Hypoxia-responsive block copolymer polyprodrugs for complementary photodynamic-chemotherapy
Hypoxia-responsive block copolymer polyprodrugs for complementary photodynamic-chemotherapy
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用于补充光动力化疗的缺氧响应性嵌段共聚物聚前药
DOI：
10.1016/j.jconrel.2021.09.023
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发表时间：
2021
影响因子：
10.8
通讯作者：
Zhishen Ge
中科院分区：
文献类型：
--
作者：
Qinghao Zhou;Fathelrahman Mohammed;Yuheng Wang;Jingbo Wang;Nannan Lu;Junjie Li;Zhishen Ge
实体瘤固有的缺氧微环境对肿瘤的生长、远处转移和侵袭性有重要影响。肿瘤内缺氧区域的不均匀分布限制了O2辅助治疗策略（例如光动力疗法（PDT））的治疗功效。另一方面，缺氧激活的前药不能有效地工作在区域与足够的O2浓度。为了解决这些问题，我们制备了一种嵌段共聚物聚前药，其由聚乙二醇（PEG）和硝基咪唑连接的喜树碱（CPT）甲基丙烯酸酯和含5，10，15，20-四苯基卟啉（TPP）的甲基丙烯酸酯单体的共聚片段组成，用于互补的光动力化学疗法。聚前药在水溶液中可以自组装成合适大小的聚合物胶束，并具有较高的稳定性。静脉注射后，聚前药胶束显示肿瘤蓄积。接着在肿瘤部位进行光照射（650 nm），TPP部分诱导富氧区域中的单线态氧（1 O2）产生以发挥PDT并导致富氧区域转化为缺氧。同时，在缺氧区域，缺氧响应性多聚前药可以被激活以释放游离CPT，这是由于硝基咪唑键的裂解。具有PDT和缺氧可激活的CPT片段的聚前药胶束有效地抑制HeLa肿瘤的生长。明确定义的聚前药两亲物提供了一种有效的策略，以克服单一治疗的PDT或低氧响应前药的缺点，用于补充光动力化学疗法的癌症。
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 O2concentration. 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.