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

通过纳米颗粒向大脑输送药物是一种有前途的策略,可以为脑肿瘤的化学疗法开辟新的可能性。如先前的研究所证明的,在涂有泊洛沙姆188 (Dox-PLGA) 的聚 (丙交酯-共-乙交酯) 纳米颗粒中装载阿霉素使得这种细胞抑制素的脑递送正常不能以自由形式穿透血脑屏障。Dox-PLGA纳米颗粒对大鼠颅内101.8胶质母细胞瘤产生了非常显著的抗肿瘤作用,因此代表了值得临床评估的脑肿瘤化疗的有希望的候选者。因此,本研究的目的是优化Dox-PLGA配方和开发中试规模的制造工艺。制备程序的优化涉及技术参数的改变,例如用可能更安全的低分子量PVA 9-10 kda替换颗粒稳定剂PVA 30-70  kDa,以及外部乳液介质的改性和均质化条件。优化的程序能够将包封效率从66% 提高到> 90%,并将纳米颗粒尺寸从250纳米减小到110纳米,从而能够通过膜过滤进行灭菌。中试规模工艺的特点是具有极好的重现性,批次间变化非常小。在治疗相关浓度下,纳米颗粒的体外血液毒性可忽略不计。通过体内实验证实了优化配方的抗肿瘤功效以及纳米颗粒渗透到颅内肿瘤和正常脑组织中的能力。

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