New systems for delivery of drugs to the brain in neurological disease.
New systems for delivery of drugs to the brain in neurological disease.
复制标题
在神经系统疾病中将药物输送到大脑的新系统。
DOI：
10.1016/s1474-4422(02)00136-9
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Cornford,MarciaE
中科院分区：
文献类型：
--
作者：
Cornford,EainM;Cornford,MarciaE
BBB. 12，13 Pardridge 8建议开发外排转运蛋白抑制剂，这将增加蛋白酶抑制剂、齐多夫定和拉米夫定的脑浓度，从而改善药物治疗。当芳香酸脱羧酶抑制剂与左旋多巴共同给药以抑制其代谢时，这种BBB导向的药物增强策略已经被使用，随着对受体介导的转胞吞系统如何运作的理解的最新进展，脑药物递送的焦点已经转向使用内源性毛细血管受体的机制，因为这些系统促进特定大分子的膜通道。Pardridge 14指出，仅有的内源性肽类（如胰岛素、胰岛素样生长因子和转铁蛋白）通过受体介导的内吞作用穿过血脑屏障。特异性受体促进这些化合物穿过管腔毛细血管膜、穿过细胞质和穿过近管腔膜至神经元的运动。该过程涉及受体和肽在BBB的腔膜处的结合、质膜囊泡的形成、受体-肽复合物通过细胞质的易位以及肽从近腔膜的外表面上的受体解离。药物的酶促降解不会发生在内皮细胞内，因为受体结合的配体包含在膜密封的胞饮囊泡内。这种受体可以将大分子传递穿过BBB（并且当与潜在的神经药物连接时倾向于具有类似的运输特性），在开发新的运输工具以促进BBB通过中提供了用作有用的“特洛伊木马”的前景。2类似地，修饰的蛋白质如阳离子化白蛋白也通过转胞吞机制穿过脑毛细血管，但尚未鉴定出该蛋白质的特异性受体。吸收介导的
BBB. 12, 13 Pardridge8 has proposed the development of effluxtransporter inhibitors, which would increase brain concentration of protease inhibitors, zidovudine, and lamivudine and thus improve drug therapy. This strategy of BBB-directed drug augmentation is already used when inhibitors of aromatic-acid decarboxylase are coadministered with levodopa to inhibit its metabolism.With the recent advances in the understanding of how receptor-mediated transcytosis systems operate, the focus of brain drug delivery has switched to mechanisms that use the endogenous capillary receptors, since these systems promote membrane passage of specific large molecules. Pardridge14 noted that the only endogenous peptides that cross the BBB to any appreciable extent (eg, insulin, insulin-like growth factor, and transferrin) use receptor-mediated endocytosis. Specific receptors facilitate the movement of these compounds across the luminal capillary membrane, through the cytoplasm, and across the abluminal membrane to the neuropil. This process involves binding of the receptor and peptide at the luminal membrane of the BBB, formation of a plasmalemmal vesicle, translocation of the receptor-peptide complex through the cytoplasm, and dissociation of the peptide from the receptor on the external surface of the abluminal membrane. Enzymatic degradation of the drug does not occur within the endothelial cell, because the receptor-bound ligands are contained within membrane-sealed pinocytotic vesicles. Such receptors, which can transmit large molecules across the BBB (and tend to have similar transport properties when linked to potential neuropharmaceuticals), offer the promise of serving as useful “Trojan horses” in the development of new transport vehicles to facilitate BBB passage. 2 Similarly, modified proteins such as cationised albumin also cross the brain capillary via a transcytosis mechanism, but no specific receptor for this protein has yet been identified. An absorptive-mediated