Reduction-sensitive platinum (IV)-prodrug nano-sensitizer with an ultra-high drug loading for efficient chemo-radiotherapy of Pt-resistant cervical cancer in vivo.

J Control Release

State Key Laboratory of Organic-Inorganic Composite Materials, Beijing University of Chemical Technology, Beijing 100029, China; Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China; Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China; College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China; Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing 100029, China. Electronic address:

Published: October 2020

Cisplatin is widely used in the chemoradiotherapy (CRT) of cervical cancers. However, despite the severe systemic side effects, the therapeutic efficacy of cisplatin is often compromised by the development of drug resistance, which is closely related to the elevated intracellular thiol-containing species (especially glutathione (GSH)) and the adenosine triphosphate (ATP)-dependent glutathione S-conjugate pumps. The construction of a safe and redox-sensitive nano-sensitizer with high disulfide density and high Pt(IV) prodrug loading capacity (up to 16.50% Pt and even higher), as described herein, is a promising way to overcome the cisplatin resistance and enhance the CRT efficacy. The optimized nanoparticles (NPs) (referred to as CV) with moderate Pt loading (7.62% Pt) and median size (c.a. 40 nm) was screened out and used for further biological evaluation. Compared with free cisplatin, more drugs could be transported and released inside the cisplatin resistant cells (Hela-CDDP) by CV NPs. With the synergistic effect of GSH scavenging and mitochondrial damage, CV NPs can easily reverse the cisplatin resistance. Moreover, the higher nucleus DNA binding Pt content of CV NPs not only caused the DNA damage and apoptosis of Hela-CDDP cells but also sensitized these cells to X-Ray radiation. The in vivo safety and efficacy results showed that CV NPs effectively accumulated inside tumor and inhibited the growth of cisplatin resistant xenograft models while alleviating the serious side effect associated with cisplatin (the maximum tolerated cisplatin equivalent of single injection is higher than 20 mg/kg body weight). The intervention of exogenous radiation further improved the anticancer efficacy of CV NPs and caused the shrinkage of tumor volume, thus making this safe and facile nano-sensitizer a promising route for the neoadjuvant CRT of cervical cancers.

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Source
http://dx.doi.org/10.1016/j.jconrel.2020.06.005DOI Listing

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