替莫唑胺-PLGA纳米缓释微球的制备及体外药效研究

Preparation of temozolomide-PLGA sustained-release nanoparticles and their in vitro efficacy

目的制备理想的可用于控制胶质瘤细胞生长进而可抑制胶质瘤的替莫唑胺-PLGA纳米缓释微球。方法用超声乳化-溶剂挥发法制备替莫唑胺-PLGA纳米缓释微球。选择测试了四种不同分子量的缓释微球的表面形态特征,并测量微球直径。检测载药量和包封率,分析制作参数、形态特征以及绘制释放曲线。结果替莫唑胺-PLGA缓释微球是一种结构稳定、大小均匀的缓释微球。分子量越大,微球直径越大。高分辨光镜及电镜观察,微球表面光滑,无裂隙,微球无明显聚集,微球大小均匀。不同分子量的TMZ-PLGA缓释微球最大载药量为10.2%,包封率都在90%以上。二氯甲烷残留量为5.70‰,达到了颅内安全应用的要求。从释放曲线可以看出,缓释系统中替莫唑胺可以持续释放2周以上,符合间质内化疗所要求的周期。结论 PLGA非常适合作为制备缓释微球的缓释载体。所制备的替莫唑胺-PLGA缓释微球符合生物力学规律,替莫唑胺虽有突释效应,但药物缓释时间可控。不同分子量及不同载药量的缓释微球均能长时间持续释放替莫唑胺。

Objective To investigate the method to prepare the ideal temozolomide-poly（ lactic-co-glycolic acid）（ PLGA） sustained-release nanoparticles used to control the growth of glioma cells and thus inhibit glioma. Methods The ultrasonic emulsification-solvent evaporation method was used to prepare the temozolomide-PLGA sustained-release nanoparticles. The surface morphological characteristics of sustained-release nanoparticles with four different molecular weights were tested,and their diameters were measured. Drug loading and encapsulation efficiency were measured,preparation parameters and morphological characteristics were analyzed,and release curves were plotted. Results The temozolomide-PLGA sustained-release nanoparticles had a stable structure and a uniform size,and their diameter increased with the increasing molecular weight. High-resolution light microscopy and electron microscopy showed that the nanoparticles had a smooth surface without any fissures,and the nanoparticles did not aggregate significantly and had a uniform size. The highest drug loading of temozolomide-PLGA sustained-release nanoparticles with different molecular weights was 10. 2%,and their encapsulation efficiency was over90%. The residual amount of methylene chloride was 5. 70‰,which met the requirement for safe use in the brain. Release curves showed that temozolomide in the sustained-release system was released for more than 2 weeks,which met the requirement for interstitial chemotherapy cycle. Conclusions PLGA is a suitable carrier for the preparation of sustained-release nanoparticles,and the temozolomide-PLGA sustainedrelease nanoparticles meet the biomechanic rules. Although temozolomide has a burst effect,the drug release time can be controlled. Nanoparticles with different molecular weights and drug loadings can keep releasing temozolomide for a long time.