Microfluidic Platform for Preparation of Biomolecule Based Nuclear Imaging Probes

用于制备基于生物分子的核成像探针的微流控平台

• 批准号: 8163770
• 负责人: Paul J. A. Kenis
• 金额: $ 44.71万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-07 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8163770
• 关键词: Adoption; Animal Model; Behavior; Biological Testing; Cancer Detection; Chelating Agents; Chemistry; Clinical; Complex; Copper; Department of Energy; Detection; Development; Devices; Dialysis procedure; Early Diagnosis; Early identification; Ensure; Exposure to; Funding; Gallium; Goals; High Pressure Liquid Chromatography; Image; In Vitro; Indium-111; Individual; Label; Malignant Neoplasms; Metals; Methods; Microfluidic Microchips; Microfluidics; Modeling; Molecular Probes; Neoplasm Metastasis; Nuclear; Organic Synthesis; Peptide antibodies; Peptides; Performance; Positron-Emission Tomography; Preparation; Procedures; Production; Prostatic Neoplasms; Protocols documentation; Radiation; Radiation therapy; Radio; Radiobiology; Radiochemistry; Radiolabeled; Reaction; Reagent; Reproducibility; Research; Scheme; System; Technetium 99m; Technology; Testing; Time; Triazoles; Validation; Work; aqueous; base; cancer diagnosis; cancer imaging; chemical synthesis; combinatorial; design; experience; flexibility; imaging probe; improved; in vivo; multidisciplinary; novel; optical imaging; pre-clinical research; prototype; radiotracer; single photon emission computed tomography; tumor

DESCRIPTION (provided by applicant): The overall goal of the project is the development of microfluidic technology for the synthesis of biomolecule (peptide/antibody) targeted nuclear imaging probes for cancer. Currently, such probes need to be synthesized by research-level synthetic chemists experienced in radio-synthetic protocols. These methods typically require HPLC purification post-labeling which adds additional time and potential radiation exposure to the preparation. The development of an automated, reliable, and robust kit-like platform for the preparation of biomolecule based imaging probes for either Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) imaging would greatly benefit both, preclinical research and clinical imaging. The proposed project focuses on the development of a microfluidic based platform capable of preparing three broad types of imaging probes consisting of: (1) a targeting biomolecule-bifunctional chelate conjugate which is then radio labeled with a desired radio metal, (2) a targeting biomolecule to which a pre-radio labeled bifunctional chelate can then be conjugated, and (3) a core molecule to which one or more targeting peptides (or optical imaging probes) will be conjugated along with a bifunctional chelate to complex the appropriate radio metal The ability of microfluidics to improve both chemical syntheses by using small volumes of highly concentrated reagents, and improved radio labeling in aqueous conditions with widely utilized radio metals provides the basis for a flexible, efficient, and automated platform for the combinatorial optimization of the syntheses or routine production of an expansive diversity of imaging agents which could greatly aid in the detection of tumors and their metastases. The specific aims of the project are: 1. Develop microfluidic devices for covalently attaching the various probe components together, radio labeling the imaging probe with a desired radio metal, and purifying the molecular probe. 2. Test and validate the microfluidic devices and conjugation reactions by using them to prepare radio labeled peptides used for cancer imaging, with commonly used bifunctional chelate groups and radio metals. 3. Test and validate the radio labeled peptides in a well developed tumor bearing animal model to ensure that the probes function in vivo. 4. With the successful development of the individual devices, develop a single integrated device incorporating the optimized versions of the individual devices of the first aim. PUBLIC HEALTH RELEVANCE: The use of microfluidics has been shown to be beneficial in the radio labeling of peptides used as imaging probes for cancer diagnosis or as radiotherapy agents. This project seeks to develop a versatile, automated microfluidic platform for producing such imaging probes eliminating several of the drawbacks limiting wider adoption of such probes.

描述（由申请人提供）：该项目的总体目标是开发用于合成生物分子（肽/抗体）靶向核成像探针的微流体技术。当前，此类探针需要由无线电协议中经历的研究级合成化学家合成。这些方法通常需要在标签后进行HPLC纯化，从而增加了制剂的额外时间和潜在的辐射暴露。用于制备基于生物分子的成像探针的自动化，可靠和健壮的套件样平台的开发，用于正电子发射断层扫描（PET）或单个光子发射计算机断层扫描（SPECT）成像，将极大地使临床前研究受益。拟议的项目着重于开发基于微流体的平台，该平台能够准备三种广泛类型的成像探针，该探针包括：（1）靶向生物分子 - 功能性螯合物结合物，然后用所需的无线电金属标记无线电，（2）目标。然后可以将预先标记的双功能性螯合物的生物分子结合在一起，并且（3）核心分子将一个或多个靶向肽（或光学成像探测器）与该核心分子一起轭，并将双功能螯合物偶联以使适当的无线电金属复杂化。通过使用少量浓缩试剂的小体积，微流体能力改善两种化学合成，并在水性条件下改进无线电标记，具有广泛使用的无线电金属，为柔性，高效且自动化的平台提供了基础，用于合成或例行或例行的合成或例行优化的组合平台产生庞大的成像剂多样性，可以极大地帮助检测肿瘤及其转移。该项目的具体目的是：1。开发微流体设备，用于将各种探针组件共价附加在一起，用所需的无线电金属将成像探针标记，并纯化分子探针。 2。通过使用常用的双功能性螯合基团和无线电金属制备无线电标记的肽来测试和验证微流体设备和共轭反应。 3。测试并验证富含肿瘤轴承动物模型的无线电标记的肽，以确保探针在体内起作用。 4。随着单个设备的成功开发，开发了一个单个集成设备，该设备结合了第一个目标的各个设备的优化版本。 公共卫生相关性：微流体的使用已被证明是对肽作为癌症诊断或放射治疗剂的成像探针的无线电标记有益的。该项目旨在开发一个多功能，自动化的微流体平台，用于产生此类成像探针，以消除几个缺点，从而限制了对此类探针的更广泛采用。