CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, China.
Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China.
J Control Release. 2021 Nov 10;339:130-142. doi: 10.1016/j.jconrel.2021.09.023. Epub 2021 Sep 21.
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 O-assisted therapeutic strategy (e.g. photodynamic therapy (PDT)). On the other hand, the hypoxia-activable prodrugs cannot work effectively in the regions with enough O 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 (O) 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.
肿瘤固有的低氧微环境对肿瘤的生长、远处转移和侵袭有重要影响。肿瘤内低氧区域的不均匀分布限制了 O 辅助治疗策略（如光动力疗法（PDT））的治疗效果。另一方面，缺氧激活前药在 O 浓度足够的区域不能有效发挥作用。为了解决这些问题，我们制备了一种由聚乙二醇（PEG）和硝基咪唑连接的喜树碱（CPT）甲基丙烯酸酯和 5,10,15,20-四苯基卟啉（TPP）含甲基丙烯酸酯单体共聚的嵌段共聚物多前药，用于互补光动力化疗。该多前药在水溶液中可自组装成具有合适尺寸和高稳定性的聚合物胶束。静脉注射后，多前药胶束在肿瘤部位积聚。随后在肿瘤部位进行 650nm 的光照射，TPP 部分在富氧区诱导单线态氧（O）的产生，从而发挥 PDT 作用，并使富氧区转化为缺氧区。同时，在缺氧区，由于硝基咪唑键的断裂，缺氧响应的多前药可以被激活释放游离的 CPT。具有 PDT 和缺氧激活 CPT 片段的多前药胶束有效地抑制了 HeLa 肿瘤的生长。这种明确的多前药两亲物为克服 PDT 单一治疗或缺氧响应前药治疗癌症的互补光动力化疗的缺点提供了一种有效的策略。
