Neuro - Molecular Imaging of Delivery Across BBB

跨 BBB 传递的神经分子成像

• 批准号: 7286695
• 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/7286695
• 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）：从血管系统到中枢神经系统（CNS）的探针穿过紧密的微血管网络（与周细胞、星形胶质细胞足突、血脑屏障（BBB）相关）的有限通道，严重阻碍了神经退行性疾病治疗/检测的潜在有用治疗/显像剂的临床应用。随着神经学研究不断揭示新的治疗靶点，有必要开发新的递送方法，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肽库作为传递模块，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进入细胞质，没有毒性。在这个应用中，我们建议使用两亲性聚精氨酸作为药物跨传递的新策略