Rational design of tumor-selective prodrug nanoassemblies: Greatly improving the in vivo fate and tolerability of high-toxic cabazitaxel

Cabazitaxel (CTX) exhibits stronger antineoplastic activity than paclitaxel and docetaxel owing to its capacity to circumvent taxane resistance. However, the therapeutic index of CTX is heavily restricted by poor pharmacokinetics and severe systemic toxicity. Here, a guerbet alcohol, octyldodecanol (OD), was chosen to chemically modify CTX employing tumor-selective sulfur/selenium bonds as linkages, and the prodrugs were capable of forming nanoassemblies spontaneously (termed CTX-S-OD NPs, CTX-Se-OD NPs, CTX-SS-OD NPs, respectively). The CTX-SS-OD NPs displayed superior pharmacokinetic behavior with a 395.5-fold higher AUC than free CTX, allowing for more efficient tumor accumulation. Moreover, the redox sensitive drug release of the prodrug improved the selectivity of cytotoxicity between normal cells and tumor cells, hence reducing the systemic toxicity of prodrug nanoassemblies and facilitating dose intensification. Notably, CTX-SS-OD NPs exhibited potent antitumor efficiency in the 4T1 mouse model due to the elevated tolerance dose. Overall, our studies provided new perspectives for the rational design of prodrug nanoassemblies to deliver high-toxic agents.