Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, PR China.
Biomaterials. 2012 Oct;33(29):7291-9. doi: 10.1016/j.biomaterials.2012.06.034. Epub 2012 Jul 12.
pH-sensitive degradable chimaeric polymersomes were developed based on asymmetric poly(ethylene glycol)-b-poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl)ethane methacrylate)-b-poly(acrylic acid) (PEG-PTTMA-PAA) triblock copolymers for active loading as well as triggered intracellular release of hydrophilic doxorubicin hydrochloride (DOX·HCl). PEG-PTTMA-PAA copolymers were readily prepared with M(n PAA) ranging from 1.5, 2.1 to 2.7 kg/mol by sequential reversible addition-fragmentation chain transfer (RAFT) copolymerization of 2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl)ethane methacrylate (TTMA) and acrylic acid (AA) using PEG-CPADN (M(n PEG) = 5.0 kg/mol; CPADN: 4-cyanopentanoic acid dithionaphthalenoate) as a macro-RAFT agent. PEG-PTTMA-PAA copolymers formed mono-disperse polymersomes with average sizes of 63.9-112.1 nm, which decreased with increasing M(n PAA). The polymersomal structure was confirmed by transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM). Notably, the acetals in polymersomes while sufficiently stable at pH 7.4 were prone to rapid hydrolysis at mildly acidic pHs of 4.0 and 5.0, which resulted in swelling and eventually disassembly of polymersomes. These chimaeric polymersomes could actively load DOX·HCl resulting in remarkably high drug loading contents (up to 15.9 wt.%) and loading efficiencies (up to 88.8%). The in vitro release studies showed that DOX·HCl was released from chimaeric polymersomes in a controlled and pH-dependent manner. CLSM observations revealed that these chimaeric polymersomes could efficiently deliver and release DOX·HCl into the nuclei of HeLa cells. MTT assays in HeLa cells demonstrated that DOX·HCl-loaded PEG-PTTMA-PAA polymersomes exhibited high anti-tumor activity with IC(50) (inhibitory concentration to produce 50% cell death) of 1.48-1.67 μg/mL, close to that of free DOX·HCl, while blank polymersomes were practically non-toxic up to a tested concentration of 2.0 mg/mL. These pH-sensitive degradable chimaeric polymersomes have appeared to be a promising alternative to liposomes for tumor-targeted delivery of DOX·HCl.
基于不对称的聚（乙二醇）-b-聚（2,4,6-三甲氧基苯甲酰基-1,1,1-三（羟甲基）乙烷甲基丙烯酰胺）-b-聚（丙烯酸）（PEG-PTTMA-PAA）嵌段共聚物，开发了 pH 敏感可降解嵌段聚合物囊，用于主动负载亲水性盐酸多柔比星（DOX·HCl）以及触发细胞内释放。通过 PEG-CPADN（M(nPEG)=5.0kg/mol；CPADN：4-氰基戊酸二硫代萘酸酯）作为大分子 RAFT 试剂，依次可逆加成-断裂链转移（RAFT）聚合 2,4,6-三甲氧基苯甲酰基-1,1,1-三（羟甲基）乙烷甲基丙烯酰胺（TTMA）和丙烯酸（AA），可以很容易地制备出具有 1.5、2.1 和 2.7kg/mol 范围内的 M(nPAA)的 PEG-PTTMA-PAA 共聚物。PEG-PTTMA-PAA 共聚物形成平均粒径为 63.9-112.1nm 的单分散聚合物囊，粒径随 M(nPAA)的增加而减小。聚合物囊的结构通过透射电子显微镜（TEM）和共聚焦激光扫描显微镜（CLSM）得到证实。值得注意的是，聚合物囊中缩醛在 pH7.4 时足够稳定，但在 pH4.0 和 5.0 时易快速水解，导致聚合物囊溶胀并最终解体。这些嵌段聚合物囊可以主动负载 DOX·HCl，从而实现高达 15.9wt%的高药物载药量和高达 88.8%的载药效率。体外释放研究表明，DOX·HCl 可以从嵌段聚合物囊中以受控和 pH 依赖性的方式释放。CLSM 观察结果表明，这些嵌段聚合物囊可以有效地将 DOX·HCl 递送到 HeLa 细胞的核内并释放。HeLa 细胞中的 MTT 测定表明，载有 DOX·HCl 的 PEG-PTTMA-PAA 聚合物囊具有高抗肿瘤活性，IC(50)（产生 50%细胞死亡的抑制浓度）为 1.48-1.67μg/mL，接近于游离 DOX·HCl，而空白聚合物囊在测试浓度高达 2.0mg/mL 时几乎没有毒性。这些 pH 敏感可降解嵌段聚合物囊似乎是脂质体用于 DOX·HCl 肿瘤靶向递送的一种有前途的替代物。
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