Efficient Synthesis of Polymer Prodrug by Thiol–Acrylate Michael Addition Reaction and Fabrication of pH-Responsive Prodrug Nanoparticles,Bioconjugate Chemistry

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Efficient Synthesis of Polymer Prodrug by Thiol–Acrylate Michael Addition Reaction and Fabrication of pH-Responsive Prodrug Nanoparticles
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-08-03 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00531
Chao-Ran Xu ₁ , Liang Qiu ₂ , Cai-Yuan Pan ₁ , Chun-Yan Hong ₁ , Zong-Yao Hao ₃

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In this study, an efficient method is proposed for the synthesis of polymer prodrug with acid-liable linkage via thiol–acrylate Michael addition reaction of the camptothecin with tethering acrylate group and polymer scaffold containing multiple thiol groups. The polymer scaffold P(HEO₂MA)-b-P(HEMA-DHLA) is prepared by reversible addition–fragmentation chain transfer (RAFT) polymerization of the methacrylate of lipoic acid (HEMA-LA) using poly(2-(2-hydroethoxy) ethyl methacrylate) (PHEO₂MA) as macro-RAFT agent followed by reduction of the disulfides in lipoic acid (LA) groups to give polymer scaffold with dihydrolipoic acid (DHLA) pendent groups. Acrylate-tethering camptothecin (ACPT) is connected to P(HEO₂MA)-b-P(HEMA-DHLA) via Michael addition reaction between thiol and acrylate with a high coupling efficiency (95%). Amphiphilic polymer prodrug P(HEO₂MA)-b-P(HEMA-DHLA-CPT) spontaneously self-assembles into nanoparticles in an aqueous solution and exhibits a CPT loading content as high as 40.1%. The prodrug nanoparticles with the acid-liable β-thiopropionate linkages can release CPT under acidic conditions, and the prodrug nanoparticles show similar cytotoxicity to HeLa cells as free CPT. Overall, the prodrug nanoparticles with high drug loading contents and acid-liable linkages are promising for pH-responsive anticancer therapy.

中文翻译：

硫醇-丙烯酸酯迈克尔加成反应有效合成高分子前药和pH响应型前药纳米粒子的制备

在这项研究中，提出了一种有效的方法，可通过硫醇-丙烯酸酯合成喜树碱与丙烯酸酯系链的迈克尔加成反应和具有多个硫醇基团的聚合物支架，从而合成具有酸依赖键的聚合物前药。聚合物支架P（HEO ₂ MA）-b -P（HEMA-DHLA）是通过使用聚（2-（2-氢乙氧基）（甲基丙烯酸乙酯）（PHEO ₂ MA）作为大分子RAFT剂，然后还原硫辛酸（LA）基团中的二硫键，得到带有二氢硫辛酸（DHLA）侧基的聚合物支架。丙烯酸酯系喜树碱（ACPT）连接到P（HEO ₂ MA）-b-P（HEMA-DHLA）通过巯基和丙烯酸酯之间的迈克尔加成反应，具有很高的偶联效率（95％）。两亲性聚合物前药P（HEO ₂ MA） - b -P（HEMA-DHLA-CPT）自发地自组装成纳米颗粒在水溶液中，并且表现出CPT装载含量高达40.1％。具有酸性依赖的β-硫代丙酸酯键的前药纳米颗粒可以在酸性条件下释放CPT，并且前药纳米颗粒对HeLa细胞的细胞毒性与游离CPT相似。总体而言，具有高载药量和酸依赖键的前药纳米颗粒有望用于pH响应型抗癌治疗。

更新日期：2018-08-03

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