Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena , Humboldtstr. 10, 07743 Jena, Germany.
Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena , Philosophenweg 7, 07743 Jena, Germany.
Biomacromolecules. 2017 Oct 9;18(10):3280-3290. doi: 10.1021/acs.biomac.7b00931. Epub 2017 Aug 31.
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.
为了获得一种新型的 pH 响应聚合物囊泡系统，通过可逆加成-断裂链转移（RAFT）聚合 3,4-二氢-2H-吡喃（DHP）保护的 2-羟乙基甲基丙烯酸酯（HEMA）（2-（四氢-2H-吡喃-2-基）氧基）乙基甲基丙烯酸酯（THP-HEMA）和 2-（二甲氨基）乙基甲基丙烯酸酯（DMAEMA），使用 p(THP-HEMA) 作为大分子链转移剂（mCTA）合成了一系列 pH 响应嵌段共聚物。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 变化到 50。在水溶液中，具有最短 p(DMAEMA) 嵌段（DP = 21）的嵌段共聚物自组装成囊泡，而具有 30 个单元的 p(DMAEMA) 的聚合物则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。通过动态光散射（DLS）和冷冻透射电子显微镜（cryo-TEM）研究发现，相应的聚合物囊泡在中性 pH 值下表现出从囊泡到胶束的形态转变，当 pH 值降低到内体 pH 值时。通过体外研究验证了聚合物囊泡包封疏水性（例如尼罗红）和亲水性（例如盐酸阿霉素（DOX·HCl））载药的能力。药物释放研究表明，与生理条件相比，在酸性 pH 值下，DOX·HCl 的释放明显加速。细胞毒性研究表明，载有 DOX·HCl 的聚合物囊泡表现出与游离 DOX·HCl 相当的有效细胞死亡。CLSM 和流式细胞术研究表明，载有 DOX·HCl 的囊泡很容易被 L929 细胞摄取，并主要位于细胞质和细胞核中。
