Biocompatible and acid-cleavable poly(epsilon-caprolactone)-acetal-poly(ethylene glycol)-acetal-poly(epsilon-caprolactone) triblock copolymers: synthesis, characterization and pH-triggered doxorubicin delivery
Biocompatible and acid-cleavable poly(epsilon-caprolactone)-acetal-poly(ethylene glycol)-acetal-poly(epsilon-caprolactone) triblock copolymers: synthesis, characterization and pH-triggered doxorubicin delivery
复制标题
生物相容性和酸可裂解的聚(ε-己内酯)-缩醛-聚(乙二醇)-缩醛-聚(ε-己内酯)三嵌段共聚物：合成、表征和pH触发的阿霉素递送
DOI：
10.1039/c3tb21170c
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发表时间：
2013
影响因子：
7
通讯作者：
Ni Peihong
中科院分区：
文献类型：
--
作者：
Wang Hairong;He Jinlin;Zhang Mingzu;Tao Yunfeng;Li Fei;Tam Kam Chiu;Ni Peihong
以丙叉醇为引发剂，通过ε-己内酯的开环聚合和与叠氮封端的缩醛聚乙二醇聚乙二醇的“CuAAAc”点击反应，合成了一系列可酸裂解的ABA型三嵌段共聚物，即聚(ε-a-ε-a-PCL)-缩醛-聚乙二醇缩甲醛-聚(PCL-a-己内酯)。用核磁共振氢谱和傅里叶变换红外光谱对聚合物的化学组成和结构进行了表征，用凝胶渗透色谱(GPC)测定了聚合物的相对分子质量和相对分子质量分布。用荧光探针法、动态光散射法(DLS)和透射电子显微镜(TEM)分别测定了PCL-a-PEG-a-PCL自组装胶束的临界聚集浓度(CAC)、尺寸参数和形貌。由于缩醛基团在弱酸性介质中不稳定，预计这类三嵌段共聚物胶束可以在细胞内环境中解离。通过监测在酸性条件下胶束尺寸随降解时间的增加以及降解产物的相对分子质量的变化，证实了这一点。研究了多柔比星(DOX)从PCL-a-PEG-a-PCL胶束中的pH触发释放，并与不含缩醛基团的pH不敏感的PCL-b-PEG-b-PCL体系进行了比较，表明缩醛键的断裂是药物释放pH响应曲线的主要原因。通过四甲基偶氮唑盐比色法对HeLa和L929细胞的体外细胞毒性实验表明，自组装胶束具有很低的细胞毒性。此外，以游离DOX为对照，用活细胞成像系统进一步研究了药物对HeLa细胞的释放。这项工作为制备一种新型的可生物降解的两亲性共聚物提供了一种简便的策略，作为一种非常有前途的疏水药物的细胞内给药系统。
A series of acid-cleavable ABA-type triblock copolymers, namely poly(ε-caprolactone)-acetal-poly(ethylene glycol)-acetal-poly(ε-caprolactone) (PCL-a-PEG-a-PCL), were synthesized via a combination of ring-opening polymerization (ROP) of ε-caprolactone initiated by propargyl alcohol and subsequent “CuAAC” click reaction with azide terminated acetal-containing poly(ethylene glycol). The chemical composition and structures of the copolymers were characterized by 1H NMR and FT-IR spectroscopy, while their molecular weights and molecular weight distributions were measured by gel permeation chromatography (GPC). The critical aggregation concentration (CAC), size parameters and morphologies of micelles self-assembled from PCL-a-PEG-a-PCL were determined by fluorescence probing, dynamic light scattering (DLS), and transmission electron microscopy (TEM), respectively. Since the acetal groups are unstable in weak acidic media, it is anticipated that this class of triblock copolymer micelles can be dissociated in an intracellular environment. This was confirmed by monitoring the size change of micelles with the increase of degradation time under acidic conditions, as well as the molecular weights of degradation products. The pH-triggered release of doxorubicin (DOX) from PCL-a-PEG-a-PCL micelles was studied and compared with a pH-insensitive PCL-b-PEG-b-PCL system without acetal groups, demonstrating that the cleavage of acetal linkages was responsible for the pH-responsive drug release profiles. In vitro cytotoxicity tests against HeLa and L929 cells by MTT assays indicated that the self-assembled micelles displayed very low cytotoxicity. In addition, the intracellular drug release against HeLa cells was further investigated by a live cell imaging system using free DOX as a control. This work provides a facile strategy for the preparation of a new type of biodegradable amphiphilic copolymer as a highly promising intracellular delivery system for hydrophobic drugs.