Polymeric micelles encapsulating pH-responsive doxorubicin prodrug and glutathione-activated zinc(II) phthalocyanine for combined chemotherapy and photodynamic therapy
Polymeric micelles encapsulating pH-responsive doxorubicin prodrug and glutathione-activated zinc(II) phthalocyanine for combined chemotherapy and photodynamic therapy
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DOI：
10.1016/j.jconrel.2018.04.030
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发表时间：
2018-07-28
影响因子：
10.8
通讯作者：
Lo, Pui-Chi
中科院分区：
文献类型：
--
作者：
Gao, Di;Lo, Pui-Chi
制备了一系列不同配比的多柔比星（DOX）和酞菁锌（ZnPc）聚合物胶束，用于双重化疗和光动力治疗（PDT）。两亲性嵌段共聚物由甲氧基聚乙二醇（PEG）和聚-苄基-l -天冬氨酸（PBLA）组成，其中DOX和ZnPc分别通过一个酸不稳定的腙连接剂和一个氧化响应的二硫连接剂偶联到天冬氨酸侧链上。聚合物自组装成直径约160-180 nm的球形聚合物胶束，由于最外层的聚乙二醇层，其表面电荷接近中性。这些聚合物胶束在水介质中表现出优异的稳定性和荧光沉默。研究了DOX和ZnPc在酸性和还原性环境下在磷酸盐溶液中的控释。体外研究表明，这些聚合物胶束可以内化到HepG2人肝癌细胞中，在细胞核中显示DOX的荧光，在细胞质中显示ZnPc的荧光。这一观察结果表明，酸性和还原性的细胞内环境可以通过切割相应的连接体来触发DOX和ZnPc的释放。由于化学细胞毒性DOX和ZnPc辐照后产生的单线态氧，这些胶束对HepG2细胞表现出不同程度的暗毒性和光毒性。DOX与ZnPc在一定比例下，通过联合指数计算，两者具有协同细胞毒性。DOX-ZnPc-胶束-2的DOX/ZnPc摩尔比为3.8，主要通过细胞凋亡诱导细胞死亡，并通过增强渗透性和保留作用在荷瘤小鼠中表现出优先的肿瘤保留作用。结果表明，这些聚合物胶束是很有前途的纳米平台，用于抗癌药物和光敏剂的双重治疗。
A series of polymeric micelles encapsulating different ratios of doxorubicin (DOX) and zinc(II) phthalocyanine (ZnPc) have been prepared for dual chemotherapy and photodynamic therapy (PDT). The amphiphilic block copolymers consist of methoxypolyethylene glycol (PEG) and poly(beta-benzyl-L-aspartate) (PBLA), in which DOX and ZnPc were conjugated to the aspartate side chain through an acid-labile hydrazone linker and a redoxresponsive disulfide linker, respectively. The polymers were self-assembled into spherical polymeric micelles with diameters of about 160-180 nm and their surface charges were found to be nearly neutral due to the outermost PEG layer. These polymeric micelles exhibited excellent stability and silenced fluorescence in aqueous media. The controlled release of DOX and ZnPc was studied in phosphate solution under acidic and reducing environments, respectively. In vitro study demonstrated that these polymeric micelles could be internalized into HepG2 human hepatocellular carcinoma cells, showing the fluorescence of DOX in the nucleus and fluorescence of ZnPc in the cytoplasm. This observation suggested that the acidic and reducing intracellular environments could trigger the release of DOX and ZnPc by cleaving the corresponding linkers. These micelles exhibited different degree of dark-and photo-cytotoxicity on the HepG2 cells due to the chemocytotoxic DOX and the singlet oxygen generated upon irradiation of the ZnPc. With a certain ratio of DOX and ZnPc, they caused a synergistic cytotoxicity as calculated by combination index. The DOX-ZnPc-micelles-2, which has a DOX/ZnPc molar ratio of 3.8, could induce cell death mainly through apoptosis and exhibit preferential tumor retention in tumor-bearing mice via the enhanced permeability and retention effect. The results suggest that these polymeric micelles are promising nanoplatforms for the delivery of anticancer drugs and photosensitizers for dual therapy.