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 215123, China.
Laboratory of Cellular and Molecular Tumor Immunology, Cyrus Tang Hematology Center, Medical College, Soochow University, Suzhou 215123, China.
J Control Release. 2014 Nov 10;193:154-61. doi: 10.1016/j.jconrel.2014.05.016. Epub 2014 May 20.
In this study, we designed and developed galactose-installed photo-crosslinked pH-sensitive degradable micelles (Gal-CLMs) for active targeting chemotherapy of hepatocellular carcinoma in mice. Gal-CLMs were readily obtained from co-self-assembly of poly(ethylene glycol)-b-poly(mono-2,4,6-trimethoxy benzylidene-pentaerythritol carbonate-co-acryloyl carbonate) (PEG-b-P(TMBPEC-co-AC)) and Gal-PEG-b-poly(ε-caprolactone) (Gal-PEG-b-PCL) copolymers followed by photo-crosslinking. Notably, paclitaxel (PTX)-loaded Gal-CLMs (Gal-PTX-CLMs) showed a narrow distribution (PDI=0.08-0.12) with average sizes ranging from 92.1 to 136.3nm depending on the Gal contents. The release of PTX from Gal-CLMs while inhibited at physiological pH was enhanced under endosomal pH conditions. MTT assays in asialoglycoprotein receptor (ASGP-R) over-expressing HepG2 cells demonstrated that half-maximal inhibitory concentration (IC50) values of Gal-PTX-CLMs decreased from 11.7 to 2.9 to 1.1μg/mL with increasing Gal contents from 10% to 20% to 30%, supporting receptor-mediated endocytosis mechanism. The in vivo biodistribution studies in human hepatoma SMMC-7721 tumor-bearing nude mice displayed that Gal20-PTX-CLMs resulted in significantly enhanced drug accumulation in the tumors over non-targeting PTX-CLM counterpart. In accordance, Gal20-PTX-CLMs caused much greater tumor growth inhibition than non-targeting PTX-CLMs as well as non-crosslinking Gal20-PTX-NCLM controls (average tumor volume: ca. 35mm(3)versus 144mm(3) and 130mm(3), respectively). Histological analysis showed that Gal20-PTX-CLMs induced more extensive apoptosis of tumor cells while less damage to normal liver and kidney compared to Taxol. Ligand-installed photo-crosslinked pH-responsive degradable micelles have a great potential for targeted cancer chemotherapy.
在这项研究中,我们设计并开发了半乳糖基光交联 pH 敏感可降解胶束(Gal-CLMs),用于小鼠肝癌的主动靶向化疗。Gal-CLMs 可通过聚乙二醇-b-聚(单-2,4,6-三甲氧基苯甲叉基-五亚乙基碳酸酯-co-丙烯酰碳酸酯)(PEG-b-P(TMBPEC-co-AC))和半乳糖基聚乙二醇-b-聚(ε-己内酯)(Gal-PEG-b-PCL)共聚物的自组装,然后进行光交联来轻易获得。值得注意的是,紫杉醇(PTX)负载的 Gal-CLMs(Gal-PTX-CLMs)表现出较窄的分布(PDI=0.08-0.12),平均粒径范围为 92.1nm 至 136.3nm,取决于半乳糖含量。在生理 pH 下,Gal-CLMs 中的 PTX 释放受到抑制,而在内涵体 pH 条件下则得到增强。在过表达去唾液酸糖蛋白受体(ASGP-R)的 HepG2 细胞中的 MTT 测定表明,Gal-PTX-CLMs 的半数最大抑制浓度(IC50)值随着半乳糖含量从 10%增加到 20%再到 30%而从 11.7μg/mL 降低至 2.9μg/mL 再降低至 1.1μg/mL,这支持受体介导的内吞作用机制。在人肝癌 SMMC-7721 荷瘤裸鼠体内的生物分布研究表明,Gal20-PTX-CLMs 导致肿瘤中药物的蓄积显著增加,超过了非靶向性的 PTX-CLM 对照物。相应地,Gal20-PTX-CLMs 引起的肿瘤生长抑制作用明显大于非靶向性的 PTX-CLMs 和非交联的 Gal20-PTX-NCLM 对照物(平均肿瘤体积:分别约为 35mm3、144mm3 和 130mm3)。组织学分析表明,与 Taxol 相比,Gal20-PTX-CLMs 诱导了更广泛的肿瘤细胞凋亡,而对正常肝脏和肾脏的损伤较小。配体安装的光交联 pH 响应可降解胶束在靶向癌症化疗方面具有巨大的潜力。
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