Chemical Derivatization of the Anticancer Agent Cabazitaxel Using a Polyunsaturated Fatty Acid for Safe Drug Delivery In Vivo

: The utilization of nonionic surfactants is a practical way to formulate hydrophobic chemotherapeutics, facilitating the clinical translation of drug candidates during the development process. However, since the drug toxicity in patients is primarily determined by the cytotoxic drugs themselves, such a formulation approach is unable to improve the drug tolerability. Therefore, additional strategies for enhancing drug safety profiles are necessary when considering the use of surfactants as formulation excipients. Using cabazitaxel as a target agent, we show that the miscibility of α-linolenic acid (LNA)tethered cabazitaxel conjugate 1 with polysorbate 80 (Tween 80) was enhanced. Upon further blending with aqueous solutions, conjugate 1 formed stable colloidal nanoemulsions with Tween 80. Thus, the nanoemulsions are systemically injectable and suitable for preclinical studies. Compared with parent cabazitaxel, conjugate 1 displayed a substantial improvement in its safety profile in animals. Therapeutic studies in a mouse xenograft model of human cancer further demonstrated the effectiveness of conjugate 1 in suppressing tumor growth. These results suggest that attaching flexible lipid chains to the highly toxic cabazitaxel generates a new drug entity that is more compatible with Tween 80-based formulations than its free drug form. This new entity retains its antitumor activity while improving its tolerability in vivo.