Neuro - Molecular Imaging of Delivery Across BBB

跨 BBB 传递的神经分子成像

• 批准号: 7099047
• 负责人: Wellington Pham
• 金额: $ 12.04万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099047
• 关键词: Alzheimer' s disease; arginine; athymic mouse; bioimaging /biomedical imaging; blood brain barrier; combinatorial chemistry; disease /disorder model; drug delivery systems; fatty acylation; fluorescence microscopy; fluorescence resonance energy transfer; fluorescent dye /probe; high performance liquid chromatography; immunoconjugates; immunocytochemistry; isothiocyanates; laboratory mouse; mass spectrometry; matrix assisted laser desorption ionization; molecular /cellular imaging; myristates; neurochemistry; neuroimaging; peptide library

DESCRIPTION (provided by applicant): Clinical application of potentially useful therapeutic/imaging agents for the treatment/detection of neurodegenerative diseases is profoundly hampered by the limited access of probes from the vasculature to the central nervous system (CNS) across the tight microvascular network of brain capillaries, associated with pericytes, and astrocyte foot processes, the blood brain barrier (BBB). As neurological research continues to reveal new targets for therapy, it is necessary to develop new delivery methods in concert, to facilitate the screening of new drug/probes for treatment and detection of diseases, respectively. We have recently designed a library of amphiphilic peptides as delivery modules, and evaluated their ability to cross the cellular membrane in vitro using fluorescence technique. This approach has been demonstrated to cross the cellular membrane of live cells efficiently and home to the cytoplasm with no registered toxicity. In this application, we propose to use amphiphilic polyarginines as a new strategy for drug delivery across the BBB for in vivo application. The underlying hypothesis focuses on a short amphiphilic myristoylated polyarginine peptide; the lipophilicity of myristic acid is designed as a steering force for the luminal membrane of brain capillaries. While, the polarity of polyarginine backbone is expected to enhance solubility of the delivery module in serum for systemic administration. In addition, the physiological expression of polycation moieties on arginines promotes electrostatic interaction with the surface of negatively charged brain capillary endothelial cells. In support of our hypothesis, we further label the delivery module with a near infrared dye as a cargo so that systemic biodistribution and accumulation of the complex in the mouse brain will be monitored using optical imaging. Overall, the proposed studies could reveal a new approach for noninvasive delivery and monitor the distribution of drug/probes a cross the BBB in an intact environment. Given the time and cost efficient of optical imaging technique, this approach will potentially facilitate the delivery of drugs/probes for treatment/detection of brain cancer, and other CNS disorders as well as for screening of new drug development, and staging of therapeutic effects on mouse models.

描述(申请人提供)：用于治疗/检测神经退行性疾病的潜在有用的治疗/显像剂的临床应用受到从血管系统到中枢神经系统(CNS)的探针的限制，这些探针通过与周细胞、星形胶质细胞足突和血脑屏障(BBB)相关的紧密的微血管网络进入中枢神经系统(CNS)。随着神经学研究不断揭示新的治疗靶点，有必要共同开发新的给药方法，以促进分别用于治疗和检测疾病的新药/探针的筛选。我们最近设计了一个两亲性多肽文库作为递送模块，并利用荧光技术评估了它们在体外穿越细胞膜的能力。这种方法已经被证明可以有效地穿过活细胞的细胞膜，并位于细胞质中，没有登记的毒性。在这项应用中，我们建议使用两亲性多精氨酸作为一种新的药物传递策略。 体内应用的血脑屏障。基本的假设集中在一种短小的两亲性肉豆蔻酰化聚精氨酸多肽；肉豆蔻酸的亲脂性被设计为大脑毛细血管管腔膜的转向力。同时，多聚精氨酸骨架的极性有望提高递送模块在血清中的溶解度，用于全身给药。此外，聚阳离子部分在精氨酸上的生理性表达促进了与带负电荷的脑毛细血管内皮细胞表面的静电相互作用。为了支持我们的假设，我们进一步用近红外染料将递送模块标记为货物，以便使用光学成像技术监测复合体在小鼠大脑中的系统生物分布和积累。总体而言，拟议的研究可能揭示一种非侵入性给药的新方法，并在完整的环境中监测药物/探针穿过血脑屏障的分布。考虑到光学成像技术的时间和成本效益，这种方法可能会促进药物/探针的输送，用于治疗/检测脑癌和其他中枢神经系统疾病，以及筛选新药开发，并在小鼠模型上进行治疗效果的分期。