肝癌靶向载多烯紫杉醇聚多巴胺修饰琥珀酸酯-聚乳酸纳米粒子的研究  

Docetaxel-loaded polydopamine-modified TPGS-PLA nanoparticles as a liver cancer targeted drug delivery system

作　　者：务圣洁 陈卓[1] 胡春艳[1] 秦玉[1] 樊帆[1] 王海[1] 张琳华[1] 陶伟[2] 刘赣[2] 曾小伟[2] 梅林[2] 朱敦皖[1] 

机构地区：[1]中国医学科学院北京协和医学院生物医学工程研究所,天津市生物医学材料重点实验室,天津300192 [2]清华大学深圳研究生院,深圳518055

出　　处：《国际生物医学工程杂志》2016年第4期193-197,232,I0002-I0004,共9页International Journal of Biomedical Engineering

基　　金：国家自然科学基金面上项目（81571793,51373199,81671806）;天津市自然科学基金重点项目（15JCZDJC38300）;中央级公益性科研院所基本科研业务费（2016ZX310095,2016ZX310098）

摘　　要：目的 建立一种简便的、具有肝癌靶向的聚多巴胺表面修饰聚合物纳米粒子以增加聚合物膜层和功能化的方法.方法 采用聚多巴胺修饰聚乙二醇1000-琥珀酸盐-聚乳酸纳米粒子（pD-TPGS-PLA/NPs）,并用其包载多烯紫杉醇（DTX）.为了达到靶向治疗肝癌的作用,再将半乳糖胺连接在pD-TPGS-PLA/NPs表面,从而通过配体-受体介导的作用提高DTX的递送效率.结果 聚多巴胺-琥珀酸酯-聚乳酸纳米粒子（pD-TPGS-PLA/NPs）和半乳糖胺-聚多巴胺-琥珀酸酯-聚乳酸纳米粒子（Gal-pD-TPGS-PLA/NPs）在粒径和形态学上与琥珀酸酯-聚乳酸纳米粒子（TPGS-PLA/NPs）有明显的不同.体外研究结果显示,TPGS-PLA/NPs、pD-TPGS-PLA/NPs和Gal-pD-TPGS-PLA/NPs对DTX有相似的释放行为.激光扫描共聚焦显微镜和流式细胞仪结果显示,HepG2细胞对于包载香豆素-6的Gal-pD-TPGS-PLA/NPs有较高地细胞摄取效率.相比于TPGS-PLA/NPs、pD-TPGS-PLA/NPs和临床应用的DTX药物多西他赛,载DTX的Gal-pD-TPGS-PLMNPs对HepG2细胞的生长有更强的抑制能力.体内抗肿瘤研究结果显示,在荷瘤裸鼠上注射包载DTX的Gal-pD-TPGS-PLA/NPs能有效减小肿瘤尺寸.结论 Gal-pD-TPGS-PLA/NPs可通过配体-受体识别与肝癌细胞发生特有的相互作用,有望成为一种极具潜力的靶向治疗肝癌的药物递送系统.Objective To develop a simple way to functionalize polymeric nanoparticle （NP） surfaces with ligands and/or additional polymeric layers with polydopamine-based surface modification.Methods The docetaxel （DTX）-loaded formulations was developed using polydopamine-modified NPs synthesized using D-α-tocopherol polyethylene glycol 1000 succinate-poly（lactide） （pD-TPGS-PLA/NPs）.To target liver cancer cells,galactosamine was conjugated on the prepared pD-TPGS-PLA/NPs to enhance the delivery of DTX via ligand-mediated endocytosis.Results The size and morphology of pD-TPGS-PLA/NPs and Gal-pD-TPGS-PLA/NPs changed obviously compared with TPGS-PLA/NPs.In vitro studies showed that TPGS-PLA/NPs,pD-TPGS-PLA/NPs and Gal-pD-TPGS-PLA/NPs had similar release profiles of DTX.Both confocal laser scanning microscopy and flow cytometric results showed that coumarin 6-loaded Gal-pD-TPGS-PLA/NPs had the highest cellular uptake efficiency in liver cancer cell line HepG2.Moreover,DTX-loaded Gal-pD-TPGS-PLA/NPs inhibited the growth of HepG2 cells more potently than TPGS-PLA/NPs,pD-TPGS-PLA/NPs,and a clinically available DTX formulation （Taxotere）.The in vivo anti-tumor effects study showed that injecting DTX-loaded Gal-pD-TPGS-PLA/NPs reduced the tumor size most significantly on hepatoma-bearing nude mice.Conclusions These results suggest that Gal-pD-TPGS-PLA/NPs prepared in the study specifically interacted with the hepatocellular carcinoma cells through ligand-receptor recognition and they may be used as a potentially eligible drug delivery system targeting liver cancers.

关 键 词：肿瘤纳米技术 多巴胺聚合 表面修饰 半乳糖化纳米粒子 肝靶向 

分 类 号：R944.9[医药卫生—药剂学]