Compact microfluidic PET probe concentrator for preclinical and in vitro imaging

描述(申请人提供)：正电子发射断层扫描(PET)是一种分子成像方式，它利用放射性标记的探针分子来靶向、成像和量化体内的生物过程。PET探针可用于研究疾病机制，开发新的诊断和治疗方法，检测早期疾病，并监测治疗反应。由于目前生产PET探头所需的设备、基础设施和人员的高昂成本，探头的可用性和多样性受到严重限制(尤其是出于研究目的)，这既阻碍了依赖于该成像工具的研究，也阻碍了新型PET探头的医学实践。这一挑战正在通过努力开发基于微流控技术的小型化PET探针生产技术来解决，最终目标是开发一种负担得起的、自动化的、用户友好的系统，该系统具有内置辐射屏蔽，在工作台上运行，而不是在“热单元”中运行。这样的系统将能够以负担得起的成本按需生产各种探头。目前的小型化努力主要集中在合成本身，而不是下游工艺，如提纯和配方。大多数PET示踪剂在配方过程中需要一个浓缩过程，以减少高效液相纯化后的体积，以便在有限的体积中包含足够数量的探针，可以注射到小动物模型(如小鼠)中，而不会对它们的生理造成不利影响。目前，浓缩是通过旋转蒸发实现的，使用的是在热室内占用宝贵土地的笨重设备。为了避免集中器成为小型化无线电合成中的尺寸限制因素，有必要开发微型集中器技术。在初步研究中，开发了一种用于蒸发浓缩水溶液的紧凑型概念验证微流控装置，并成功地实现了PET探针1-(2‘-脱氧-2’-[18F]氟代呋喃)胞嘧啶([18F]FAC)在1：99乙醇：10 mM NH_4H_2PO_4(高效液相色谱流动相)中的浓缩。这种概念验证芯片将在这一应用中进一步开发成一个强大的、自动化的、紧凑的系统，用于常规集中不同的探头。目标1专注于开发一种微流控芯片，其性能提高到至少与旋转蒸发的典型性能相当。在目标2中，将对芯片参数和操作条件进行表征，以实现进一步的性能优化。在目标3中，浓缩样品收集过程将得到优化。在目标4中，将开发一个上游模块，以实现非水溶液的浓缩，从而将这项技术扩展到所有PET探针。AIM 5将开发一个完全自动化的系统(样品加载、浓缩和回收)。这一应用将导致开发一个原型微流控浓缩器，该浓缩器将成为用于各种PET探针的新兴台式生产平台的关键部分，该平台将通过增加使用PET进行分子成像来加速临床前研究和诊断和治疗的转移。

DESCRIPTION (provided by applicant): Positron emission tomography (PET) is a molecular imaging modality that utilizes radiolabeled probe molecules to target, image and quantify biological processes in vivo. PET probes can be used to study disease mechanisms, to develop novel diagnostics and therapeutics, detect early stage disease, and monitor response to therapy. Due to the high cost of equipment, infrastructure, and personnel currently required to produce PET probes, the availability and diversity of probes is severely limited (especially for research purposes), hindering both research that depends on this imaging tool and the translation of novel PET probes into medical practice. This challenge is being addressed by efforts to develop miniaturized PET probe production technology based on microfluidics with the eventual goal of an affordable, automated, user-friendly system with built-in radiation shielding that operates on a bench top instead of in a "hot cell". Such a system would enable on-demand production of diverse probes at affordable cost. Current miniaturization efforts have focused primarily on the synthesis itself, and not on downstream processes such as purification and formulation. Most PET tracers require a concentration process during formulation to reduce the volume after HPLC purification so that a sufficient amount of probe is contained in the limited volume that can be injected into small animal models such as mice without adversely affecting their physiology. Concentration is currently achieved by rotary evaporation, using bulky equipment occupying valuable real estate inside the hot cell. To prevent the concentrator from becoming the size-limiting factor in miniaturized radio synthesis, there is a need for development of miniature concentration technologies. In preliminary studies, a compact proof-of-concept microfluidic device to evaporatively concentrate aqueous solutions was developed, and successful concentration of the PET probe 1-(2'-deoxy-2'-[18F]fluoro- arabinofuranosyl) cytosine ([18F]FAC) dissolved in 1:99 EtOH : 10mM NH4H2PO4 (HPLC mobile phase) was demonstrated. This proof-of-concept chip will be further developed in this application into a robust, automated, compact system for routinely concentrating diverse probes. Aim 1 focuses on the development of a microfluidic chip with performance increased to at least match that typically achieved by rotary evaporation. In Aim 2, the chip parameters and operating conditions will be characterized to enable further performance optimization. The concentrated sample collection process will be optimized in Aim 3. In Aim 4, an upstream module will be developed to enable concentration of non-aqueous solutions, thereby extending this technology to all PET probes. A fully automated system (sample loading, concentration, and recovery) will be developed in Aim 5. This application will result in the development of a prototype microfluidic concentrator that will be a critical part of emerging benchtop production platforms for diverse PET probes that will accelerate preclinical research and translation of diagnostics and therapies to the clinic by increasing access to molecular imaging with PET.