Tailoring drug‐to‐lipid ratio in redox‐responsive lipid‐mimetic prodrug liposomes for superior cabazitaxel delivery and antitumor efficacy

Abstract Liposomes represent one of the most extensively investigated nanocarriers in drug delivery. However, the efficient encapsulation of highly hydrophobic drugs like cabazitaxel (CTX) remains challenging due to their limited affinity with phospholipid bilayers. Herein, a lipid‐mimetic modification strategy was applied to improve the affinity between CTX and phospholipids. Briefly, octyldodecanol (ODA) which possessed a similar structure with the phospholipids' tail group was connected to CTX via disulfide bond to design a lipid‐mimetic CTX prodrug (CTX‐SS‐ODA). Thereafter, CTX prodrug‐loaded liposomes (CPLs) with varying drug‐to‐lipid ratios (1:10, 1:20, and 1:30) were successfully prepared and systematically evaluated. Compared with CTX liposomes, the CPLs had higher encapsulation efficiency, drug loading capacity and stability. More notably, a high drug‐to‐lipid ratio could reduce the particle concentration, thereby improving cell uptake and pharmacokinetic behavior. CPLs@D/L 1:10 with the highest drug‐to‐lipid ratio demonstrated remarkable pharmacokinetic improvements, exhibiting a 402‐fold increase in AUC 0‐72h compared to free CTX. This optimized formulation not only displayed potent antitumor activity but also maintained an excellent safety profile. Our findings underscore the effectiveness of lipid‐mimetic prodrug modification for liposome and emphasize the crucial role of drug‐to‐lipid ratio in developing high‐performance nanomedicines.