Clinically ineffective transplatin is highly potent against cancer cells when transformed into a transplatin(IV) prodrug nanoparticle. Herein, a hydrophobic transplatin(IV) was synthesized by H2O2-oxidization of transplatin and attachment of two hydrophobic aliphatic chains. Transplatin(IV) was subsequently encapsulated by a biodegradable amphiphilic copolymer, MPEG-PLA, forming a well-defined spherical micelles (M(TransPt)). Transplatin(IV) was protected efficiently and could be released under a simulated cancerous intracellular condition. Compared to the cisplatin and transplatin, M(TransPt) showed the highest Pt uptake and a clathrin-dependent endocytosis pathway. Most importantly, M(TransPt) displayed a nanomolar IC50 on A2780 cells and a great potency on cisplatin resistant A2780DDP cell line. Overall, this nanoplatform for delivering trans-geometry platinum(IV) drug exhibits excellent characteristics for enhancing efficacy and overcoming cisplatin drug resistance, and holds a strong promise for clinical use in the near future.
Here, a nanoparticle-mediated delivery of multinuclear platinum(IV) prodrugs [biodegradable polymer-di-cisPt(IV)] for overcoming cisplatin drug resistance is reported. From the MTT assays, lower IC50 values of polymer-di-cisPt(IV) on A2780DDP cells than A2780 were observed with the lowest resistance factor of 0.7. Inductively coupled plasma mass spectroscopy results showed that more drugs were delivered into cancer cells and greater number of Pt-DNA adducts were formed with the use of the polymer-di-cisPt(IV) conjugate nanoparticles. By a mechanistic study with endocytosis inhibitors to treat A2780 cells, we proved that polymer-di-cisPt(IV) conjugate nanoparticles were internalized by the cancer cells through endocytosis rather than through passive diffusion or copper transporter 1-mediated active transportation. This well illustrates the way how the polymer-di-cisPt(IV) micelles overcome cisplatin resistance.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.