Department of Mechanical Engineering, Vanderbilt University, Nashville, TN, 37235, USA.
Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
Mol Imaging Biol. 2020 Oct;22(5):1370-1379. doi: 10.1007/s11307-020-01515-7.
Current PET radiotracer production models result in facility and operational costs that scale prohibitively with the number of tracers synthesized, particularly those made as a single dose-on-demand. Short of a paradigm shift in the technology and economics of radiotracer production, the impact of PET on precision medicine will be limited. Inexpensive, microfluidic radiochemistry platforms have the potential to significantly reduce costs associated with dose-on-demand production and expand the breadth of PET tracers accessible for molecular imaging.
To produce a miniaturized dose-on-demand device for [Ga]Ga-PSMA-11 production, a microfluidic chip was assembled in polydimethylsiloxane (PDMS), combining all components of tracer production in an integrated, compact, and easily utilized platform. On-chip radionuclide concentration, as well as radionuclide and precursor starting material mixing and reaction were incorporated. The radionuclide was sourced from a standard, commercially available Ge/Ga generator. Optimal reaction conditions were determined, which included precursor concentration (5 μg/mL), temperature (95 °C), and reaction time (1 min).
The total trapping efficiency of combined on-chip SCX and SAX columns was greater than 70 % and could be accomplished in ~ 12 min. Under optimized conditions, [Ga]Ga-PSMA-11 could be reliably synthesized starting from a complete generator elution (1100 MBq [29.7 mCi]) in ~ 12 min, with an average radiochemical yield of 70 %, radiochemical purity > 99 %, and specific activity > 740 MBq/μg (20 mCi/μg). Quality control testing demonstrated that tracer produced using this platform met or exceeded all typical FDA requirements for human use.
A simple, low-cost, dose-on-demand radiosynthesis strategy, such as the chip presented here, represents an opportunity to reduce the financial barriers associated with PET imaging. While this study focused on a device for [Ga]Ga-PSMA-11, the technology is also applicable to a wide range of other tracers where low-cost, automated, dose-on-demand production is highly desirable.
目前的 PET 放射性示踪剂生产模式导致设施和运营成本随着所合成示踪剂数量的增加而呈指数级增长，特别是那些作为单剂量按需合成的示踪剂。除非放射性示踪剂生产技术和经济学发生范式转变，否则 PET 对精准医学的影响将受到限制。廉价的微流控放射化学平台有可能显著降低与按需生产相关的成本，并扩大可用于分子成像的 PET 示踪剂的范围。
为了生产用于 [Ga]Ga-PSMA-11 生产的微型按需剂量装置，我们在聚二甲基硅氧烷（PDMS）中组装了一个微流控芯片，将示踪剂生产的所有组件集成到一个集成、紧凑且易于使用的平台中。在芯片上进行放射性核素浓度以及放射性核素和前体起始材料的混合和反应。放射性核素源自标准的商业可用 Ge/Ga 发生器。确定了最佳反应条件，包括前体浓度（5μg/mL）、温度（95°C）和反应时间（1 分钟）。
组合的在线 SCX 和 SAX 柱的总捕获效率大于 70%，可在12 分钟内完成。在优化条件下，从完整的发生器洗脱液（1100MBq [29.7mCi]）开始，可在12 分钟内可靠地合成 [Ga]Ga-PSMA-11，平均放射化学产率为 70%，放射化学纯度>99%，比活度>740MBq/μg（20mCi/μg）。质量控制测试表明，使用该平台生产的示踪剂符合或超过了 FDA 对人类使用的所有典型要求。
像这里展示的这种简单、低成本、按需剂量的放射合成策略代表了降低与 PET 成像相关的财务障碍的机会。虽然本研究侧重于用于 [Ga]Ga-PSMA-11 的设备，但该技术也适用于其他广泛的示踪剂，在这些示踪剂中，低成本、自动化、按需剂量生产是非常需要的。
