New insight on designing docetaxel prodrug liposomes with high stability and intelligent release: Length-like or structure-like modification strategy

Fatty acid modification enhances DTX affinity to phospholipids, increasing encapsulation efficiency and in vitro stability. • D-BC PLs with “structure-like” prodrugs enhance lipid interactions, showing modest redox sensitivity, good PK, and tolerance. • D-SC PLs with “length-like” prodrugs show high redox sensitivity, cytotoxicity, tumor suppression yet mild high-dose toxicity. Liposomes are one of the most promising nano-delivery systems to deliver chemotherapeutic drugs. Docetaxel (DTX) is a classic type of taxane drug widely used in clinical practice. However, no liposomal DTX formulation has been approved for marketing. It is speculated that the structure of DTX was highly rigid and hydrophobic, making it hard to encapsulate DTX in either lipid membranes nor aqueous phase. Therefore, designing novel DTX liposomes with high encapsulation efficiency and stability deserves further exploration. Phospholipid molecules have a hydrophilic head and two hydrophobic fatty acids as tail chains. Inspired by the structure of phospholipids, two fatty acid modification strategies were developed to construct length-like DTX prodrug (D-SC) and structure-like DTX prodrug (D-BC). Compared with DTX liposomes, two DTX prodrug liposomes (D-SC PLs and D-BC PLs) were equipped with improved drug-carrier affinity reflecting in higher encapsulation efficiency and stability in vitro. Moreover, both prodrug liposomes exhibited intelligent drug release in tumor cells. Further, D-BC PLs outperformed in the circulation stability and tolerance probably due to the improved affinity by structure-like modification strategy. In turn, D-SC PLs exhibited rapid DTX release to effectively inhibit tumor growth but cause reversible toxicity at high dosage. Overall, this work provides new insights to construct advanced prodrug liposomes for efficient cancer therapy.