Kinetic Stability-driven cytotoxicity of small-molecule prodrug nanoassemblies
Nanoassemblies (NAs) of small-molecule lipophilic prodrugs have been widely investigated for the efficient drug delivery in cancer therapy, but their kinetic stability has not been attracted sufficient attentions in the past studies. We report herein that the kinetic stability exerted a great influence on the drug release from NAs of lipophilic prodrugs in physiologically relevant media. Based on co-assembling FRET NAs of two lipophilic fluorescent prodrugs, we demonstrated that NAs constructed by lipophilic prodrugs containing shorter alkyl chain or that with higher unsaturated degrees displayed a poorer kinetic stability, which further resulted in remarkably faster drug release in mice plasma and various tissue homogenates. More importantly, these kinetically unstable NAs also induced rapid intracellular drug release, resulting in the much more potent cytotoxicity. These findings highlight the crucial role of kinetic stability in determining the drug release from NAs of lipophilic prodrugs, which would effectively guide their rational designs for cancer therapy.