Hypoxia-responsive block copolymer polyprodrugs for complementary photodynamic-chemotherapy.

ABSTRACT

The inherent hypoxic microenvironment of solid tumors has an important influence on tumor growth, distant metastasis, and invasiveness. The heterogeneous distribution of hypoxic regions inside tumors limits the therapeutic efficacy of O2-assisted therapeutic strategy (e.g. photodynamic therapy (PDT)). On the other hand, the hypoxia-activable prodrugs cannot work effectively in the regions with enough O2 concentration. To address the issues, we prepare a block copolymer polyprodrug consisting of polyethylene glycol (PEG) and copolymerized segments of nitroimidazole-linked camptothecin (CPT) methacrylate and 5,10,15,20-tetraphenylporphyrin (TPP)-containing methacrylate monomers for complementary photodynamic-chemotherapy. The polyprodrug can self-assemble into polymeric micelles in aqueous solution with suitable size and high stability. After intravenous injection, the polyprodrug micelles show tumor accumulation. Followed by light irradiation (650 nm) at tumor sites, TPP moieties induce singlet oxygen (1O2) production in the oxygen-rich area to exert PDT and cause transformation of the oxygen-rich areas into hypoxia. Simultaneously, in the hypoxic areas, the hypoxia-responsive polyprodrugs can be activated to release free CPT due to the cleavage of nitroimidazole linkages. The polyprodrug micelles with the segments for PDT and hypoxia-activable CPT efficiently suppress the growth of HeLa tumors. The well-defined polyprodrug amphiphiles offer an effective strategy to overcome the disadvantages of single treatment of PDT or hypoxia-responsive prodrugs for complementary photodynamic-chemotherapy of cancers.