Microfluidic Platform for Preparation of Biomolecule Based Nuclear Imaging Probes

描述(由申请人提供)：该项目的总体目标是开发微流控技术，用于合成针对癌症的生物分子(肽/抗体)靶向核成像探针。目前，这种探针需要由在无线电合成方案方面经验丰富的研究级合成化学家来合成。这些方法通常需要高效液相色谱纯化后标记，这增加了制备的额外时间和潜在的辐射暴露。开发一种自动化、可靠和坚固的试剂盒类平台，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)成像的生物分子成像探针，将极大地促进临床前研究和临床成像。所提出的项目集中于基于微流体的平台的开发，该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，然后用所需的放射性金属进行放射性标记；(2)靶向生物分子，然后可以将预射频标记的双功能螯合物偶联到其上；以及(3)核心分子，一个或多个靶标多肽(或光学成像探针)将与双功能螯合物结合以使适当的放射性金属络合。微流控通过使用小体积的高浓缩试剂来改进两种化学合成的能力，广泛使用的放射性金属在水溶液条件下改进的放射性标记为灵活、高效和自动化的平台提供了基础，用于组合优化合成或常规生产广泛多样的显像剂，这些显像剂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.开发微流控设备，用于将各种探针组件共价连接在一起，用所需的放射性金属对成像探针进行放射性标记，并对分子探针进行纯化。2.利用微流控装置和偶联反应制备用于肿瘤显影的放射性标记多肽，并与常用的双功能螯合基团和放射性金属进行比较，验证微流控装置和偶联反应的有效性。3.在成熟的荷瘤动物模型中测试和验证放射性标记多肽，以确保探针在体内发挥作用。4.随着单个设备的成功开发，开发一个单一的集成设备，其中包括第一个目标的单个设备的优化版本。 公共卫生相关性：微流体的使用已被证明在多肽的放射性标记中是有益的，这些多肽被用作癌症诊断的成像探针或作为放射治疗试剂。该项目寻求开发一种多功能、自动化的微流控平台，用于生产此类成像探针，消除限制此类探针广泛采用的几个缺陷。

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.