目的 以树状大分子为载体材料并修饰血脑屏障（blood brain barrier，BBB）靶向短肽TGN和肿瘤靶向短肽iRGD构建脑胶质瘤靶向递药系统（iRGD/TGN-PEG-PAMAM/ATO），旨在解决三氧化二砷（arsenic trioxide，As₂O₃，ATO）在治疗脑胶质瘤过程中分布缺乏特异性、透BBB难等问题，使其具有更好抗脑胶质瘤作用。方法 核磁共振图谱（¹H-NMR）、透射电子显微镜（TEM）等考察载体的理化性质；电感耦合等离子发射光谱（ICP）、透析袋法分析其包封率及体外释放情况；通过激光共聚焦及流式细胞仪分析iRGD、TGN对细胞摄取的影响；MTT法考察纳米载体对脑微血管内皮细胞（HBMEC）和脑胶质瘤U87细胞的毒性及BBB模型中递药系统抑制U87细胞生长的情况。结果 成功合成了iRGD/TGN-PEG-PAMAM载体，其形态规整，大小均匀，测得其粒径（24.87±0.84）nm，电位（17.26±1.64）mV；该载体对HBMEC和U87细胞均具有较小的毒性；递药系统iRGD/TGN-PEG-PAMAM/ATO的包封率为（71.92±1.17）%，体外释放表明ATO经载体包载后呈现一种缓慢释放趋势，且在酸性条件下更有利于ATO的释放；细胞摄取结果提示iRGD/TGN的修饰有利于U87细胞对递药系统的摄取；体外跨BBB抑制U87细胞生长实验结果表明，iRGD/TGN-PEG-PAMAM/ATO组具有更好的跨BBB抑制U87细胞生长效果。结论 iRGD/TGN-PEG-PAMAM/ATO脑胶质瘤靶向递药系统具有较好的体外跨BBB抑制U87细胞生长的效果，为脑胶质瘤治疗提供了新的策略。

Objective To construct a glioma targeting delivery system, PAMAM G5 were modified with the oligopeptide of blood brain barrier (BBB) targeting TGN and tumor targeting oligopeptide iRGD to solve the problem of non-specificity in distribution and difficulty in permeating BBB of ATO, in order to have better anti-glioma effect. Methods The physical and chemical properties of nanocarriers were investigated by ¹H-NMR and transmission electron microscopy (TEM); The encapsulation efficiency and in vitro release were analyzed by inductively coupled plasma emission spectrum (ICP) and dialysis bag method; The effects of iRGD and TGN on cellular uptake of the carriers were analyzed by laser confocal and flow cytometry. The cytotoxicity of nanocarriers on brain microvascular endothelial cells (HBMEC) and glioma cells (U87), the inhibition effect on U87 cells of drug delivery systems after acrossing the BBB model in vitro were investigated by MTT method. Results The iRGD/TGN-PEG-PAMAM was synthesized successfully. The TEM results showed that iRGD/TGN-PEG-PAMAM was regular in shape and uniform in size. The particle size of iRGD/TGN-PEG-PAMAM/ATO was (24.87 ±0.84) nm and the potential was (17.26 ±1.64) mV. The synthesized carrier had less toxicity to HBMEC and U87 cells. The encapsulation efficiency of iRGD/TGN-PEG-PAMAM/ATO delivery system was (71.92 ±1.17)%. The in vitro release showed that ATO had a slow release trend after entrapment, and it was more favorable for ATO release under acidic conditions. The cell uptake indicated that iRGD/TGN modification was more beneficial for U87 cell to uptake the drug delivery system. The in vitro inhibition effect on U87 cells after acrossing the BBB model showed iRGD/TGN-PEG-PAMAM/ATO had better inhibition effect on U87 cells. Conclusion The iRGD/TGN-PEG-PAMAM/ATO targeting drug delivery system has good inhibition effect on U87 cells effect after acrossing the BBB model in vitro, which provides a new strategy for the treatment of glioma.

R283.6

双重血栓靶向定位释放水蛭素融合蛋白基因给药系统的研究（81603303）；国家自然科学基金面上项目"协同靶向"策略构建两性寡肽脂质体介导三氧化二砷前药脑胶质瘤胞药及机理研究（81673607）