Shein Sergey A, Kuznetsov Ilya I, Abakumova Tatiana O, Chelushkin Pavel S, Melnikov Pavel A, Korchagina Anna A, Bychkov Dmitry A, Seregina Irina F, Bolshov Mikhail A, Kabanov Alexander V, Chekhonin Vladimir P, Nukolova Natalia V
Department of Fundamental and Applied Neurobiology, Serbsky Medical Research Center of Psychiatry and Narcology , Moscow, Russia.
Department of Molecular and Cellular Biology, The International Biotechnology Center Generium , Volginsky Village, Russia.
Mol Pharm. 2016 Nov 7;13(11):3712-3723. doi: 10.1021/acs.molpharmaceut.6b00519. Epub 2016 Oct 3.
Targeted delivery of anticancer drugs to brain tumors, especially glioblastoma multiforme, which is the most frequent and aggressive type, is one of the important objectives in nanomedicine. Vascular endothelial growth factor (VEGF) and its receptor type II (VEGFR2) are promising targets because they are overexpressed by not only core tumor cells but also by migrated glioma cells, which are responsible for resistance and rapid progression of brain tumors. The purpose of the present study was to develop the liposomal drug delivery system combining enhanced loading capacity of cisplatin and high binding affinity to glioma cells. This was achieved by using of highly soluble cisplatin analogue, cis-diamminedinitratoplatinum(II), and antibodies against the native form of VEGF or VEGFR2 conjugated to liposome surface. The developed drug delivery system revealed sustained drug release profile, high affinity to antigens, and increased uptake by glioma C6 and U-87 MG cells. Pharmacokinetic study on glioma C6-bearing rats revealed prolonged blood circulation time of the liposomal formulation. The above features enabled the present drug delivery system to overcome both poor pharmacokinetics typical for platinum formulations and low loading capacity typical for conventional liposomal cisplatin formulations.
将抗癌药物靶向递送至脑肿瘤，尤其是多形性胶质母细胞瘤（最常见且侵袭性最强的类型），是纳米医学的重要目标之一。血管内皮生长因子（VEGF）及其II型受体（VEGFR2）是很有前景的靶点，因为它们不仅在肿瘤核心细胞中过度表达，而且在迁移的胶质瘤细胞中也过度表达，而这些迁移的胶质瘤细胞与脑肿瘤的耐药性和快速进展有关。本研究的目的是开发一种脂质体药物递送系统，该系统既能提高顺铂的负载能力，又能对胶质瘤细胞具有高结合亲和力。这是通过使用高溶解性的顺铂类似物顺-二氨二硝基铂（II）以及与脂质体表面偶联的针对天然形式的VEGF或VEGFR2的抗体来实现的。所开发的药物递送系统显示出持续的药物释放曲线、对抗原的高亲和力以及胶质瘤C6和U-87 MG细胞对其摄取的增加。对携带胶质瘤C6的大鼠进行的药代动力学研究表明脂质体制剂的血液循环时间延长。上述特性使本药物递送系统能够克服铂制剂典型的不良药代动力学以及传统脂质体顺铂制剂典型的低负载能力。
