Brain delivery of drugs by nanoparticles is a promising strategy that could open up new possibilities for the chemotherapy of brain tumors. As demonstrated in previous studies, the loading of doxorubicin in poly(lactide-co-glycolide) nanoparticles coated with poloxamer 188 (Dox-PLGA) enabled the brain delivery of this cytostatic that normally cannot penetrate across the blood-brain barrier in free form. The Dox-PLGA nanoparticles produced a very considerable anti-tumor effect against the intracranial 101.8 glioblastoma in rats, thus representing a promising candidate for the chemotherapy of brain tumors that warrants clinical evaluation. The objective of the present study, therefore, was the optimization of the Dox-PLGA formulation and the development of a pilot scale manufacturing process. Optimization of the preparation procedure involved the alteration of the technological parameters such as replacement of the particle stabilizer PVA 30-70 kDa with a presumably safer low molecular mass PVA 9-10 kDa as well as the modification of the external emulsion medium and the homogenization conditions. The optimized procedure enabled an increase of the encapsulation efficiency from 66% to >90% and reduction of the nanoparticle size from 250 nm to 110 nm thus enabling the sterilization by membrane filtration. The pilot scale process was characterized by an excellent reproducibility with very low inter-batch variations. The in vitro hematotoxicity of the nanoparticles was negligible at therapeutically relevant concentrations. The anti-tumor efficacy of the optimized formulation and the ability of the nanoparticles to penetrate into the intracranial tumor and normal brain tissue were confirmed by in vivo experiments.

译文

:纳米粒子脑部给药是一种很有前途的策略,可以为脑肿瘤化疗开辟新的可能性。如先前的研究所示,阿霉素在涂有泊洛沙姆188(Dox-PLGA)的聚(丙交酯-共-乙交酯)纳米颗粒中的负载量使这种细胞抑制剂能够以大脑的形式传递,而后者通常无法以自由形式穿透血脑屏障。 Dox-PLGA纳米粒子对大鼠颅内101.8胶质母细胞瘤产生了非常显着的抗肿瘤作用,因此代表了有希望进行临床评估的脑肿瘤化学疗法的有希望的候选者。因此,本研究的目的是优化Dox-PLGA配方并开发中试规模的制造工艺。制备程序的优化涉及改变工艺参数,例如用可能更安全的低分子量PVA 9-10kDa代替颗粒稳定剂PVA 30-70kDa,以及外部乳液介质的改性和均质化条件。优化的程序可以将包封效率从66%提高到> 90%,并将纳米颗粒的尺寸从250nm减小到110nm,从而可以通过膜过滤进行灭菌。中试规模工艺的特点是具有出色的重现性,并且批间差异非常小。在治疗相关浓度下,纳米粒子的体外血液毒性可忽略不计。通过体内实验证实了优化制剂的抗肿瘤功效以及纳米颗粒渗透入颅内肿瘤和正常脑组织的能力。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录