具有GLUT1主动转运、TDS“锁定”功能、葡萄糖和叶酸双重肿瘤识别的脑靶向磁性脂质体的制备及应用

On the basis of our research and others’ at home and abroad, we propose the theory of the preparation and application of magnetic brain-targeted liposomes with active transport by GLUT1, TDS ‘lock in’ function, dual cancer recognition by glucose and folic acid for the first time. After designing and synthesizing series liposome ligands, glucose-TDS-folic acid-cholestane conjugates, the docetaxel-loaded magnetic liposomes modified with the ligands will be prepared. The liposomes have the following characteristics: 1. The cholesteric part of the ligand is embedded in the phospholipid bilayer of liposomes and the rest are exposed on the surface of liposomes, which could enhance the stability in systemic circulation as PEGylation. 2. The magnetic field on the brain tumor site could increase the enrichment of the drug near the blood-brain barrier (BBB). 3. The exposed glucose residues could recognize GLUT1, which would transport the liposomes across the BBB into brain. Subsequently, the TDS system will be reduced to the quaternary ammonium salt of the thiazole ring in the central, making the liposome ‘locked’ in the brain. 4. Then, the glucose and folic acid residues can identify the receptors on the surface of tumor cells, and the liposomes were targeted to the tumor cells and released the original drug docetaxel in the cells, playing an effective treatment of brain tumors. The study of cell uptake in vitro, activity and targeting of liposomes in vitro and in vivo can suppose new ideas and methods of the treatment of brain cancer and other brain diseases, with high academic and applied value.

在我们及国内外研究基础上，首次提出“具有GLUT1主动转运、TDS‘锁定’功能、葡萄糖和叶酸双重肿瘤识别的脑靶向磁性脂质体的制备及应用”的设想，设计并合成系列葡萄糖-TDS-叶酸-胆甾偶联物，以此为配体，制备包封多西紫杉醇的磁性脂质体。该脂质体具有以下特点：1，配体的胆甾部分嵌入到脂质体的双分子层中，其余部分暴露在表面，起到类似PEG化作用，增强在体循环中的稳定性；2，脑肿瘤部位的外加磁场可增加该脂质体在血脑屏障的富集；3，暴露在脂质体表面的葡萄糖残基可识别GLUT1转运蛋白，透过血脑屏障进入脑中，随后TDS被还原成噻唑环季铵盐，使得该脂质体被“锁定”在脑内；4，葡萄糖和叶酸残基识别肿瘤细胞表面的受体，将脂质体靶向到肿瘤细胞释放原药，进而对脑肿瘤起到有效的治疗。并对比研究该类脂质体的体外细胞摄取、体内外活性及靶向性，为脑肿瘤及其他脑部疾病的治疗创立新思路和新方法，具极高的学术和应用价值。

在我们及国内外研究基础上，首次提出“具有GLUT1主动转运、TDS‘锁定’功能、葡萄糖和叶酸双重肿瘤识别的脑靶向磁性脂质体的制备及应用”的设想，设计并合成了葡萄糖-TDS-叶酸-胆甾偶联物A，以此为配体，制备包封多西紫杉醇的磁性脂质体。该脂质体具有以下特点：1.配体的胆甾部分嵌入到脂质体的双分子层中，其余部分暴露在表面，起到类似PEG化作用，增强在体循环中的稳定性；2.脑肿瘤部位的外加磁场可增加该脂质体在血脑屏障的富集；3.暴露在脂质体表面的葡萄糖残基可识别GLUT1转运蛋白，透过血脑屏障进入脑中，随后TDS被还原成噻唑环季铵盐，使得该脂质体被“锁定”在脑内；4.葡萄糖和叶酸残基识别肿瘤细胞表面的受体，将脂质体靶向到肿瘤细胞释放原药，进而对脑肿瘤起到有效的治疗。体外细胞毒性和凋亡实验表明：葡萄糖-TDS-叶酸-胆甾偶联物修饰后的脂质体LipA显示出良好的抑制活性和缓释效果，有较强的诱导凋亡和坏死能力。体外细胞摄取实验进一步验证了设计思路：葡萄糖和叶酸的修饰均可促进C6细胞对脂质体的摄取，双重修饰的脂质体可在单一靶向分子修饰的基础上进一步提高对C6细胞的脑靶向能力，TDS“锁定”功能的引入也可以增强C6细胞对脂质体的摄取。并且TDS的加入使得脂质体表面变为正电荷，从而使脂质体从溶酶体逃逸，同时增加了脂质体在肿瘤部位的滞留。摄取机制实验说明C6细胞对脂质体LipA’的摄取具有能量依赖性的、GLUT1和叶酸受体主动转运的、通过多种入胞途径综合介导实现的。在动物模型中，外加磁场作用下各组磁性脂质体的脑靶向性较无磁场时均有提升。在给药4h后，脑部荧光较强，而给药24h后，荧光明显降低，脂质体在体内被大量代谢，仅有含有TDS单元的脂质体还有少量残余。脂质体LipA组中位生存期相比于生理盐水组延长197%，表现出最佳的抗肿瘤活性，且具有良好的生物安全性。总的来说，在叶酸、葡萄糖以及外加磁场的共同作用下，增加了脂质体对肿瘤细胞的选择性，促进肿瘤细胞对药物的摄取，降低药物对正常细胞的毒性。

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