Neuro - Molecular Imaging of Delivery Across BBB

跨 BBB 传递的神经分子成像

基本信息

批准号：
7658138
负责人：
Wellington Pham
金额：
$ 12.04万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
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/7658138
关键词：
Active Sites Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Precursor Antibodies Arginine Astrocytes Biocompatible Biodistribution Biological Assay Biological Availability Blood - brain barrier anatomy Blood capillaries Brain Capillary Endothelial Cell Cell Line Cells Cellular Membrane Central Nervous System Diseases Charge Cleaved cell Complex Cytoplasm Data Deposition Detection Disease Drug Delivery Systems Dyes Electrostatics Environment Enzymes Evaluation Fatty Acids Fluorescence Fluorescence Microscopy Fluorescence Resonance Energy Transfer Foot Process High Pressure Liquid Chromatography Home environment Image Imaging Techniques Immunohistochemistry In Vitro Isothiocyanates Label Libraries Life MALDI-TOF Mass Spectrometry Malignant neoplasm of brain Methods Modeling Molecular Monitor Mus Myristic Acids Neuraxis Neurodegenerative Disorders Neurologic Optics Peptide Library Peptides Pericytes Pharmaceutical Preparations Physiological Principal Investigator Property Research Screening procedure Serum Site Solubility Spectrometry Staging Surface Techniques Testing Therapeutic Therapeutic Agents Therapeutic Effect Time Toxic effect Transgenic Mice Vertebral column base beta-site APP cleaving enzyme 1 brain cell capillary clinical application cost efficient design drug development drug distribution fluorescence imaging imaging modality in vivo intravenous injection lipophilicity luminal membrane molecular imaging mouse model novel novel strategies optical imaging overexpression polyarginine polycation programs protein aminoacid sequence research study uptake

项目摘要

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）：潜在有用的治疗/成像剂用于治疗/检测神经退行性疾病的临床应用，这严重阻碍了从脉管系统到中枢神经系统（CNS）跨毛细血管的紧密微血管网络的探针的有限获取，与周围的毛细血管紧密的微血管网络相关，与bar骨相关。随着神经学研究继续揭示新的治疗靶标，有必要共同开发新的分娩方法，以促进筛查新药物/探针以治疗和检测疾病。我们最近设计了一个两亲性肽的库作为递送模块，并评估了它们使用荧光技术在体外越过细胞膜的能力。已证明这种方法可以有效地越过活细胞的细胞膜，并且没有注册的毒性。在此应用中，我们建议将两亲甲素多修正金用作整个药物输送的新策略用于体内应用的BBB。基本假设的重点是短两亲肉豆蔻酰胺多精氨酸肽。肉豆蔻酸的亲脂性被设计为脑毛细血管腔膜的转向力。而多精氨酸骨架的极性有望提高血清中全身给药的递送模块的溶解度。另外，精氨酸在精氨酸上的生理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，我们将近红外染料的递送模块进一步标记为货物，以便使用光学成像来监测综合体的全身生物分布和复合物在小鼠脑中的积累。总体而言，拟议的研究可以揭示一种新的非侵入性输送方法，并在完整的环境中监测跨BBB的药物的分布。鉴于光学成像技术的时间和成本效益，这种方法可能有助于促进药物/探针用于治疗/检测脑癌以及其他CNS疾病，以及筛查新药物开发以及对小鼠模型的治疗作用的分期。