摘要
目的合成一类新的具有酸敏感性能的阿霉素前药纳米粒(PEG-DOX NPs),对其结构进行表征,并研究其在体外抗脑胶质瘤中的作用和透过血脑屏障的效率。方法通过席夫碱反应合成具有酸敏感的聚乙二醇-阿霉素(PEG-DOX)单体,通过自组装制备PEG-DOX NPs。利用动态光散射(DLS)和核磁对单体进行结构表征,通过透射电镜(TEM)对纳米粒的微观形貌进行观察,紫外检测法测定PEG-DOX NPs在酸性条件下的释放行为,荧光显微镜观察脑胶质瘤细胞对PEG-DOX NPs的摄取行为。利用MTT法测定PEG-DOX NPs与阿霉素(DOX)对脑胶质瘤细胞的杀伤作用。PEG-DOX NPs修饰吐温80(PS-80)获得PS80-PEG-DOX NPs。将9只BALB/c小鼠随机均分为Free DOX组、PEG-DOX NPs组和PS80-PEG-DOX NPs组,利用小动物活体成像系统比较其修饰前后脑及主要脏器内DOX的荧光强度。结果 PEG-DOX能够自组装成直径100 nm左右的纳米粒;在酸性条件下PEG-DOX NPs能够快速释放DOX,肿瘤细胞对PEG-DOX NPs的摄取虽然比DOX慢,但蓄积时间更长;PEG-DOX NPs和Free DOX对C6细胞的增殖抑制均呈现浓度依赖性,PEG-DOX NPs组细胞增殖抑制率在各个浓度下均低于Free DOX组。PS-80修饰后,PS80-PEG-DOX NPs透过血脑屏障的效率显著高于DOX和PEG-DOX NPs组。结论 PEG-DOXNPs具有良好的体外抗肿瘤作用,修饰后可高效透过血脑屏障,使其体内治疗脑胶质瘤成为可能。
Objective To synthesize a new kind of acid-sensitive doxorubicin prodrug nanoparticles and to evaluate its anti-brain glioma effect and efficiency through blood-brain barrier （BBB）. Methods The prodrug acid-sensitive poly- ethylene glycol （PEG） - doxorubicin （PEG-DOX） copolymer was synthesized by Schiff base reaction, and PEG-DOX pro- drug nanoparticles （PEG-DOX NPs） were prepared by self-assembling. The character of PEG-DOX copolymer was detected by dynamic light scattering （DLS） instrument and ~H NMR. The morphology of PEG-DOX NPs was observed by transmission electron microscopy （TEM）. The character of drug release was detected by UV mothed. The cellular uptake efficiency of glio- ma cells to PEG-DOX NPs was observed by inverted fluorescence microscope. The anti-brain glioma effects of PEG-DOX NPs and Free DOX were studied by MTT toothed. PS80-PEG-DOX NPs were gained by the modification of PEG-DOX NPs with Tween 80. Nine BALB/c mice were separated into Free DOX, PEG-DOX NPs and PS80-PEG-DOX NPs groups by random drawing lots. The mean fluorescence intensity of brain and main organs were observed by in vivo imaging system. Re- suits The copolymer of PEG-DOX can self-assemble into nanoparticles with the diameter of 100 nm. PEG-DOX NPs can quickly release DOX in acid environment. Although PEG-DOX NPs had slow cancer cell uptake than Free DOX, it had longer accumulation. MTF results showed that PEG-DOX NPs had concentration dependent anti-brain glioma effect. Indepen- dent samples t-test indicated that the efficiency through BBB was significantly higher in PSS0-PEG-DOX NPs group than that of Free DOX group and PEG-DOX NPs group. Conclusion PEG-DOX NPs show well anti-brain glioma effect in vitro, and can across BBB with high efficiency after modification, which make it possible for a potential therapeutic prodrug for brain glioma.
出处
《天津医药》
CAS
2016年第1期33-37,共5页
Tianjin Medical Journal
基金
国家自然科学基金资助项目(51203189
51303213
81171371)
天津市应用基础与前沿技术研究计划重点项目(13JCZD-JC28100)
"协和青年基金资助"和"中央高校基本科研业务费专项资金资助"(3332015100)
中国医学科学院放射医学研究所发展基金(1550
1428)
关键词
血脑屏障
阿霉素前药
纳米粒
脑胶质瘤
酸敏感
blood-brain barrier
doxorubicin prodrug
nanoparticle
brain glioma
acid-sensitive
