Experimental Pharmacology, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin-Buch, Germany.
Pharm Res. 2012 Jul;29(7):1949-59. doi: 10.1007/s11095-012-0723-7. Epub 2012 Mar 8.
To test targeted liposomes in an effort to improve drug transport across cellular barriers into the brain.
Therefore we prepared Mitoxantrone (MTO) entrapping, rigid and fluid liposomes, equipped with a 19-mer angiopeptide as ligand for LDL lipoprotein receptor related protein (LRP) targeting.
Fluid, ligand bearing liposomes showed in vitro the highest cellular uptake and transcytosis and were significantly better than the corresponding ligand-free liposomes and rigid, ligand-bearing vesicles. Treatment of mice, transplanted with human breast cancer cells subcutaneously and into the brain, with fluid membrane liposomes resulted in a significant reduction in the tumor volume by more than 80% and in a clear reduction in drug toxicity. The improvement was mainly depended on liposome fluidity while the targeting contributed only to a minor degree. Pharmacokinetic parameters were also improved for liposomal MTO formulations in comparison to the free drug. So the area under the curve was increased and t(1/2) was extended for liposomes.
Our data show that it is possible to significantly improve the therapy of brain metastases if MTO-encapsulating, fluid membrane liposomes are used instead of free MTO. This effect could be further enhanced by fluid, ligand bearing liposomes.
研究靶向脂质体以改善药物穿越细胞屏障进入大脑的转运。
为此，我们制备了米托蒽醌（MTO）包封的刚性和流体脂质体，并配备了 19 个氨基酸的血管生成肽作为 LDL 脂蛋白受体相关蛋白（LRP）靶向配体。
带配体的流体脂质体在体外表现出最高的细胞摄取和转胞吞作用，明显优于相应的无配体脂质体和刚性带配体囊泡。用流体膜脂质体治疗皮下和脑内移植人乳腺癌细胞的小鼠，肿瘤体积减少了 80%以上，药物毒性明显降低。这种改善主要取决于脂质体的流动性，而靶向作用只起次要作用。与游离药物相比，脂质体 MTO 制剂的药代动力学参数也得到了改善。因此，脂质体的曲线下面积增加，t（1/2）延长。
我们的数据表明，如果使用包封 MTO 的流体膜脂质体代替游离 MTO，可显著改善脑转移的治疗效果。如果使用带配体的流体脂质体，这种效果可以进一步增强。
