Optimization and validation of integrated microscale technologies for low-cost, automated production of PET molecular imaging tracers for cancer research

集成微尺度技术的优化和验证，用于低成本、自动化生产用于癌症研究的 PET 分子成像示踪剂

• 批准号: 9982914
• 负责人: Robert Michael van Dam
• 金额: $ 37.91万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982914
• 关键词: 3-Dimensional; Advanced Development; Amino Acids; Animal Model; Animals; Apoptosis; Biochemical Process; Biological; Biological Assay; Biological Process; Cell Culture Techniques; Cells; Cellular Assay; Clinical; Computer software; Consumption; Cost Sharing; Data; Development; Devices; Disease; Equipment; Fluorine; Gamma Rays; Glucose; Goals; High Pressure Liquid Chromatography; Human Resources; Hypoxia; Image; In Vitro; Individual; Infrastructure; Institution; Isotopes; Label; Liquid substance; Malignant Neoplasms; Measurement; Metabolism; Methods; Microfluidic Microchips; Microfluidics; Modeling; Molecular; Molecular Probes; Patients; Penetration; Performance; Positron; Positron-Emission Tomography; Preparation; Problem Solving; Production; Public Health; Pump; Radiation; Radioactive; Radioactivity; Radiochemistry; Radioisotopes; Radiolabeled; Radiometry; Reagent; Reporting; Research; Research Activity; Research Personnel; Research Project Grants; Sampling; Scanning; Schedule; System; Technology; Thick; Tissues; Tracer; Translating; Translations; Treatment Efficacy; Validation; angiogenesis; anticancer research; attenuation; base; cost; design; flexibility; fluorodeoxyglucose; fluorophore; in vivo; in vivo imaging; insight; molecular imaging; neoplastic cell; novel; operation; overexpression; pre-clinical; predicting response; prototype; quantitative imaging; radiochemical; radiotracer; receptor density; technology validation; tool; treatment response; tumor microenvironment; wasting

PROJECT SUMMARY Positron-emission tomography (PET) probes (or “tracers”) are biological molecules containing positron-emitting isotopes, the decay of which can be detected with high sensitivity to perform a variety of in vitro or 3D in vivo assays of biochemical processes for cancer research. A significant advantage of radiolabels is the high tissue penetration of gamma rays – this allows discoveries at the cellular level to be translated to new animal models (e.g. to study the mechanisms and treatment of disease) and then to assays in patients (e.g. to predict response to treatment or assess efficacy of treatment), all with the same probe. Thousands of PET tracers have been reported for assessing angiogenesis, tumor microenvironment (e.g. hypoxia), metabolism (e.g., glucose or amino acids), density of receptors, etc. Another advantage is that many PET tracers are labeled with a single radioactive atom, typically causing less disruption to biological function compared to bulky labels such as fluorophores. Current methods for routine production of these short-lived PET tracers are aimed largely at the clinical market, i.e. for production of large, multi-patient batches. For a few tracers (e.g. [18F]FDG), there is sufficient demand that scheduling can be coordinated (i.e. many patient scans and research projects on the same day) and the high production cost can be divided among many patients and researchers. In cases where demand is insufficient to enable cost-sharing, PET tracers are prohibitively expensive. Since the radioisotope is only a fraction of the production cost, scaling down to a smaller amount of radioactivity does not provide significant cost reduction for researchers that only need a small quantity of the probe. Other drivers of cost are the expensive equipment and specialized facilities (i.e. hot cells, to protect operators when using high amounts of radioisotope) that are not available to cancer researchers at many institutions, and the high cost of reagents consumed for each batch of tracer produced. Due to the high cost, many researchers choose alternative labeling methods (e.g. fluorescent, bioluminescent) despite the limitations of these approaches. Our preliminary data have shown that microfluidic synthesizers can successfully produce diverse PET tracers while providing unique advantages to solve the above problems: (1) Droplet microreactors consume 10-1000x less reagents than conventional systems; (2) Unlike conventional systems, molar activity in microreactors remains high even when producing small quantities (radioactivity) of the tracer; (3) The compact size of microreactors enables local radiation shielding and avoids the need for hot cells; (4) Production of small batches for individual researcher use will require much less radiation shielding (thickness), compared to typical hot cells. Previous studies have established feasibility and suggest that microdroplet synthesizers are poised to enable routine, low-cost production of tracers on demand. This could “commoditize” PET and make diverse tracers available to any investigator. This proposal seeks to perform advanced development and validation of this technology to make radiolabeled tracers widely available for assays in a variety of cancer research applications.

项目摘要 正电子发射断层扫描（PET）问题（或“示踪剂”）是包含阳性发射的生物分子 同位素，可以用高灵敏度检测到的衰减以在体内进行各种体外或3D 癌症研究生化过程的测定。放射性标记的重要优势是高组织 伽玛射线的穿透 - 这允许在细胞水平上的发现转化为新动物模型 （例如，研究疾病的机制和治疗），然后在患者中进行测定（例如，预测反应 治疗或评估效率），均具有相同的探针。成千上万的宠物示踪剂已经 报道了评估血管生成，肿瘤微环境（例如缺氧），代谢（例如葡萄糖或氨基） 酸），受体的密度等。另一个优点是，许多宠物示踪剂都标有一个放射性 原子，与诸如荧光团等笨重的标签相比，通常会导致生物功能的破坏较少。 这些短暂宠物示踪剂的常规生产的当前方法主要针对临床市场 即用于生产大型多门批次。对于一些示踪剂（例如[18F] FDG），有足够的需求 该计划可以协调（即，同一天的许多患者扫描和研究项目）和 许多患者和研究人员可以分配高生产成本。在需求不足的情况下 为了实现成本分配，禁止宠物示踪剂昂贵。由于放射性同位素只是一小部分 生产成本，缩小到较小的放射性并不能显着降低成本 只需要少量探针的研究人员。其他成本驱动力是昂贵的设备， 专用设施（即热细胞，使用大量放射性同位素时保护操作员） 可供许多机构的癌症研究人员使用，每批消耗的试剂成本高昂 制作示踪剂。由于成本高，许多研究人员选择替代标签方法（例如荧光，， 生物发光）使命这些方法的局限性。 我们的初步数据表明，微流体合成器可以成功生产潜水员宠物示踪剂 在提供独特的优势来解决上述问题的同时：（1）液滴微反应器消耗10-1000x 比常规系统少的试剂较少； （2）与常规系统不同，微反应器中的摩尔活性 即使产生示踪剂的少量（放射性），也保持高。 （3）紧凑的大小 微反应器可实现局部辐射屏蔽并避免对热细胞的需求； （4）生产小批量 与典型的热细胞相比，用于个人研究人员的使用将需要更少的辐射屏蔽（厚度）。 先前的研究已经确定了可行性，并表明微芯合成器被中毒以实现 常规，按需示踪剂的低成本生产。这可以“商品化”宠物并制作潜水员示踪剂 任何调查员可用。该建议旨在对此进行高级发展和验证 在各种癌症研究应用中，可以使放射标记的示踪剂广泛可用于测定技术。