An assembly modules deformation strategy improved the chemical stability and self-assembly stability of docetaxel prodrugs nanoassemblies

Self-assembly prodrugs usually consist of drug modules, activation modules, and assembly modules. The selection of suitable modules to construct prodrug nanoassemblies with self-assembly stability and "intelligent" activation is a challenge. As a common assembly module, oleic acid can provide a driving force and steric hindrance for prodrugs self-assembly. However, the unsaturated double bond of oleic acid is readily oxidized and it affects its chemical stability. Herein, two docetaxel (DTX) prodrugs were designed using disulfide bonds as activation modules and two different fatty acids (isostearic acid and oleic acid) as assembly modules, respectively. Compared with oleic acid, isostearic acid had higher chemical stability. Simultaneously, the terminal propyl structure of isostearic acid compensated for the steric hindrance without a double bond. Overall, this structural deformation improved the self-assembly ability and chemical stability of the prodrug nanoassemblies, thus balancing the effectiveness and safety of the prodrugs. Our findings reveal the importance of the assembly modules and provide a guidance for the rational design of prodrug nanoassemblies.