) in cancer treatment. Specifically, hydrophilic anticancer irinotecan (Ir) and hydrophobic P-gp protein inhibitor quinine (Qu) are linked by a redox responsive bridge for overcoming MDR of tumors. Results: Ir-ss-Qu is able to self-assemble into nanoparticles (NPs) in water and shows the longer blood retention half-life compared with that of free Ir or Qu, which facilitates drug accumulation in tumor site. After endocytosis of Ir-ss-Qu NPs by drug-resistant tumor cells, the disulfide bond in the linkage between Ir and Qu is cleaved rapidly induced by glutathione (GSH) to release anticancer drug Ir and inhibitor Qu synchronously. The released Qu can markedly reduce the expression of P-gp in drug-resistant tumor cells and inhibits P-gp to pump Ir out of the cells. The increased concentration of intracellular Ir can effectively improve the therapeutic efficacy. Conclusions: Such redox-responsive Ir-ss-Qu NPs, as a drug delivery system, exhibit very high cytotoxicity and the most effective inhibitory to the growth of drug-resistant breast cancer compared with that of free therapeutic agents in vitro and in vivo.
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