Poly(ethylene glycol) shell-sheddable nanomicelle prodrug of camptothecin with enhanced cellular uptake
Poly(ethylene glycol) shell-sheddable nanomicelle prodrug of camptothecin with enhanced cellular uptake
复制标题
具有增强细胞摄取作用的聚（乙二醇）壳可脱落的喜树碱纳米胶束前药
DOI：
10.1016/j.colsurfb.2013.01.014
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发表时间：
2013-05-01
影响因子：
5.8
通讯作者：
Liu, Shiyuan
中科院分区：
文献类型：
--
作者：
Wu, Qinge;Du, Fang;Liu, Shiyuan
用聚（乙二醇）（PEG）对纳米颗粒进行表面修饰显示出较差的细胞摄取，尽管它提供了较长的循环时间和对肿瘤组织的被动靶向潜力。本研究以喜树碱（CPT）为前体药物，以聚乙二醇为壳层，制备了喜树碱前体药物的可脱落纳米胶束，以增强CPT的细胞摄取能力，实现CPT对肿瘤组织的被动靶向作用和长循环时间，并提高CPT在水介质中的稳定性。首先，用端氨基二硫键连接的聚乙二醇单甲醚（mPEG-SS-NH 2）和6-氨基己酸对聚L-琥珀酰亚胺（PSI）的五元环进行开环，得到mPEG-SS-NH-g-PHAsp接枝共聚物。然后将mPEG-SS-NH-g-PHAsp-CPT的羧基与CPT的20-OH进行酯化反应得到mPEG-SS-NH-g-PHAsp-CPT的前药。由于其两亲性，该前药能够在水性介质中形成球形胶束，通过动态光散射（DLS）测量的平均粒径约为100 nm，表明其对肿瘤组织的被动靶向潜力。由于二硫苏糖醇（DTT）存在时PEG壳层的脱落，纳米胶束表现出聚集倾向，大量释放CPT，增强细胞摄取能力。mPEG-SS-NH-g-PHAsp-CPT纳米胶束能有效地保护CPT的活性内酯环在生理条件下不被水解。与游离CPT相比，mPEG-SS-NH-g-PHAsp-CPT纳米胶束对L929细胞的24 h细胞毒活性明显降低，尤其是在高剂量时，其细胞毒活性明显降低，表明mPEG-SS-NH-g-PHAsp-CPT纳米胶束具有作为肿瘤组织靶向药物的潜力。(C)2013爱思唯尔有限公司版权所有。
Surface modification of nanoparticles with poly (ethylene glycol) (PEG) shows poor cellular uptake, although it affords long circulation time and passive targeting potential to the tumor tissue. In this research, poly(ethylene glycol) shell-sheddable nanomicelle prodrug of camptothecin (CPT) was developed, in order to enhance the cellular uptake ability, achieve the passive targeting potential to tumor tissue and long circulation time, and to improve the stability of CPT in aqueous media. Firstly, the five-member rings in poly (L-succinimide) (PSI) were successively opened by the amino terminated disulfide-linked poly (ethylene glycol) monomethyl ether (mPEG-SS-NH2) and 6-aminocaproic acid to produce the graft copolymer of mPEG-SS-NH-g-PHAsp. And then, the resultant prodrug of mPEG-SS-NH-g-PHAsp-CPT was obtained by the esterification between carboxylic groups of mPEG-SS-NH-g-PHAsp and 20-OH of CPT. The prodrug was able to form spherical micelles in aqueous media because of its amphiphilic nature with average particle size of about 100 nm measured by dynamic light scattering (DLS), suggesting its passive targeting potential to tumor tissue. Due to the detachment of PEG shell in the presence of dithiothreitol (DTT), the nanomicelle showed a tendency to aggregation, intense release of CPT, and enhanced cellular uptake ability. Also, the mPEG-SS-NH-g-PHAsp-CPT nanomicelle effectively protected the active lactone ring of CPT from hydrolysis under physiological condition. Compared with free CPT, mPEG-SS-NH-g-PHAsp-CPT nanomicelle showed essentially decreased cytotoxicity against L929 cell line in 24 h, especially at high dosage, indicating its great potential as tumor tissue targeted prodrug. (C) 2013 Elsevier B.V. All rights reserved.