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Polymer-paclitaxel conjugates based on disulfide linkers for controlled drug release

机译：基于二硫键的聚合物-紫杉醇偶联物可控制药物释放

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摘要

A novel redox-responsive polymer-drug conjugate (PDC) based on hydrophilic diblock copolymer covalently linked paclitaxel (PTX) via a disulfide linker was prepared and evaluated for intracellular drug delivery. The well-defined hydrophilic diblock copolymer, PEG-b-PHEMA, was synthesized via atom transfer radical polymerization of 2-(trimethylsilyloxyl)ethyl methacrylate (HEMA-TMS), using PEG-Br as a macroinitiator and CuBr/PMDETA as the catalytic system, followed by selectively hydrolyzing the trimethylsilane group to hydroxyl groups. Utilizing the hydroxyl groups as an active reaction site, paclitaxel was covalently conjugated onto the backbone of the diblock copolymer, with a disulfide linker as a spacer to bridge the copolymer and PTX, and the loading content of paclitaxel was 18.4 wt%. Due to the different solubility of segments in the polymer-drug conjugate, the amphiphilic PEG-b-P(HEMA-PTX) could self-assemble into spherical micelles in aqueous solution, with hydrophobic PTX as core and hydrophilic PEG chains as shell. The in vitro cytotoxicity experimental results showed that the diblock copolymer was biocompatible, with no obvious cytotoxicity, whereas the PEG-b-P(HEMA-PTX) conjugate showed glutathione-dependent cytotoxicity with higher cellular proliferation inhibition against glutathione monoester pretreated HeLa cells than that of the nonpretreated HeLa cells. We are convinced that polymer-drug conjugates based on disulfide linkers will be a promising platform for targeted intracellular controlled drug delivery in cancer therapy.
机译：制备了一种基于亲水性二嵌段共聚物通过二硫键共价连接的紫杉醇（PTX）的新型氧化还原反应性聚合物-药物偶联物（PDC），并评估了其在细胞内的递送。定义明确的亲水性二嵌段共聚物PEG-b-PHEMA是通过以PEG-Br为大分子引发剂和CuBr / PMDETA为催化体系的甲基丙烯酸2-（三甲基甲硅烷基氧基）乙酯（HEMA-TMS）进行原子转移自由基聚合而合成的，然后选择性地将三甲基硅烷基团水解为羟基。利用羟基作为活性反应位点，将紫杉醇共价键合在二嵌段共聚物的主链上，并用二硫键作为间隔物桥接共聚物和PTX，紫杉醇的负载量为18.4重量％。由于链段在聚合物-药物偶联物中的溶解度不同，两亲性PEG-b-P（HEMA-PTX）在水溶液中可自组装成球形胶束，疏水性PTX为核心，亲水性PEG链为壳。体外细胞毒性实验结果表明，二嵌段共聚物具有生物相容性，没有明显的细胞毒性，而PEG-bP（HEMA-PTX）缀合物显示出谷胱甘肽依赖性细胞毒性，对谷胱甘肽单酯预处理的HeLa细胞具有更高的细胞增殖抑制作用。未经预处理的HeLa细胞。我们相信，基于二硫键的聚合物-药物缀合物将成为癌症治疗中靶向细胞内控制药物递送的有前途的平台。

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