Bypassing the Blood-Brain Barrier:Modulation of Transporters in the Nasal Mucos

绕过血脑屏障：鼻粘膜转运蛋白的调节

基本信息

批准号：
7442099
负责人：
Maureen D Donovan
金额：
$ 29.16万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-11 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7442099
关键词：
Address Affinity Amantadine Amino Acid Transport System L Antihistamines Area Baclofen Bathing Behavior Biological Availability Blood - brain barrier anatomy Brain Brain region Bypass Carrier Proteins Cations Cattle Central Nervous System Diseases Cerebellum Cerebrospinal Fluid Characteristics Chemicals Clinical Convection Coupled DNA Microarray Chip DNA Microarray format Development Diffuse Diffusion Disease Dopamine Drug Compounding Drug Delivery Systems Drug Design Drug Efflux Drug Formulations Drug Regulations Drug Transport Epithelial Glycoproteins Goals Heavy Metals Human In Vitro Intercellular Fluid Intranasal Administration Intravenous Kinetics Knowledge Lead Location Measures Membrane Transport Proteins Methods Microarray Analysis Midbrain structure Mucous Membrane Multi-Drug Resistance Nasal cavity Neuraxis Neurons Nose Numbers Olfactory Epithelium Olfactory Mucosa Olfactory Pathways Olfactory tract Organic Cation Transporter Pathway interactions Patients Pattern Permeability Pharmaceutical Preparations Play Process Property Proteins Public Health Rattus Recovery Regulation Relative (related person)Research Research Personnel Role Role playing therapy Route Site Spinal Structure of mucous membrane of nose Surface System Technical Expertise Therapeutic Therapeutic Agents Tissues Treatment Protocols Valproic Acid Vascular Endothelium Virus Work Xenobiotics absorption base brain pathway brain tissue design desire dopamine transporter drug distribution experience fluid flow improved in vivo inhibitor/antagonist innovation novel olfactory bulb programs respiratory therapeutic effectiveness uptake

项目摘要

DESCRIPTION (provided by applicant): Effective systemic treatments for diseases of the central nervous system require therapeutic agents that are able to cross the blood-brain barrier (BBB). Significant efforts are devoted to design drug molecules with the correct permeability characteristics in order to achieve this goal, yet many promising agents are still not able to cross the barrier into the brain in sufficient amounts to achieve therapeutic effectiveness. The olfactory mucosa is one of the few areas of the central nervous system which lack a traditional "blood-brain barrier", and drug transport directly from the nasal cavity into the brain tissue or cerebrospinal fluid has been observed for a number of compounds. Uptake and efflux membrane transporters play a significant role in determining which drugs can access the CNS from the olfactory mucosa. It is the goal of this research to identify key drug transporters in the nasal mucosa, and to use this information to identify efficient pathways for direct, safe delivery of drugs to the CNS. Amantadine, baclofen and valproic acid will be used to determine the activities of the organic cation-2 transporter, large neutral amino acid carrier, and multi-drug resistance-associated transporters, respectively. Current evidence suggests that each of these protein transporters is present in the nasal mucosa, yet their role in the direct nose-to-brain transport of the substrate drug molecules is unknown. In vitro methods using excised nasal mucosal tissues will be used to determine the affinities and capacities of the transporters for these substrates. Modulation of their behaviors will also be addressed using known transporter inhibitors. In vivo studies will be carried out to determine the extent to which modulation of the transporters might serve as an effective strategy for the optimization of nose-to-brain transport of substrate drug compounds. The public health relevance of this research is that utilization of specific transporters present in the olfactory mucosa for direct CNS targeting may well provide a wealth of new opportunities for the targeted treatment of CNS disorders. New drugs could be designed and synthesized for specific transporter interactions, rather than merely for high passive permeability across the BBB. The resulting significant increase in the number of potentially effective drug molecules, coupled with this simple, accessible site of delivery could provide new, efficacious therapies to treat a multitude of CNS - based disorders.

描述（由申请人提供）：中枢神经系统疾病的有效全身治疗需要能够穿过血脑屏障（BBB）的治疗剂。为了实现这一目标，人们投入了大量精力来设计具有正确渗透性特征的药物分子，但许多有前途的药物仍然无法以足够的量穿过屏障进入大脑以实现治疗效果。嗅粘膜是中枢神经系统中少数缺乏传统“血脑屏障”的区域之一，并且已经观察到许多化合物直接从鼻腔转运到脑组织或脑脊液中。摄取和流出膜转运蛋白在确定哪些药物可以从嗅粘膜进入中枢神经系统方面发挥着重要作用。这项研究的目标是确定鼻粘膜中的关键药物转运蛋白，并利用这些信息来确定直接、安全地将药物输送到中枢神经系统的有效途径。金刚烷胺、巴氯芬和丙戊酸将分别用于测定有机阳离子 2 转运蛋白、大中性氨基酸载体和多药耐药相关转运蛋白的活性。目前的证据表明，这些蛋白质转运蛋白中的每一种都存在于鼻粘膜中，但它们在底物药物分子从鼻子到大脑的直接转运中的作用尚不清楚。使用切除的鼻粘膜组织的体外方法将用于确定转运蛋白对这些底物的亲和力和能力。他们的行为调节也将使用已知的转运蛋白抑制剂来解决。将进行体内研究以确定转运蛋白的调节在多大程度上可以作为优化底物药物化合物从鼻到脑转运的有效策略。这项研究与公共卫生的相关性在于，利用嗅粘膜中存在的特定转运蛋白来直接靶向中枢神经系统很可能为中枢神经系统疾病的靶向治疗提供大量新机会。可以针对特定转运蛋白相互作用来设计和合成新药物，而不仅仅是针对血脑屏障的高被动渗透性。由此产生的潜在有效药物分子数量的显着增加，再加上这种简单、可及的递送部位，可以为治疗多种中枢神经系统疾病提供新的、有效的疗法。