Oxidation-strengthened disulfide-bridged prodrug nanoplatforms with cascade facilitated drug release for synergetic photochemotherapy

One of the major barriers in utilizing prodrug nanocarriers for cancer therapy is the slow release of parent drug in tumors. Tumor cells generally display the higher oxidative level than normal cells, and also displayed the heterogeneity in terms of redox homeostasis level. We previously found that the disulfide bond-linkage demonstrates surprising oxidation-sensitivity to form the hydrophilic sulfoxide and sulphone groups. Herein, we develop oxidation-strengthened prodrug nanosystem loaded with pyropheophorbide a (PPa) to achieve light-activatable cascade drug release and enhance therapeutic efficacy. The disulfide bond-driven prodrug nanosystems not only respond to the redox-heterogeneity in tumor, but also respond to the exogenous oxidant (singlet oxygen) elicited by photosensitizers. Once the prodrug nanoparticles (NPs) are activated under irradiation, they would undergo an oxidative self-strengthened process, resulting in a facilitated drug cascade release. The IC(50) value of the PPa@PTX-S-S NPs without irradiation was 2-fold higher than those of NPs plus irradiation. In vivo, the PPa@PTX prodrug NPs display prolonged systemic circulation and increased accumulation in tumor site. The PPa@PTX-S-S NPs showed much higher efficiency than free PTX or the PPa@PTX-C-C NPs to suppress the growth of 4T1 tumors. Therefore, this novel oxidation-strengthened disulfide-bridged prodrug-nanosystem has a great potential in the enhanced efficacy of cancer synergetic photochemotherapy.