Abstract

A novel type of diselenide bond-bridged hydroxyethyl starch-doxorubicin conjugate, HES-SeSe-DOX, was synthesized via a specially designed multistep synthetic route. The optimally achieved HES-SeSe-DOX was further combined with photosensitizer, chlorin E6 (Ce6), to self-assemble into HES-SeSe-DOX/Ce6 nanoparticles (NPs) for potentiating chemo-photodynamic anti-tumor therapy via diselenide-triggered cascade actions. HES-SeSe-DOX/Ce6 NPs were observed to disintegrate through the cleavage or oxidation of diselenide-bridged linkages in response to the stimuli arising from glutathione (GSH), hydrogen peroxide and Ce6-induced singlet oxygen, respectively, as evidenced by the enlarged size with irregular shapes and cascade drug release. In vitro cell studies exhibited that HES-SeSe-DOX/Ce6 NPs in combination with laser irradiation effectively consumed intracellular GSH and promoted a large rise in levels of reactive oxygen species in tumor cells, actuating the disruption of intracellular redox balance and the enhanced chemo-photodynamic cytotoxicity against tumor cells. The in vivo investigations revealed that HES-SeSe-DOX/Ce6 NPs were inclined to accumulate in tumors with persistent fluorescence emission, inhibited tumor growth with high efficacy and had good safety. These findings demonstrate the potential of HES-SeSe-DOX/Ce6 NPs for use in chemo-photodynamic tumor therapy and suggest their viability for clinical translation.