Neuro - Molecular Imaging of Delivery Across BBB

跨 BBB 传递的神经分子成像

• 批准号: 7473211
• 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/7473211
• 关键词: Active Sites; Alzheimer' 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; Invasive; Isothiocyanates; Label; Libraries; Life; MALDI-TOF Mass Spectrometry; Malignant neoplasm of brain; Methods; Modality; Modeling; Molecular; Monitor; Mus; Myristic Acids; Neuraxis; Neurodegenerative Disorders; Neurologic; Optics; Peptide Library; Peptides; Pericytes; Pharmaceutical Preparations; Physiological; Principal Investigator; Property; Protein Overexpression; Research; Screening procedure; Serum; Site; Solubility; Spectrometry; Staging; Surface; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Toxic effect; Transgenic Organisms; Vertebral column; base; beta-site APP cleaving enzyme 1; brain cell; capillary; clinical application; cost efficient; design; drug development; drug distribution; fluorescence imaging; in vivo; intravenous injection; lipophilicity; luminal membrane; molecular imaging; mouse model; novel; novel strategies; optical imaging; polyarginine; polycation; programs; protein aminoacid sequence; research study; uptake

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（由申请人提供）：用于治疗/检测神经退行性疾病的潜在有用的治疗/成像剂的临床应用受到探针从脉管系统穿过与周细胞和星形胶质细胞足突、血脑屏障（BBB）相关的脑毛细血管的紧密微血管网络到达中枢神经系统（CNS）的有限通路的严重阻碍。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递送方法，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肽库作为递送模块，并使用荧光技术评估了它们在体外穿过细胞膜的能力。这种方法已被证明可以有效地穿过活细胞的细胞膜并回到细胞质中，没有登记的毒性。在本申请中，我们提出使用两亲性聚乙烯醇作为跨膜药物递送的新策略。 用于体内应用的BBB。基本假设集中在短的两亲性肉豆蔻酰化聚精氨酸肽;肉豆蔻酸的亲脂性被设计为脑毛细血管的管腔膜的转向力。同时，预期聚精氨酸主链的极性增强递送模块在血清中的溶解度以用于全身施用。此外，聚阳离子部分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，我们进一步用近红外染料标记递送模块作为货物，以便使用光学成像监测复合物在小鼠大脑中的全身生物分布和积累。总的来说，所提出的研究可以揭示一种新的无创递送方法，并监测药物/探针在完整环境中穿过BBB的分布。考虑到光学成像技术的时间和成本效益，这种方法将潜在地促进用于脑癌和其他CNS疾病的治疗/检测的药物/探针的递送，以及用于新药开发的筛选和对小鼠模型的治疗效果的分期。