In order to obtain a novel, pH responsive polymersome system, a series of pH responsive block copolymers were synthesized via the reversible addition–fragmentation chain transfer (RAFT) polymerization of 3,4-dihydro-2H-pyran (DHP) protected 2-hydroxyethyl methacrylate (HEMA) (2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl methacrylate (THP-HEMA)) and 2-(dimethylamino) ethyl methacrylate (DMAEMA) using p(THP-HEMA) as a macro chain transfer agent (mCTA). The degree of polymerization (DP) of the p(THP-HEMA) block was fixed to 35, whereas the DP of the p(DMAEMA) block was systematically varied from 21 to 50. In aqueous solution, the block copolymer with the shortest p(DMAEMA) block (DP = 21) self-assembled into vesicles, while the polymer with 30 units of p(DMAEMA) formed a mixture of micelles and vesicles. The polymer with the longest p(DMAEMA) block (DP = 50) formed exclusively micelles. The corresponding polymersomes exhibited a morphology transition from vesicles at neutral pH values to micelles upon lowering the pH value down to endosomal pH value as investigated by DLS and cryo-TEM. The capability of polymersomes to encapsulate both hydrophobic (e.g., Nile Red) and hydrophilic (e.g., doxorubicin hydrochloride (DOX·HCl)) cargos was verified by in vitro studies. Drug release studies demonstrated that the DOX·HCl release is significantly accelerated under acidic pH values compared to physiological conditions. Cytotoxicity studies revealed that DOX·HCl loaded polymersomes exhibited an efficient cell death comparable to free DOX·HCl. CLSM and flow cytometry studies showed that DOX·HCl loaded vesicles were easily taken up by L929 cells and were mainly located in the cytoplasm and cell nuclei.

中文翻译：

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具有内体pH诱导的囊泡向胶束形态转变的聚合物囊泡，以及潜在的可控阿霉素递送应用

为了获得新颖的pH响应性聚合物囊泡体系，通过3,4-二氢-2 H-吡喃（DHP）保护的2-的可逆加成-断裂链转移（RAFT）聚合反应，合成了一系列pH响应性嵌段共聚物。甲基丙烯酸羟乙酯（HEMA）（2-（（tetrahydro-2 H使用对（THP-HEMA）作为大分子链转移剂（mCTA）的甲基丙烯酸-吡喃-2-基）氧基）甲基丙烯酸乙酯（THP-HEMA）和甲基丙烯酸2-（二甲基氨基）乙基酯（DMAEMA）。p（THP-HEMA）嵌段的聚合度（DP）固定为35，而p（DMAEMA）嵌段的DP则系统地从21变为50。 （DMAEMA）嵌段（DP = 21）自组装成囊泡，而具有30个单位p（DMAEMA）的聚合物形成胶束和囊泡的混合物。具有最长p（DMAEMA）嵌段（DP = 50）的聚合物仅形成胶束。如通过DLS和冷冻-TEM研究的，当将pH值降低至内体pH值时，相应的聚合物囊泡显示出从中性pH值的囊泡到胶束的形态转变。体外研究证实了聚合物囊泡既能包裹疏水性货物（如尼罗红）又能包裹亲水性货物（如盐酸阿霉素（DOX·HCl））的能力。药物释放研究表明，与生理条件相比，在酸性pH值下DOX·HCl的释放明显加快。细胞毒性研究表明，载有DOX·HCl的聚合物囊泡具有与游离DOX·HCl相当的有效细胞死亡。CLSM和流式细胞术研究表明，装载DOX·HCl的囊泡很容易被L929细胞吸收，并且主要位于细胞质和细胞核中。药物释放研究表明，与生理条件相比，在酸性pH值下DOX·HCl的释放明显加快。细胞毒性研究表明，载有DOX·HCl的聚合物囊泡具有与游离DOX·HCl相当的有效细胞死亡。CLSM和流式细胞术研究表明，装载DOX·HCl的囊泡很容易被L929细胞吸收，并且主要位于细胞质和细胞核中。药物释放研究表明，与生理条件相比，在酸性pH值下DOX·HCl的释放明显加快。细胞毒性研究表明，载有DOX·HCl的聚合物囊泡具有与游离DOX·HCl相当的有效细胞死亡。CLSM和流式细胞术研究表明，装载DOX·HCl的囊泡很容易被L929细胞吸收，并且主要位于细胞质和细胞核中。