Fabrication of Hyperbranched Block-Statistical Copolymer-Based Prodrug with Dual Sensitivities for Controlled Release,Bioconjugate Chemistry

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Fabrication of Hyperbranched Block-Statistical Copolymer-Based Prodrug with Dual Sensitivities for Controlled Release
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-12-21 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00699
Luping Zheng ₁ , Yunfei Wang ₁ , Xianshuo Zhang ₁ , Liwei Ma ₁ , Baoyan Wang ₁ , Xiangling Ji ₂ , Hua Wei ₁

Affiliation

Dendrimer with hyperbranched structure and multivalent surface is regarded as one of the most promising candidates close to the ideal drug delivery systems, but the clinical translation and scale-up production of dendrimer has been hampered significantly by the synthetic difficulties. Therefore, there is considerable scope for the development of novel hyperbranched polymer that can not only address the drawbacks of dendrimer but maintain its advantages. The reversible addition–fragmentation chain transfer self-condensing vinyl polymerization (RAFT-SCVP) technique has enabled facile preparation of segmented hyperbranched polymer (SHP) by using chain transfer monomer (CTM)-based double-head agent during the past decade. Meanwhile, the design and development of block-statistical copolymers has been proven in our recent studies to be a simple yet effective way to address the extracellular stability vs intracellular high delivery efficacy dilemma. To integrate the advantages of both hyperbranched and block-statistical structures, we herein reported the fabrication of hyperbranched block-statistical copolymer-based prodrug with pH and reduction dual sensitivities using RAFT-SCVP and post-polymerization click coupling. The external homo oligo(ethylene glycol methyl ether methacrylate) (OEGMA) block provides sufficient extracellularly colloidal stability for the nanocarriers by steric hindrance, and the interior OEGMA units incorporated by the statistical copolymerization promote intracellular drug release by facilitating the permeation of GSH and H⁺ for the cleavage of the reduction-responsive disulfide bond and pH-liable carbonate link as well as weakening the hydrophobic encapsulation of drug molecules. The delivery efficacy of the target hyperbranched block-statistical copolymer-based prodrug was evaluated in terms of in vitro drug release and cytotoxicity studies, which confirms both acidic pH and reduction-triggered drug release for inhibiting proliferation of HeLa cells. Interestingly, the simultaneous application of both acidic pH and GSH triggers promoted significantly the cleavage and release of CPT compared to the exertion of single trigger. This study thus developed a facile approach toward hyperbranched polymer-based prodrugs with high therapeutic efficacy for anticancer drug delivery.

中文翻译：

具有双敏感性的控释超支化嵌段统计共聚物基前药的制备

具有高支化结构和多价表面的树枝状聚合物被认为是最接近理想药物递送系统的最有希望的候选者之一，但是由于合成困难，树枝状聚合物的临床翻译和规模化生产受到了很大的阻碍。因此，开发新型的超支化聚合物具有很大的范围，该聚合物不仅可以解决树枝状聚合物的缺点，而且可以保持其优点。可逆的加成-断裂链转移自缩合乙烯基聚合（RAFT-SCVP）技术使过去十年来，通过使用基于链转移单体（CTM）的双头剂，可以轻松制备分段超支化聚合物（SHP）。同时，嵌段统计共聚物的设计和开发在我们最近的研究中已被证明是解决细胞外稳定性与细胞内高传递功效难题的一种简单而有效的方法。为了整合超支化和嵌段统计结构的优势，我们在本文中报道了使用RAFT-SCVP和聚合后点击偶联制备具有pH和还原双重敏感性的超支化嵌段统计共聚物基前药。外部均聚物（乙二醇甲基醚甲基丙烯酸甲酯）（OEGMA）嵌段通过位阻为纳米载体提供了足够的细胞外胶体稳定性，并且通过统计共聚结合的内部OEGMA单元通过促进GSH和H的渗透促进了细胞内药物的释放。⁺用于裂解还原反应性二硫键和pH值可靠的碳酸酯键，以及削弱药物分子的疏水包封作用。根据体外药物释放和细胞毒性研究评估了目标超支化嵌段统计共聚物基前药的递送功效，这证实了酸性pH和降低触发的药物释放均能抑制HeLa细胞的增殖。有趣的是，与施加单一触发相比，同时施加酸性pH和GSH触发显着促进了CPT的裂解和释放。因此，这项研究开发了一种针对高支化聚合物基前药的简便方法，该方法具有很高的抗癌药物治疗功效。

更新日期：2017-12-21

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