Modulating the BBB to Improve Drug Delivery to the Brain

描述(申请人提供)：血脑屏障(BBB)是将治疗脑部疾病(如脑瘤、阿尔茨海默氏症、帕金森氏症)的药物输送到大脑的主要障碍。由于紧密连接和外排泵的存在，小分子和大分子(即多肽、蛋白质和寡核苷酸)通过血脑屏障的低渗透性阻碍了作为抗癌药物的这些分子的发展。因此，我们的长期目标是提高抗癌药物在体内的大脑递送。我们的中心假设是，用E-钙粘附素多肽调节血脑屏障的黏附连接可以增加细胞间连接的孔隙度，从而增强大小抗癌药物的细胞旁渗透。在大鼠原位脑灌流模型中，我们发现甲肝病毒多肽可以促进甘露醇和抗癌药物(柔红霉素)在脑内的渗透。此外，甲型肝炎病毒多肽和维拉帕米的联合使用对改善柔红霉素在脑内的转运具有协同作用。因此，本项目的首要目标是优化甲型肝炎病毒多肽在增强细胞旁标志向脑内传递方面的作用。其次，研究甲型肝炎病毒多肽和维拉帕米联合调节血脑屏障时柔红霉素的转运机制。第三，甲型肝炎病毒多肽的BBB调节活性将通过形成环肽来提高。第四，甲型肝炎病毒多肽在细胞间连接中调节钙粘蛋白-钙粘蛋白相互作用的作用机制将被阐明。最后，将确定甲型肝炎病毒多肽对体内脑瘤反应性的影响。

DESCRIPTION (provided by applicant): The blood-brain barrier (BBB) is the major obstacle to delivery of drugs to the brain for treating brain disorders (i.e., brain tumor, Alzheimer's, Parkinson's). The development of small and large molecules (i.e., peptides, proteins, and oligonucleotides) as anticancer agents has been hampered by the low permeation of these molecules through the BBB due to the presence of tight junctions and efflux pumps. Therefore, our long-term goal is to improve the in vivo delivery of anticancer drugs to the brain. Our central hypothesis is that modulating the adherens junction of the BBB using E-cadherin peptides can enhance the porosity of the intercellular junctions and, thus, enhance the paracellular permeation of small and large anticancer drugs. We found that an HAV peptide can improve the permeation of mannitol and an anticancer agent (daunomycin) into the brain using the in-situ brain perfusion rat model. In addition, a combination of HAV peptide and verapamil has a synergistic effect to improve the delivery of daunomycin to the brain. Therefore, the first aim of this project is to optimize the effect of HAV peptide in enhancing the delivery of paracellular markers into the brain. Second, the mechanism of transport of daunomycin upon modulation of the BBB with a combination of HAV peptide and verapamil will be investigated. Third, the BBB modulatory activity of HAV peptides will be improved by forming cyclic peptides. Fourth, the mechanism of action of HAV peptide in modulating cadherin-cadherin interactions in the intercellular junctions will be elucidated. Finally, the effects of HAV peptides on brain tumor responsiveness in vivo will be determined.