Modulating the BBB to Improve Drug Delivery to the Brain

调节血脑屏障以改善药物向大脑的输送

• 批准号: 8666676
• 负责人: TERUNA J. SIAHAAN
• 金额: $ 30.16万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666676
• 关键词: Adherens Junction; Alzheimer' s Disease; Animal Model; Antineoplastic Agents; Binding; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain Neoplasms; Cadherins; Cyclic Peptides; Daunorubicin; Development; Drug Delivery Systems; E-Cadherin; Equilibrium; Goals; HAV peptide; In Situ; In Vitro; Intercellular Junctions; Intestinal Mucosa; Mannitol; Mediating; Modeling; Oligonucleotides; Oral; Parkinson Disease; Pathway interactions; Patients; Penetration; Peptides; Perfusion; Pharmaceutical Preparations; Porosity; Property; Proteins; Rattus; Sprague-Dawley Rats; System; Therapeutic Agents; Tight Junctions; Time; Verapamil; absorption; cadherin 5; chemotherapy; design; efflux pump; improved; in vivo; mouse model; prevent

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.

描述（由申请人提供）：血脑屏障（BBB）是将药物输送到大脑以治疗脑部疾病（即脑肿瘤、阿尔茨海默病、帕金森病）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（即肽、蛋白质和寡核苷酸）作为抗癌药物的开发受到了这些分子通过血脑屏障的低渗透性的阻碍。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 BBB 的粘附连接可以增强细胞间连接的孔隙率，从而增强小型和大型抗癌药物的细胞旁渗透。我们通过原位脑灌注大鼠模型发现，HAV 肽可以改善甘露醇和抗癌剂（道诺霉素）向大脑的渗透。此外，HAV肽和维拉帕米的组合具有协同作用，可改善道诺霉素向大脑的输送。因此，该项目的首要目标是优化 HAV 肽在增强细胞旁标记物向大脑中的递送方面的效果。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而得到提高。第四，将阐明HAV肽调节细胞间连接中钙粘蛋白-钙粘蛋白相互作用的作用机制。最后，将确定 HAV 肽对体内脑肿瘤反应性的影响。