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癌症生物分子（肽/抗体）靶向核成像探针的微流体技术。目前，此类探针需要由具有放射合成方案经验的研究级合成化学家来合成。这些方法通常需要在标记后进行 HPLC 纯化，这会增加制备过程的额外时间和潜在的辐射暴露。开发一个自动化、可靠且强大的类似套件的平台，用于制备用于正电子发射断层扫描 (PET) 或单光子发射计算机断层扫描 (SPECT) 成像的基于生物分子的成像探针，将极大地有益于临床前研究和临床成像。拟议的项目重点是开发基于微流体的平台，能够制备三种广泛类型的成像探针，包括：（1）靶向生物分子双功能螯合物缀合物，然后用所需的放射性金属进行放射性标记，（2）靶向然后可以与预放射性标记的双功能螯合物缀合的生物分子，以及（3）核心分子，一种或多种靶向肽（或光学成像探针）将与双功能螯合物一起缀合微流体通过使用少量高浓度试剂来改善化学合成的能力，以及通过广泛使用的放射性金属改进水性条件下的放射性标记的能力，为灵活、高效和自动化的平台提供了基础对多种成像剂的合成或常规生产进行组合优化，这可以极大地帮助检测肿瘤及其转移。该项目的具体目标是： 1. 开发微流体装置，将各种探针组件共价连接在一起，用所需的无线电金属对成像探针进行无线电标记，并纯化分子探针。 2. 通过使用微流体装置和常用的双功能螯合基团和放射性金属制备用于癌症成像的放射性标记肽来测试和验证微流体装置和缀合反应。 3. 在成熟的荷瘤动物模型中测试和验证放射性标记的肽，以确保探针在体内发挥作用。 4. 随着单个设备的成功开发，开发包含第一个目标的单个设备的优化版本的单个集成设备。 公共健康相关性：微流体的使用已被证明有益于对用作癌症诊断成像探针或放射治疗剂的肽进行放射性标记。该项目旨在开发一种多功能、自动化的微流体平台，用于生产此类成像探针，消除限制此类探针更广泛采用的几个缺点。