Wu Jia-Shuan, Mu Li-Min, Bu Ying-Zi, Liu Lei, Yan Yan, Hu Ying-Jie, Bai Jing, Zhang Jing-Ying, Lu Weiyue, Lu Wan-Liang
State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Molecular Pharmaceutics and New Drug System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Oncotarget. 2017 Jun 20;8(25):40906-40921. doi: 10.18632/oncotarget.16641.
Chemotherapy of brain glioma faces a major obstacle owing to the inability of drug transport across the blood-brain barrier (BBB). Besides, neovasculatures in brain glioma site result in a rapid infiltration, making complete surgical removal virtually impossible. Herein, we reported a novel kind of C-type natriuretic peptide (CNP) modified vinorelbine lipid vesicles for transferring drug across the BBB, and for treating brain glioma along with disrupting neovasculatures. The studies were performed on brain glioma U87-MG cells in vitro and on glioma-bearing nude mice in vivo. The results showed that the CNP-modified vinorelbine lipid vesicles could transport vinorelbine across the BBB, kill the brain glioma, and destroy neovasculatures effectively. The above mechanisms could be associated with the following aspects, namely, long circulation in the blood; drug transport across the BBB via natriuretic peptide receptor B (NPRB)-mediated transcytosis; elimination of brain glioma cells and disruption of neovasculatures by targeting uptake and cytotoxic injury. Besides, CNP-modified vinorelbine lipid vesicles could induce apoptosis of the glioma cells. The mechanisms could be related to the activations of caspase 8, caspase 3, p53, and reactive oxygen species (ROS), and inhibition of survivin. Hence, CNP-modified lipid vesicles could be used as a carrier material for treating brain glioma and disabling glioma neovasculatures.
由于药物难以穿过血脑屏障（BBB），脑胶质瘤的化疗面临着重大障碍。此外，脑胶质瘤部位的新生血管导致肿瘤快速浸润，使得完全手术切除几乎不可能。在此，我们报道了一种新型的C型利钠肽（CNP）修饰的长春瑞滨脂质体，用于将药物转运穿过血脑屏障，并用于治疗脑胶质瘤以及破坏新生血管。研究在体外对脑胶质瘤U87-MG细胞以及在体内对荷瘤裸鼠进行。结果表明，CNP修饰的长春瑞滨脂质体能够将长春瑞滨转运穿过血脑屏障，有效杀死脑胶质瘤并破坏新生血管。上述机制可能与以下方面有关，即：在血液中长循环；通过利钠肽受体B（NPRB）介导的转胞吞作用使药物穿过血脑屏障；通过靶向摄取和细胞毒性损伤消除脑胶质瘤细胞并破坏新生血管。此外，CNP修饰的长春瑞滨脂质体能够诱导胶质瘤细胞凋亡。其机制可能与半胱天冬酶8、半胱天冬酶3、p53和活性氧（ROS）的激活以及生存素的抑制有关。因此，CNP修饰的脂质体可作为一种载体材料用于治疗脑胶质瘤和破坏胶质瘤新生血管。
