The value of the clinical application of chemotherapeutic drugs is dependent on both systemic toxicity and treatment efficacy. Dose intensification and high tolerability suggest the potential for clinical cancer therapy. In this study, we developed a novel strategy for reconstructing a drug molecule into remote-loading liposomes. Two weak-base cabazitaxel derivatives were synthesized, and named CN and CN2. CN exhibited higher cytotoxic effects compared to CN2, and was selected for further study. CN was remotely loaded into nano-size liposomes (CN-LPs) via an ammonium sulfate gradient with high loading and encapsulation efficiency. When compared to the commercial formulation of cabazitaxel, JEVTANA®, CN-LPs showed less systemic toxicity and enhanced tolerability, with at least a 24-fold increase in the tolerated dose. Furthermore, CN-LPs significantly inhibited tumor growth in mice bearing 4T1 and RM-1 xenograft tumors. After intravenous injection, CN-LPs exhibited an extremely high drug concentration in blood, with a 757-fold increase in the area under the curve (AUC). Moreover, 48 h after a single intravenous injection, CN-LPs promoted higher drug accumulation in tumors compared to JEVTANA®. In summary, our liposome delivery system exhibits favorable pharmacologic efficacy and an improved safety profile.
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