Abstract
Given the over-production of glutathione (GSH) and hydrogen peroxide (H2O2) in tumor cells, redox-responsive linkers such as disulfide bonds have been widely used to develop site-specific prodrug system, but may suffer from their poor sensitivity that results in low efficacy. Herein, we report the development of a class of redox-triggered small molecule prodrugs (RhB-S(Se)-CPT), by conjugating zwitterionic rhodamine B (RhB) and camptothecin (CPT) with thio-/seleno-ether linkers. The amphiphilic prodrug can self-assemble into stable nanoparticles in water, and zwitterionic RhB is located on the surface of RhB-S(Se)-CPT nanoparticles, tracking the distribution and kinetics of drug delivery in real time, and reducing the non-specific binding to in vivo components, thus decreasing the side effects of nanomedicines. The thio-/seleno-ether linkers enable selective and rapid release of CPT in response to a redox heterogeneous intratumoral microenvironment. Interestingly, selenoether bonds exhibit significant advantages over thioether in terms of CPT release rate, intracellular toxicity and therapeutic efficacy against large tumors (∼ 200 mm3) in mice. These results provide insights to the rational design of subsequent redox-responsive nanoprodrug system, which may contribute to the material selection and structural design of next-generation nanomedicines for tumor theranostics.
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