Drug Release from Disulfide-Linked Prodrugs: Role of Thiol Agents

The disulfide bond (SS) has been widely used in prodrugs for the redox-responsive drug release, but its drug release mechanism and rate were seldom compared in different thiol agents. Herein, self-assembling nanoaggregates (NAs) formed by camptothecin (CPT)-oleic acid (OA) prodrugs linked by two frequently used SS linkers (ETCSS and ACSS) were used for such comparative investigation. It is found that the cleavage of ETCSS was directly coupled with CPT release, whereas the breakage of ACSS resulted in the generation of CPT intermediates, the chemical stability of which determined CPT release. In both cases, the redox-responsive drug release was highly dependent on the reactivity between SS and thiol agents, with an order of dithiothreitol > cysteine ≈ glutathione. Moreover, the presence of SS significantly accelerated the extracellular CPT release, which was around 3-4 fold higher than intracellular CPT release. Therefore, the in vitro cytotoxicity of SS-linked CPT-OA NAs could not be ascribed to the glutathione-trigged intracellular drug release but rather to the SS-accelerated extracellular CPT release. The above results would effectively guide the rational design and evaluation of SS-linked prodrug NAs for efficient drug delivery.