Kinetically-stable small-molecule prodrug nanoassemblies for cancer chemotherapy

Self-delivering nanocarrier based on the small-molecule prodrug nanoassemblies (NAs) have been widely used for the efficient delivery of chemotherapeutics, but the effect of kinetic stability of NAs on their delivery performance has not been illuminated. In this study, two camptothecin (CPT)-oleic acid (OA) prodrugs were used to fabricate self-assembling nanorods with similar size distribution, zeta potential and morphology but having sharply different kinetic stability, which provided an ideal platform to investigate the effects of kinetic stability. It is found that the nanorods with high kinetic stability showed a lower in vitro cytotoxicity, but were more effective to inhibit the tumor growth probably by decreasing the premature CPT release and subsequent generation of the inactive carboxylate CPT. However, such kinetically stable nanorods also resulted in the increased toxicity, probably due to the high prodrug accumulation in tissues after multiple injections. These results outlined the pivotal role of kinetic stability in determining antitumor efficacy of prodrug NAs, which provided a new insight into the delivery mechanism for the small-molecule prodrug self-delivering nanosystems.