Biodegradation and Toxicity of Protease/Redox/pH Stimuli-Responsive PEGlated PMAA Nanohydrogels for Targeting Drug delivery
Biodegradation and Toxicity of Protease/Redox/pH Stimuli-Responsive PEGlated PMAA Nanohydrogels for Targeting Drug delivery
复制标题
用于靶向药物递送的蛋白酶/氧化还原/pH 刺激响应性聚乙二醇化 PMAA 纳米水凝胶的生物降解和毒性
DOI：
10.1021/acsami.5b05984
复制
发表时间：
2015-09-09
影响因子：
9.5
通讯作者：
Wang, Changchun
中科院分区：
文献类型：
--
作者：
Jin, Sha;Wan, Jiaxun;Wang, Changchun
纳米材料在癌症治疗中的智能给药应用正在迅速发展。本文以甲基丙烯酸（MAA）为单体，N，N-二（丙烯酰1）半胺（BACy）为交联剂，采用易回流沉淀聚合法制备了一种新型蛋白酶/氧化还原/pH刺激响应型可生物降解纳米水凝胶。然后，将聚乙二醇（PEG）和叶酸（FA）共价接枝到纳米水凝胶表面，以增强其较长的体内循环寿命和对肿瘤细胞和组织的活性靶向能力。这种纳米水凝胶在谷胱甘肽（GSH）的作用下，可以通过减少敏感的二硫键而分解成短的聚合物链（m < 1140; PDI < 1.35），也可以通过破坏交联网络中的酰胺键而分解成蛋白酶。利用纳米水凝胶同时负载亲水性药物阿霉素（DOX）和疏水性药物紫杉醇（PTX），具有较高的负载效率。累积释放谱显示，弱酸性（pH 5.0）和还原性环境（GSH）显著加速了载药纳米水凝胶的药物释放，表现出明显的氧化还原/pH双刺激反应性药物释放，减少了药物在到达肿瘤部位之前的泄漏。此外，体外实验结果表明，该多药负载系统具有协同治疗肿瘤的作用。同时，通过急性毒性和活体荧光成像研究对纳米水凝胶的生物相容性和生物毒性进行了评价，实验结果表明，PEG修饰后的纳米水凝胶的体内循环寿命较长，急性毒性（LD50从138.4 mg/kg降低到499.7 mg/kg）显著降低。
The application of nanomaterials in intelligent drug delivery is developing rapidly for treatment of cancers. In this paper, we fabricated a new kind of protease/redox/pH stimuli-responsive biodegradable nanohydrogels with methacrylic acid (MAA) as the monomer and N,N-bis(acryloy1)cystamine (BACy) as the cross-linker through a facile refluxprecipitation polymerization. After that, the polyethylene glycol (PEG) and folic acid (FA) were covalently grafted onto the surface of the nanohydrogels for enhancement of their long in vivo circulation lifetime and active targeting ability to the tumor cells and tissues. This kind of nanohydrogels could be disassembled into short polymer chains (M. < 1140; PDI < 1.35) both in response to glutathione (GSH) through reduction of the sensitive disulfide bonds and protease by breakage of the amido bonds in the cross-linked networks. The nanohydrogels were utilized to simultaneously load both hydrophilic drug doxorubicin (DOX) and hydrophobic drug paclitaxel (PTX) with high drug loading efficiency. The cumulative release profile showed that the drug release from the drug-loaded nanohydrogels was significantly expedited by weak acidic (pH 5.0) and reducing environment (GSH), which exhibited an distinct redox/pH dual stimuli-responsive drug release to reduce the leakage of drugs before they reach tumor site. In addition, the in vitro experiment results indicated that the multidrug-loaded system had synergistic effect on cancer therapy. Meanwhile, the acute toxicity and intravital fluorescence imaging studies were adopted to evaluate the biocompatibility and biotoxicity of the nanohydrogels, the experimental results showed that the PEG modification could greatly enhance the long in vivo circulation lifetime and reduce the acute toxicity (LD50: from 138.4 mg/kg to 499.7 mg/ kg) of the nanohydrogels.