Institute of Drug Discovery and Development, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai 200062, PR China.
Colloids Surf B Biointerfaces. 2013 May 1;105:294-302. doi: 10.1016/j.colsurfb.2013.01.014. Epub 2013 Jan 16.
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 100nm 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 24h, especially at high dosage, indicating its great potential as tumor tissue targeted prodrug.
纳米颗粒经聚乙二醇（PEG）表面修饰后，虽然具有长循环时间和被动靶向肿瘤组织的潜力，但细胞摄取能力较差。本研究中，制备了喜树碱（CPT）的聚乙二醇壳可脱落纳米胶束前药，以增强细胞摄取能力，实现对肿瘤组织的被动靶向潜力和长循环时间，并提高 CPT 在水介质中的稳定性。首先，通过末端为氨基的二硫键连接的聚乙二醇单甲醚（mPEG-SS-NH2）和 6-氨基己酸使聚（L-琥珀酰亚胺）（PSI）中的五元环依次开环，得到 mPEG-SS-NH-g-PHAsp 的接枝共聚物。然后，通过 mPEG-SS-NH-g-PHAsp 上的羧基与 CPT 的 20-OH 之间的酯化反应得到 mPEG-SS-NH-g-PHAsp-CPT 前药。由于其两亲性，该前药在水介质中能够形成球形胶束，平均粒径约为 100nm，通过动态光散射（DLS）测量，提示其具有被动靶向肿瘤组织的潜力。由于在二硫苏糖醇（DTT）存在下 PEG 壳的脱落，纳米胶束表现出聚集、CPT 强烈释放和增强细胞摄取能力的趋势。此外，mPEG-SS-NH-g-PHAsp-CPT 纳米胶束在生理条件下有效地保护了 CPT 的活性内酯环免受水解。与游离 CPT 相比，mPEG-SS-NH-g-PHAsp-CPT 纳米胶束在 24 小时内对 L929 细胞系的细胞毒性明显降低，尤其是在高剂量时，表明其作为肿瘤组织靶向前药具有很大的潜力。
