Retro-inverso isomer of Angiopep-2: a stable d-peptide ligand inspires brain-targeted drug delivery.
Retro-inverso isomer of Angiopep-2: a stable d-peptide ligand inspires brain-targeted drug delivery.
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DOI：
10.1021/mp500086e
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发表时间：
2014-03
影响因子：
4.9
通讯作者：
Xiaoli Wei;Changyou Zhan;Xishan Chen;J. Hou;Cao Xie;Weiyue Lu
中科院分区：
文献类型：
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作者：
Xiaoli Wei;Changyou Zhan;Xishan Chen;J. Hou;Cao Xie;Weiyue Lu
血脑屏障(BBB)阻止大多数药物到达中枢神经系统(CNS)疾病的部位，严重限制了治疗效果。Angiopep-2(这里称为(L)Angiopep)是一种来源于人的kunitz域的19肽，通过识别表达在脑毛细血管内皮细胞上的低密度脂蛋白相关蛋白1(LRP-1)而触发跨细胞吞噬和穿越血脑屏障。然而，血液和血脑屏障中的各种酶对多肽启发的脑靶向药物传递构成了多种代谢障碍。在这里，我们设计了一种(L)Angiopep的逆转录异构体，称为(D)Angiopep，以激发脑靶向给药。(D)Angiopep和(L)Angiopep在LRP-1高表达细胞中均表现出高摄取能力，包括bEnd.3和U87细胞。(D)Angiopep在两种细胞系中的摄取效率均低于(L)Angiopep，这表明Angiopep与d-肽的LRP-1结合亲和力较低。(D)Angiopep对新鲜大鼠血清中的蛋白水解酶具有抵抗力，而(L)Angiopep的85%以上在2 h内消失，内切的(D)Angiopep和(L)Angiopep与bEnd.3细胞的溶酶体隔室共存，提示(L)Angiopep在血脑屏障中对蛋白分解的敏感性可能进一步降低其跨细胞效率。在体内，(D)Angiopep修饰的PEG-DSPE胶束在正常脑和脑胶质母细胞瘤中有较高的分布。由于LRP-1在血脑屏障和胶质母细胞瘤细胞上的表达，蛋白水解性稳定的(D)Angiopep在设计二阶脑肿瘤靶向递送系统方面具有很大的潜力。
The blood-brain barrier (BBB) prevents most drugs from reaching the site of central nervous system (CNS) diseases, intensively confining the therapeutic efficiency. Angiopep-2 (here termed (L)Angiopep), which is a 19-mer peptide derived from human Kunitz domain, can trigger transcytosis and traverse the BBB by recognizing low density lipoprotein-related protein 1 (LRP-1) expressed on the brain capillary endothelial cells. Various enzymes in the blood and the BBB, however, present multiple metabolic barriers to peptide-inspired brain-targeted drug delivery. Here we designed a retro-inverso isomer of (L)Angiopep, termed (D)Angiopep, to inspire brain-targeted drug delivery. Both (D)Angiopep and (L)Angiopep displayed high uptake capacity in LRP-1 overexpressed cells, including bEnd.3 and U87 cells. (D)Angiopep demonstrated lower uptake efficiency in both cell lines than did (L)Angiopep, suggestive of lower binding affinity to LRP-1 of the d-peptide. (D)Angiopep was resistant to proteolysis in fresh rat blood serum, while more than 85% of (L)Angiopep disappeared within 2 h. Endocytosed (D)Angiopep and (L)Angiopep were found to be colocalized with lysosomal compartments of bEnd.3 cells, indicating that susceptibility to proteolysis of (L)Angiopep in the BBB may further attenuate its transcytosis efficiency. In vivo, (D)Angiopep modified PEG-DSPE micelles displayed high distribution in normal brain and intracranial glioblastoma. Due to the expression of LRP-1 on the BBB and glioblastoma cells, proteolytically stable (D)Angiopep holds much potential for designing two-order brain tumor targeted delivery systems.