药学学报, 2019, 54(3): 547-554
引用本文:
郭权, 郑雅娴, 吴蕾, 周锐, 刘晨冬, 黄园. 两性离子聚合物链长对纳米粒穿黏液及细胞摄取能力的影响[J]. 药学学报, 2019, 54(3): 547-554.
GUO Quan, ZHENG Ya-xian, WU Lei, ZHOU Rui, LIU Chen-dong, HUANG Yuan. Effect of zwitterionic polymer chain length on mucus penetration and cellular uptake of nanoparticles[J]. Acta Pharmaceutica Sinica, 2019, 54(3): 547-554.

两性离子聚合物链长对纳米粒穿黏液及细胞摄取能力的影响
郭权, 郑雅娴, 吴蕾, 周锐, 刘晨冬, 黄园
四川大学华西药学院, 四川 成都 610041
摘要:
本研究旨在构建不同链长的聚磺酸甜菜碱甲基丙烯酸酯[poly(sulfobetaine methacrylate),pSBMA]修饰的纳米粒(pSBMAn NPs),以探究两性离子聚合物链长对纳米粒穿黏液及细胞摄取能力的影响。结合己内酯的开环聚合反应和原子转移自由基聚合反应(atom transfer radical polymerization,ATRP)合成不同链长的两嵌段聚合物——聚己内酯-聚磺酸甜菜碱甲基丙烯酸酯共聚物[poly(ε-caprolactone)-block-poly(sulfobetaine methacrylate),PCL-pSBMA],并通过纳米沉淀法制备相应的纳米粒。采用黏蛋白吸附实验和Transwel小室实验考察纳米粒的穿黏液能力。以人源结肠癌Caco-2细胞和可分泌黏液的HT-MTX-E12细胞为模型,考察链长对纳米粒摄取及穿黏液能力的影响。研究结果表明:制得的pSBMAn NPs粒径相近,均约为100 nm,电位约为-7 mV。短链pSBMA修饰的纳米粒(pSBMA10 NPs)的表观渗透系数(apparent permeability coefficient,Papp)仅是长链pSBMA纳米粒(pSBMA80 NPs)的42.83%,但细胞摄取是pSBMA80 NPs的2.44倍。有黏液存在时,pSBMAn NPs的摄取均降低,但pSBMA10 NPs的细胞摄取能力仍最强。体内实验结果表明,pSBMA20 NPs的口服生物利用度高于pSBMA10 NPs(动物实验根据四川大学关于实验动物的饲养和使用准则进行,并得到四川大学实验动物伦理委员会批准)。本文为两性离子纳米粒的口服研究提供了参考。
关键词:   
Effect of zwitterionic polymer chain length on mucus penetration and cellular uptake of nanoparticles
GUO Quan, ZHENG Ya-xian, WU Lei, ZHOU Rui, LIU Chen-dong, HUANG Yuan
West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Abstract:
To investigate the influences of zwitterionic polymer chain length on mucus permeability and cellular uptake, the nanoparticles (NPs) were coated with poly(sulfobetaine methacrylate) (pSBMA) with different chain lengths. The di-block polymer poly(ε-caprolactone)-block-poly(sulfobetaine methacrylate) (PCL-pSBMA) with different chain lengths were synthesized via atom transfer radical polymerization (ATRP) combining with ring-opening polymerization of ε-caprolactone, and corresponding nanoparticles (pSBMAn NPs) were prepared by nanoprecipitation method. The sizes of different pSBMAn NPs were around 100 nm, and zeta potential were about -7 mV. Mucin interaction or mucus penetration study based on transwell systems were employed to evaluate mucus permeability of NPs. Caco-2 cells and mucus-producing HT-MTX-E12 cells were employed to illustrate the endocytosis efficiency of pSBMAn NPs. The results showed that the permeability coefficient of NPs coated with shorter chain length of pSBMA (pSBMA10 NPs) was only 42.83% of that coated with longer pSBMA (pSBMA80 NPs). On the contrary, the cellular uptake of pSBMA10 NPs was 2.44 fold higher compared to pSBMA80 NPs. Although the cellular uptake of pSBMAn NPs was reduced in the presence of mucus, pSBMA10 NPs still presented the highest cellular uptake. However, the in vivo results indicated that the oral bioavailability of pSBMA20 NPs was higher than that of pSBMA10 NPs. All animal procedures were performed in accordance with the Guidelines of the Sichuan University Animal Care and Use Committee and were approved by the Animal Ethics Committee of Sichuan University. This study provides a reference for oral delivery of zwitterionic nanoparticles.
Key words:   
收稿日期: 2018-12-04
DOI: 10.16438/j.0513-4870.2018-1080
基金项目: 国家自然科学基金面上项目(81872818);国家杰出青年科学基金资助项目(81625023).
通讯作者: 黄园
Email: huangyuan0@163.com
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