New Dopamine Transporter MRI Nanoprobes for Addiction Research

用于成瘾研究的新型多巴胺转运蛋白 MRI 纳米探针

• 批准号: 7740251
• 负责人: GORDANA D. VITALIANO
• 金额: $ 23.7万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740251
• 关键词: Abstinence; Affinity; Animals; Antibodies; Area; Autoradiography; Binding; Biodistribution; Biological Assay; Biology; Blood - brain barrier anatomy; Brain; Brain imaging; Brain region; Cell Culture Techniques; Cells; Cerebrum; Chronic; Clathrin; Clone Cells; Complex; Contrast Media; Corpus striatum structure; Data; Dependence; Development; Diagnosis; Disease; Disease Progression; Dopamine Receptor; Drug Delivery Systems; Drug abuse; Effectiveness; Encapsulated; Foundations; Future; Gadolinium; Gadolinium DTPA; Goals; Human; Image; In Vitro; Institution; Law Enforcement; Lead; Ligands; Magnetic Resonance Imaging; Measurement; Medicine; Mental Health; Methamphetamine; Molecular; Monitor; Nanotechnology; Nucleus Accumbens; Patients; Pharmaceutical Preparations; Polyethylene Glycols; Positron-Emission Tomography; Process; Proteins; Radioactive; Rattus; Recovery; Research; Research Personnel; Research Project Grants; Resolution; Series; Specificity; Substantia nigra structure; System; Techniques; Technology; Time; Tracer; addiction; base; density; design; dopamine transporter; in vitro testing; in vivo; methamphetamine abuse; molecular imaging; molecular transporter; nanometer; nanoparticle; nanoprobe; particle; public health relevance; radioligand; receptor; therapeutic target; tool

DESCRIPTION (provided by applicant): Methamphetamine (METH) abuse and dependence represent major mental health and law enforcement problems in the US and abroad. PET studies consistently showed chronic reduction in dopamine transporter (DAT) density in the striatum of methamphetamine addicts. This is a special class of dopamine receptors that are primarily localized in striatum, nucleus accumbens and substantia nigra, and have been implicated in drug abuse as important targets for therapeutic drugs. PET scans have facilitated major advances in studies of METH addiction and drug abuse in general, by using probes selective for certain classes of dopamine receptors--An approach limited by relatively low resolution of PET scans and also relatively few institutions have PET facilities. This application's goal is to develop non-radioactive bio-nanoparticles that can be used in addiction research for receptor based imaging with conventional MRI scanners, which are available in many more facilities, and which provide better anatomical resolution than PET. Two-part nanoprobes (< 100 nanometers) will be designed. One part is a molecular cage carrier containing an MRI contrast agent. This carrier will be constructed out of clathrin, a naturally occurring protein the body uses for transporting materials inside cells. The second component will be a molecule that binds with high affinity and high specificity to DAT. This component will be attached to polyethylene glycol molecules coating the carrier. A series of studies will ascertain the affinity and specificity of these nanoprobes in vivo and in vitro. The feasibility of this MRI tool to detect DAT changes will be demonstrated in future imaging studies of animals and humans exposed to METH. This non-radioactive nanoprobe may be used repeatedly to monitor progression of the disease and recovery process. Long-term monitoring is especially important for chronic METH users. If this research project were successful it would provide tools and techniques for molecular brain imaging that theoretically could have higher resolution than PET. The development of high-resolution stable molecular nanoprobes will provide a major new research tool for research of receptor and transporter abnormalities in addiction and drug abuse. This new nanotechnology may have utility as an agent to enhance diagnosis, and may serve as a drug-delivery system that can specifically target relevant brain systems. PUBLIC HEALTH RELEVANCE: The development of high-resolution stable MRI molecular nanoprobes will provide a major new research tool for research of transporter abnormalities in addiction and drug abuse. This new nanotechnology may have utility as an agent to enhance diagnosis, and may serve as a drug-delivery system that can specifically target relevant brain systems.

描述（由申请人提供）：甲基苯丙胺（甲基苯丙胺）滥用和依赖代表美国和国外的主要心理健康和执法问题。 PET研究一致表明，甲基苯丙胺成瘾者纹状体中多巴胺转运蛋白（DAT）密度的慢性降低。这是一类特殊的多巴胺受体，主要定位在纹状体，伏隔核和黑质中，并与药物滥用有关，作为治疗药物的重要靶标。 PET扫描通过对某些类型的多巴胺受体的选择性进行选择性的探针，从而促进了对甲基苯丙胺成瘾和药物滥用研究的重大进展，这种方法受PET扫描的分辨率相对较低，而相对较少的机构具有宠物设施的限制。该应用程序的目标是开发非放射性生物 - 纳米颗粒，这些粒子可用于与常规MRI扫描仪的基于受体成像的成瘾研究中，这些扫描仪可在更多的设施中使用，并提供比PET更好的解剖分辨率。将设计两部分的纳米探针（<100纳米）。一个部分是包含MRI对比剂的分子笼载体。该载体将由网格蛋白（一种天然存在的蛋白质）构建，该蛋白质用于人体在细胞内运输材料。第二个成分将是具有高亲和力结合且与DAT高特异性结合的分子。该成分将连接到载体涂层的聚乙烯甘油分子上。一系列研究将确定这些纳米探针在体内和体外的亲和力和特异性。该MRI工具检测DAT变化的可行性将在未来暴露于甲基苯酚的动物和人类的成像研究中证明。这种非放射性纳米探针可反复使用来监测疾病的进展和恢复过程。长期监测对于慢性甲基苯丙胺使用者尤其重要。如果该研究项目成功，它将为分子脑成像提供工具和技术，从理论上讲，该分子可能比PET具有更高的分辨率。高分辨率稳定的分子纳米探针的发展将为成瘾和药物滥用方面的受体和转运蛋白异常研究提供主要的新研究工具。这种新的纳米技术可能具有效用作为增强诊断的药物，并且可以作为可以专门针对相关大脑系统的药物输送系统。公共卫生相关性：高分辨率稳定的MRI分子纳米探针的发展将为成瘾和药物滥用方面的转运蛋白异常研究提供主要的新研究工具。这种新的纳米技术可能具有效用作为增强诊断的药物，并且可以作为可以专门针对相关大脑系统的药物输送系统。

项目成果

New clathrin-based nanoplatforms for magnetic resonance imaging.

用于磁共振成像的新型网格蛋白纳米平台。

• DOI: 10.1371/journal.pone.0035821
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Vitaliano,GordanaD;Vitaliano,Franco;Rios,JoseD;Renshaw,PerryF;Teicher,MartinH
• 通讯作者: Teicher,MartinH