Functional 2-methylene-1,3-dioxepane (MDO) terpolymers were explored here as a versatile platform to construct biodegradable pH sensitive polymeric prodrugs for intracellular drug delivery. A series of MDO-based biodegradable functional polyester P(MDO-co-PEGMA-co-PDSMA) with different compositions were synthesized by terpolymerization of MDO, poly(ethylene glycol) methyl ether methacrylate (PEGMA) and pyridyldisulfide ethylmethacrylate (PDSMA) via a simple one-pot radical ring-opening copolymerization. Mal-DOX, which contains a pH-sensitive hydrazone bond between doxorubicin (DOX) and the maleimide group, was covalently conjugated in one pot to free thiol groups of PDSMA units via thiol–ene click chemistry in the presence of tri(2-carboxyethyl)phosphine (TCEP). The DOX-conjugated P(MDO-co-PEGMA-co-PDSMA) can self-assemble into prodrug micelles. The diameter and morphology of the polymeric prodrug micelles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Because of the existence of the pH-sensitive hydrazone bonds, in vitro drug release results showed that the release of DOX was much faster at pH 5.5 than that at pH 7.4. Flow cytometry and fluorescence microscopy demonstrated that the prodrug micelles could be efficiently internalized by cancer cells. In vitro cytotoxicity showed that the DOX-conjugated prodrug micelles can strongly inhibit the proliferation of cancer cells remarkably. Importantly, this work provides a versatile strategy for the fabrication of biodegradable polymeric prodrug nanocarriers.

中文翻译：

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功能性2-亚甲基-1,3-二氧戊环三元共聚物：构建用于细胞内药物递送的可生物降解聚合物前药的多功能平台†

本文探讨了功能性2-亚甲基-1,3-二氧杂环丁烷（MDO）三元共聚物作为构建可生物降解的pH敏感聚合物前药用于细胞内药物递送的通用平台。一系列基于MDO生物降解的官能团的聚酯的P（MDO-共-PEGMA-共同具有不同组成的-PDSMA）由MDO，聚（乙二醇）甲基醚甲基丙烯酸酯（PEGMA）和吡啶基二硫化物甲基丙烯酸乙酯（PDSMA）的合成三元共聚经由一个简单的一锅自由基开环共聚。Mal-DOX包含一个在阿霉素（DOX）和马来酰亚胺基团之间的pH敏感键，可通过一瓶共价键合到PDSMA单元的游离巯基上，通过在三（2-羧乙基）膦（TCEP）存在下，硫醇-烯点击化学。结合了DOX的P（MDO- co -PEGMA- co -PDSMA）可以自组装成前药胶束。聚合物前药胶束的直径和形态通过动态光散射（DLS）和透射电子显微镜（TEM）进行测量。由于存在pH敏感的bonds键，体外药物释放结果表明，在pH 5.5时DOX的释放比在pH 7.4时DOX的释放快得多。流式细胞仪和荧光显微镜显示，前药胶束可以被癌细胞有效地内化。体外细胞毒性表明，与DOX结合的前药胶束可以显着抑制癌细胞的增殖。重要的是，这项工作为生物可降解聚合物前药纳米载体的制备提供了一种通用的策略。