Acid-sensitive polymeric prodrug micelles for achieving enhanced chemo-photodynamic therapy

Multimodal combination therapy is considered more effective in cancer treatment than monotherapy, because it overcomes some limitations of monotherapy. In this study, acid-sensitive polymeric prodrugs consisting of photosensitizer (Hemin) and ortho ester-terminated PEG were synthesized and loaded with doxorubicin (DOX) to obtain a dual-modal therapeutic nanoplatform (Hemin/DOX-M). This nanoplatform demonstrated good drug encapsulation and stability. In vitro experiments have confirmed that Hemin/DOX-M can be effectively internalized by HepG2 cells, trigger rapid drug release via the cleavage of ortho ester and alleviate tumor hypoxia to amplify the PDT effect under laser irradiation. In vivo experiments revealed that Hemin/DOX-M caused decreased hemolysis and selective accumulation in the tumor tissue, thereby significantly reducing the side effects. Intriguingly, In vivo antitumor evaluation revealed that Hemin/DOX-M had stronger capability at tumor growth inhibition (TGI, 79.63%) than chemo- or photodynamic therapy alone. Overall, Hemin/DOX-M is a promising candidate to increase therapeutic efficacy by achieving combination therapy against tumors.