Modulating the BBB to Improve Drug Delivery to the Brain

描述（由申请人提供）：血脑屏障（BBB）是将药物递送至脑以治疗脑疾病（即，脑肿瘤，阿尔茨海默氏症，帕金森氏症）。小分子和大分子的发展（即，肽、蛋白质和寡核苷酸）作为抗癌剂的应用受到这些分子通过BBB的低渗透性的阻碍，这是由于紧密连接和外排泵的存在。因此，我们的长期目标是改善抗癌药物向大脑的体内递送。我们的中心假设是，使用E-钙粘蛋白肽调节BBB的粘附连接可以增强细胞间连接的孔隙度，从而增强小的和大的抗癌药物的细胞旁渗透。我们发现，HAV肽可以提高甘露醇和抗癌剂（道诺霉素）的渗透到大脑中使用原位脑灌注大鼠模型。此外，HAV肽和维拉帕米的组合具有协同作用以改善道诺霉素向脑的递送。因此，本项目的第一个目的是优化HAV肽在增强细胞旁标志物向脑中的递送中的作用。其次，将研究HAV肽和维拉帕米组合调节BBB后道诺霉素的转运机制。第三，HAV肽的BBB调节活性将通过形成环肽来改善。第四，将阐明HAV肽在调节细胞间连接中的钙粘蛋白-钙粘蛋白相互作用中的作用机制。最后，将确定HAV肽对体内脑肿瘤反应性的影响。 公共卫生相关性：开发用于脑部疾病的药物的问题之一是难以将其输送到大脑;这是由于血脑屏障（BBB）的存在，它阻止药物进入大脑。因此，如果找到一种方法来改善药物通过血脑屏障的渗透，这将对患有脑疾病包括脑肿瘤的患者非常有益。小分子和大分子的最新发展（即，肽、蛋白质和寡核苷酸）作为脑疾病的治疗剂的应用受到这些分子通过BBB的低渗透性的阻碍。因此，我们的长期目标是改善通过血脑屏障的小型和大型药物的体内递送。使用动物模型，我们已经发现了一种HAV肽，它可以改善抗癌药物（道诺霉素）向大脑的递送。因此，本项目旨在优化抗癌药物在脑肿瘤动物模型中的递送以治疗脑肿瘤。

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. PUBLIC HEALTH RELEVANCE: One of the problems in developing drugs for brain disease is the difficulty in delivering them to the brain; this is due to the presence of the blood-brain barrier (BBB), which prevents the drug from entering the brain. Thus, if a way is found to improve the permeation of drugs through the blood-brain barrier, it will very beneficial to patients with brain disorders including brain tumors. Recent development of small and large molecules (i.e., peptides, proteins, and oligonucleotides) as therapeutic agents for brain diseases has been hampered by the low permeation of these molecules through the BBB. Therefore, our long-term goal is to improve the in vivo delivery of small and large drugs through the BBB. Using an animal model, we have found an HAV peptide that improves the delivery of anticancer drug (daunomycin) to the brain. Thus, this project is designed to optimize the delivery of anticancer agents to treat brain tumor in the brain tumor animal model.