Self-Strengthened Oxidation-Responsive Bioactivating Prodrug Nanosystem with Sequential and Synergistically Facilitated Drug Release for Treatment of Breast Cancer.

Although environment-sensitive prodrug-based nanoparticles (NPs) have developed rapidly, lots of prodrug NPs still show poor selectivity and efficiency of parent drug bioactivation because of tumor heterogeneity. Herein, self-strengthened bioactivating prodrug-based NPs are fabricated via co-encapsulation of oxidation-responsive thioether-linked linoleic acid-paclitaxel conjugates (PTX-S-LA) and β-lapachone (LPC) into polymeric micelles (PMs). Following cellular uptake, PMs first release LPC to significantly elevate the reactive oxidative species (ROS) level through NAD(P)H: quinone oxidoreductase-1 (NQO1) catalysis. Then, NQO1-generated ROS in combination with endogenous high ROS levels in tumor cells could synergistically facilitate PTX-S-LA to release the active cytotoxic agent PTX. Such a novel prodrug nanosystem exhibits self-strengthened prodrug bioactivation, ultraselective release, and cytotoxicity between cancer and normal cells, prolonged circulation time, and enhanced tumor accumulation, leading to high antitumor efficiency and superior biosafety. Our findings pave the new way for the rational design of oxidation-responsive prodrug NPs for high-efficacy cancer chemotherapy.