Precise engineering of disulfide bond-bridged prodrug nanoassemblies to balance antitumor efficacy and safety.

Prodrug-based nanoassemblies, which combine the merits of prodrug technology and nanocarriers, are regarded as promising platforms for cancer treatment. Notably, the chemical structure of prodrugs is closely associated with antitumor efficacy and safety, and the intrinsic relationships among them need further exploration. Herein, paclitaxel was conjugated with 2-octyldodecan-1-ol through different positions of disulfide bond to construct the prodrug nanoassemblies. Interestingly, the minor differences in chemical structure not only dominated the assembly performance and drug release of nanoassemblies, but also significantly impacted the pharmacokinetics, antitumor efficacy, and safety. It was worth noting that prodrug nanoassemblies with one carbon atom between disulfide bond and ester bond had faster drug release and better antitumor effect, while prodrug nanoassemblies with three carbon atoms between disulfide bond and ester bond possessed moderate antitumor effect and better safety. Our findings illustrated the structure-function relationships of self-assembled prodrugs and provided a promising paradigm for the precise engineering of advanced prodrug nanoplatforms. STATEMENT OF SIGNIFICANCE: 1. The major effects of minor differences in prodrug chemical structure on pharmacodynamics and safety were explored, which had important clinical reference significance and value. 2. The in-depth exploration of structure-function relationships to balance efficacy and safety had important guiding significance for the design of prodrug nanoassemblies.