Modulating the BBB to Improve Drug Delivery to the Brain

描述（由申请人提供）：血脑屏障（BBB）是治疗脑部疾病（即脑肿瘤、阿尔茨海默病、帕金森病）的药物输送到脑部的主要障碍。由于存在紧密连接和外排泵，这些分子通过血脑屏障的低渗透阻碍了小分子和大分子（即肽、蛋白质和寡核苷酸）作为抗癌剂的发展。因此，我们的长期目标是改善抗癌药物在体内向大脑的输送。我们的中心假设是，使用e -钙粘蛋白肽调节血脑屏障的粘附连接可以增强细胞间连接的孔隙度，从而增强小剂量和大剂量抗癌药物的细胞旁渗透。通过原位脑灌注大鼠模型，我们发现一种HAV肽可以促进甘露醇和一种抗癌剂（道诺霉素）在脑内的渗透。此外，HAV肽和维拉帕米联合使用具有协同作用，可改善道诺霉素向大脑的递送。因此，本项目的第一个目标是优化HAV肽在增强细胞旁标记物进入大脑中的作用。其次，我们将研究HAV肽和维拉帕米联合作用对血脑屏障的调节，并探讨道诺霉素的转运机制。其三，HAV肽通过形成环状肽提高血脑屏障调节活性。第四，阐明HAV肽在细胞间连接处调节钙粘蛋白-钙粘蛋白相互作用的作用机制。最后，确定HAV肽在体内对脑肿瘤反应性的影响。

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.