Self-Assembly of Intelligent Nanoplatform for Endogenous H2S-Triggered Multimodal Cascade Therapy of Colon Cancer

The specific in situ generation and activation of therapeuticagents with high spatiotemporal precision is expected to revolutionize cancertreatment. Here, we develop an intelligent nanoplatform (termed as NP-Cu),which is constructed by assembling photosensitizer chlorin e6 (Ce6),hypoxia-responsive prodrug banoxantrone (AQ4N) with clickable dibenzo-cyclooctyne (DIBO) functionalized lysine (D-K), and cyclen-Cu2+complex,for improving combination anticancer therapy. Cyclen-Cu2+complex-induced photodynamic therapy (PDT) quenching in NP-Cu can beeffectively and selectively activated by tumor-overproduced hydrogen sulfide(H2S). More importantly, the reaction of endogenous H2S with Cu2+cangenerate photothermal agent copper sulfide (CuS) for photothermal therapy(PTT). Furthermore, with the activation of PTT and PDT, intracellularhypoxic stress is amplified to trigger AQ4N-associated chemodynamictherapy (CDT), leading to light-enhanced cascade therapy of PDT, PTT andCDT. Therefore, we present a simple and practical strategy for developing pathological stimuli responsive combination therapy,which has the potential of advancing precision cancer medicine