The tumor hypoxic environment as well as photodynamic therapy (PDT)-induced hypoxia could severely limit the therapeutic efficacy of traditional PDT. Fortunately, the smart integration of hypoxia-responsive drug delivery system with PDT might be a promising strategy to enhance the PDT efficiency that is hindered by the hypoxic environment. Herein, a novel azobenzene (AZO) containing conjugated polymers (CPs)-based nanocarriers (CPs-CPT-Ce6 NPs) was constructed for the combination of PDT with chemotherapy, as well as to enhance the hypoxia-responsive drug release by light. The conjugated polymer chains, used as a matrix to prepare the CPs-CPT-Ce6 NPs, were beneficial for loading hydrophobic photosensitizers and chemotherapy drugs, to improve their cellular uptake. Moreover, the AZO group (-N═N-) in CPs, which can be reduced and cleaved by azoreductase (a typical biomarker of hypoxia) under the hypoxic environment of tumor cells, acts as the hypoxia-responsive linker component. Upon laser irradiation, the CPs-CPT-Ce6 NPs could produce ROS for PDT and then facilitate the enhancement of tumor hypoxic condition, which could further promote the dissociation of CPs via reductive cleavage of AZO bridges to subsequently release cargos (chemotherapeutic drug, CPT) and then significantly enhance the killing effects to tumor cells that were resistant to PDT. Both in vitro and in vivo studies confirmed the improvement of synergistic therapeutic effects of our CPs-CPT-Ce6 NPs. This cascade responsive approach provides an excellent complementary mode for PDT and could open new insights for constructing programmable and controllable responsive systems in biomedical applications.
Keywords: camptothecin (CPT); chemotherapy; conjugated polymers; hypoxia; photodynamic therapy.