局部重复应用控释BCNU聚乳酸微球治疗U251胶质瘤的实验研究  

Growth Inhibition Against U251 Gliomas by Repeated Local Administration of BCNU from Controlled Release Poly(D,L-Lactic acid) Microspheres

作　　者：王虹 康春生[2] 原续波[3] 浦佩玉[2] 林立生 林洁 

机构地区：[1]天津金耀药业集团氨基酸公司,天津300171 [2]天津医科大学总医院神经外科,天津300052 [3]天津大学材料科学与工程学院,天津300072

出　　处：《中国药学杂志》2009年第5期337-340,共4页Chinese Pharmaceutical Journal

基　　金：天津市科技攻关项目(06YFGZSH00800);天津市社会发展计划项目(023111511-2)

摘　　要：目的研究局部重复应用聚乳酸[poly(D,L-lactic acid),PLA]控释卡莫司汀[1,3-bis(2-chlorethyl)-1-nitrosourea,BCNU]微球(BCNU-PLA)对U251人脑胶质瘤的生长抑制作用。方法应用沉淀方法制备包载BCNU的PLA纳米微球。应用扫描电子显微镜观察载药微球形态,分别应用Bratton-Marshall比色法和紫外分光光度法测定微球载药率与药物释放曲线。应用MTT方法检测PBS、BCNU、PLA微球和BCNU-PLA等不同处理方法对U251胶质瘤细胞增殖活性的影响。应用U251裸鼠皮下移植瘤模型为研究对象,连续3次进行PBS、BCNU、PLA微球和BCNU-PLA的治疗,观察实验动物的生存期与皮下肿瘤生长情况。结果扫描电子显微镜观察载药纳米微球呈球形,具有良好的单分散性;BCNU-PLA平均粒径为23.5μm。BCNU-PLA平均载药率为11.5%;以相对分子质量30×103的PLA制备BCNU-PLA微球的体外药物释放分析显示:BCNU在释放开始的10d表现出较大的突释,释放量达到载药量的40%;随后进入控释期,至4周左右释放了所载药物的50%。与BCNU原药治疗组比较,BCNU-PLA控释微球治疗在体外持续抑制U251胶质瘤细胞的生长;在体内明显抑制裸鼠皮下荷U251胶质瘤的生长,并显著改善荷瘤鼠的全身状况。结论BCNU-PLA载药微球可有效抑制皮下荷U251胶质瘤的生长,是局部化疗治疗胶质瘤的一种新策略。OBJECTIVE To study the inhibitory effects of local administration of BCNU-loaded poly （lactic acid） microspheres BCNU-PL on U251 human gliomacells. METHODS BCNU-PLA was prepared with nano-precipitation technology. Scanning electronic microscope was used to profile the morphologyl of microspheres .Bratton-Marshall colorimetric method and spectrophotometry were used respectively to determine the drug loading and release behavior. The proliferative activities of U251 glioma cells treated by PBS, PLA microspheres, BCNU and BCNU-PLA were measured by MTT respectively. The subcutaneous U251 glioma model in nude mice was used to evaluate the anti-tumor effect of repeated administration of BCNU-PLA. RESULTS The resulting particles were fractured and showed the characteristic alveolar morphology. The average particle size was 23.5 lμm for BCNU-PLA. The drug loading was 11.5% w/w. Drug release behavior in vitro indicated the burst effect was high （40%） after incubation for 10 d. 50% Accumulated release was observed after sustained release for 4 weeks. In vitro study indicated BCNU-PLA exerted sustained inhibition effect up to 6 d compared with BCNU administration. In vivo study demonstrated significant anti-tumor effect had been achieved by repeated local administration of BCNU-PLA and general condition of tumor-bearing mice was improved CONCLUSION The BCNU-PLA can inhibite the growth of subcutaneous U251 gliomas, thus will be a good stratagy of local chemotherapy of gliomas.

关 键 词：微球 卡莫司汀 聚乳酸 胶质瘤 

分 类 号：R965[医药卫生—药理学]