Synthesis of an acid-cleavable and fluorescent amphiphilic block copolymer as a combined delivery vector of DNA and doxorubicin
Synthesis of an acid-cleavable and fluorescent amphiphilic block copolymer as a combined delivery vector of DNA and doxorubicin
复制标题
作为 DNA 和阿霉素联合递送载体的酸可裂解荧光两亲嵌段共聚物的合成
DOI：
10.1039/c4tb00334a
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发表时间：
2014
影响因子：
7
通讯作者：
Ni Peihong
中科院分区：
文献类型：
--
作者：
Hao Ying;He Jinlin;Li Sen;Liu Jian;Zhang Mingzu;Ni Peihong
基因和药物协同治疗的一个新策略是建立一种新的范式，用于合成从基因和药物输送到荧光检测的各种功能嵌段共聚物。通过原子转移自由基聚合、开环聚合和CuAAC“点击”反应合成了一种新型的两亲性嵌段共聚物，它含有荧光香豆素衍生物(CE)、疏水性聚(ε-己内酯)(PCL)与亲水性聚[2-(二甲氨基)甲基丙烯酸乙酯](PDMAEMA)和聚[聚乙二醇甲基甲基丙烯酸乙酯](PPEGMA)之间的可酸裂解(缩醛基团，-a-)键。用核磁共振氢谱和傅立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。这些嵌段共聚物自组装的胶束可以同时包裹抗癌药物阿霉素(DOX)和DNA，与表面亲水的刷型PPEGMA形成胶束复合体，在胞内酸性条件下切割缩醛键后，负载的货物可以被释放。随后，通过凝胶滞留实验、Zeta电位、动态光散射(DLS)和透射电子显微镜(TEM)对所形成的胶束作为药物和基因共传递载体进行了研究。并用荧光光谱仪对聚合物的荧光性能进行了评价。最后，对其体外释药、细胞毒性和转染性进行了研究。所有这些结果表明，这种酸可裂解的荧光嵌段共聚物作为药物和DNA载体的组合具有很大的潜力。
An emerging strategy for synergistic gene and drug therapy is establishing a new paradigm for the synthesis of diversified and functional block copolymers with applications ranging from gene and drug delivery to fluorescence detection. In this paper, we report on a novel amphiphilic block copolymer containing a fluorescent coumarin derivative (CE), an acid-cleavable (acetal group, -a-) linkage between hydrophobic poly(ε-caprolactone) (PCL) and hydrophilic poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) and poly[poly(ethylene glycol)methyl ether methacrylate] (PPEGMA) blocks, abbreviated as CE-PCL-a-(PDMAEMA-co-PPEGMA), which was synthesized by a combination of atom transfer radical polymerization (ATRP), ring-opening polymerization (ROP) and CuAAC “click” reaction. The chemical composition and structures of these copolymers were fully characterized by 1H NMR and FT-IR analyses, while the molecular weights and molecular weight distributions were measured by gel permeation chromatography (GPC). The micelles self-assembled from these block copolymers could simultaneously encapsulate anti-cancer drug doxorubicin (DOX) and DNA to form a micelleplex with the hydrophilic brush-type PPEGMA on the surface, and the loaded cargoes could be released after the acetal linkage was cleaved under intracellular acidic conditions. Subsequently, the formed micelles as the drug and gene co-delivery vectors were investigated by employing gel retardation assay, zeta potential, dynamic light scattering (DLS), and transmission electron microscopy (TEM). A fluorescence spectrometer was further used to evaluate the fluorescence of polymers. Finally, in vitro drug release, cytotoxicity and transfection were also studied. All these results indicated that this acid-cleavable and fluorescent block copolymer would hold significant potential as a combined drug and DNA carrier.