In Situ Supramolecular Self-Assembly of Pt(IV) Prodrug to Conquer Cisplatin Resistance

Drug resistance has always been a huge challenge that should be urgently conquered to improve the efficacy of anticancer drugs. Herein, a synergistic Pt(IV) prodrug, Npx-p(p)-Pt(IV), is proposed, combining dual responsive behavior with dual drug resistance-related pathways deactivation. First, Npx-p(p)-Pt(IV) can in situ form a supramolecular self-assembly with a nanofiber structure on the cancer cell surface triggered by phosphatase, which confines the drug in the tumor and effectively enhances the cellular uptake of cisplatin, resulting in a high cancer cell selectivity and an extremely low non-targeted cytotoxicity. After being endocytosed, the self-assembly shows glutathione-responsive cisplatin release and reverses the IC50 of cisplatin-resistant cancer cells to that of sensitive ones. Second, the obtained Pt(IV) prodrug can significantly damage cisplatin-resistance cancer cells through cyclooxygenase-2 and nuclear factor-kappa B-mediated apoptosis pathways, which benefit from the integration of naproxen into the prodrug. The in vivo experiment demonstrates a tumor inhibition rate of 80%. Therefore, Npx-p(p)-Pt(IV) is a multispecific cisplatin derivative, and in situ self-assembly is believed to be a new strategy to conquer drug resistance for clinical care.