细胞内氧化还原响应型肝靶向嵌段聚合物的合成及纳米自组装性能  

Synthesis and Self-assembly Properties of Intracellular Redox Bioresponsive Block Copolymers with Hepatoma-targeting Groups

作　　者：赵军强[1] 闫彩霞 陈泽 杨宁[1] 冯霞[1] 赵义平[1] 陈莉[1] ZHAO Junqiang;YAN Caixia;CHEN Ze;YANG Ning;FENG Xia;ZHAO Yiping;CHEN Li(School of Material Science and Engineering, Tianjin Polytechnic University, State Key Laboratory of Separation Membranes and Membrane Processes, Tianjin 300587, Chin)

机构地区：[1]天津工业大学材料科学与工程学院分离膜与膜过程国家重点实验室,天津300387

出　　处：《高等学校化学学报》2018年第7期1592-1601,共10页Chemical Journal of Chinese Universities

基　　金：国家自然科学基金(批准号:81502624和31200719);天津市教委科研计划项目(批准号:2017KJ071);天津市应用基础与前沿技术研究计划面上项目(批准号:15JCYBJC17900;14JCTPJC00515)资助~~

摘　　要：通过两步可逆加成-断裂链转移自由基聚合(RAFT)和缩醛脱保护反应合成了一种亲水段含半乳糖侧基和疏水段含吡啶环二硫键侧基的两亲性嵌段聚合物PMAIg GP-b-PPDSMA(PMg PP),用核磁共振氢谱(~1H NMR)和凝胶渗透色谱(GPC)分析验证了目标产物的化学结构.利用纳米沉淀技术和巯基氧化自交联反应制备内核二硫键交联的PMg PP纳米粒(PMg PP-CC NPs).动态光散射(DLS)和透射电子显微镜(TEM)测定结果表明,PMg PP-CC NPs粒径较小(<30 nm),且粒径分布较窄.在谷胱甘肽(GSH)还原环境下,PMg PPCC NPs粒径不断增大,发生了解组装.以阿霉素(DOX)为模型药物制备了PMg PP-CC/DOX NPs,载药量可达12.5%,对应包封率为83.3%,其粒径与空白PMg PP-CC NPs粒径大小相近,且粒径分布均匀.体外药物释放实验表明,PMg PP-CC/DOX NPs在体液条件下46 h释放了4.47%的DOX,而在10 mmol/L GSH条件下累积释放量达到了50.6%.细胞胞吞实验进一步验证了PMg PP-CC/DOX NPs可高效入胞并在细胞内快速释放DOX.体外细胞毒性(MTT)实验表明,PMg PP-CC/DOX NPs对肝癌Hep G-2细胞表现出良好的增殖抑制活性.因此,多功能PMg PP-CC NPs在实现肝靶向纳米精准给药上呈现出良好的应用前景.The amphiphilic block copolymers PMAIg GP-b-PPDSMA（ PMg PP） with a hydrophilic block containing galactose side groups and a hydrophobic segment containing pyridine ring disulfide pendant groups were prepared by two-step reversible addition-fragmentation chain transfer（ RAFT） polymerization and acetal deprotection reaction. Their well-defined chemical structures were confirmed by proton nuclear magnetic resonance（1 H NMR） and gel permeation chromatography（ GPC）. Core-crosslinked PMg PP nanoparticles（ PMg PP-CC NPs） were prepared by nano-precipitation technology and thiol oxidation self-crosslinking reaction. Dynamic light scattering（ DLS） and transmission electron microscopy（ TEM） were used to determine the size of PMg PP-CC NPs（ 30 nm） and the particle size distribution indexes were narrow. Under the reduction environment of GSH,the particle sizes of PMg PP-CC NPs were increasing with incubation time,indicating the disassembly of PMg PP-CC NPs. PMg PP-CC/DOX NPs were prepared by DOX as the model drug,and drug loading content up to 12. 5% and entrapment efficiency of 83. 3%. The particle sizes were similar to that of the corresponding blank CC NPs,and the particle size distribution was uniform. Within 46 h in vitro,4. 47% of DOX was released from the PMg PP-CC/DOX NPs in normal physiological conditions,whereas50. 6% was released in the presence of 10 mmol/L GSH condition analogous to the reductive microenvironment in cytoplasm. The cell uptake tests further confirmed that PMg PP-CC/DOX NPs could be efficiently released in the Hep G-2 cells. 3-（ 4,5-dimethyethiazol-2-yl）-2,5-diphemptetrazolium bromide（ MTT） assays show that PMg PP-CC/DOX NPs has good proliferation inhibitory activity against Hep G-2 cells. Therefore,multifunctional PMg PP-CC NPs have a good prospect in the field of precise hepatoma-targeting drug delivery.

关 键 词：半乳糖 氧化还原敏感 核交联嵌段聚合物 可逆加成-断裂链转移自由基聚合(RAFT) 药物递送 

分 类 号：O631[理学—高分子化学] TQ463[理学—化学]