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

项目摘要 正电子发射断层扫描（PET）探针（或“示踪剂”）是含有正电子发射的生物分子。 同位素，其衰变可以高灵敏度检测，以进行各种体外或体内3D测量。 用于癌症研究的生化过程分析。放射性标记的一个显著优点是高组织特异性。 伽马射线的穿透-这使得细胞水平的发现可以转化为新的动物模型 (e.g.研究疾病的机制和治疗），然后用于患者的测定（例如，预测反应 治疗或评估治疗效果），所有这些都使用相同的探针。成千上万的PET示踪剂已经被 据报道用于评估血管生成、肿瘤微环境（例如缺氧），代谢（例如，葡萄糖或氨基 另一个优点是许多PET示踪剂用单个放射性标记物标记。 原子，与诸如荧光团的大体积标记相比，通常对生物功能造成较少的破坏。 目前常规生产这些短寿命PET示踪剂的方法主要针对临床市场， 即用于大批量、多患者的生产。对于少数示踪剂（例如[18 F]FDG），有足够的需求 可以协调调度（即，在同一天进行许多患者扫描和研究项目）， 高生产成本可以由许多患者和研究人员分摊。在需求不足的情况下 为了能够分摊成本，PET示踪剂非常昂贵。因为放射性同位素只是 尽管如此，由于生产成本的增加，按比例缩小到较少量的放射性并不能显著降低生产成本， 研究人员只需要少量的探针。成本的其他驱动因素是昂贵的设备， 专用设施（即热室，在使用大量放射性同位素时保护操作人员）， 许多机构的癌症研究人员都可以获得，每批药物消耗的试剂成本很高， 生产的示踪剂由于成本高，许多研究人员选择替代标记方法（例如荧光， 生物发光的），尽管这些方法有局限性。 我们的初步数据表明，微流控合成器可以成功地产生不同的PET示踪剂 同时为解决上述问题提供了独特的优势：（1）液滴微反应器消耗10- 1000 × 与常规系统不同，微反应器中的摩尔活性 即使在产生少量（放射性）示踪剂时也保持高水平;（3） 微型反应器能够实现局部辐射屏蔽，避免了对热室的需要;（4）小批量生产 与典型的热室相比，对于个人研究者使用，将需要更少的辐射屏蔽（厚度）。 以前的研究已经建立了可行性，并表明微滴合成器准备使 按需生产常规低成本示踪剂。这可以使PET“商品化”，并使示踪剂多样化 提供给任何调查员。该提案旨在进行先进的开发和验证， 技术，使放射性标记的示踪剂广泛用于各种癌症研究应用中的测定。

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.