Toward miniaturized analysis of chemical identity and purity of radiopharmaceuticals via microchip electrophoresis

Ly, Jimmy; Ha, Noel S.; Cheung, Shilin; Dam, R. Michael van

doi:10.1007/s00216-018-0924-y

Cited by 15 publications

(16 citation statements)

References 42 publications

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“…Operation of the chip was carried out as described previously. 34 Briefly, to load a sample with the new chip design, valves 1, 2, and 3 are closed, while valves 4, 5, and 6 are opened. The sample vial is pressurized to 3 psi, allowing the sample to flow from the inlet, through the injection chamber to the sample waste.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…Operation of the chip was carried out as described previously . Briefly, to load a sample with the new chip design, valves 1, 2, and 3 are closed, while valves 4, 5, and 6 are opened.…”

Section: Methodsmentioning

confidence: 99%

“…Importantly, MCE also has the benefit of high flexibility of flow cell geometry and detector integration that can be implemented into a microfluidic format. Ultimately this approach could reduce the resources needed for radiopharmaceutical analysis and could become an integral part of emerging, compact microfluidic radiopharmaceutical production systems. , We previously demonstrated the analysis of the nonradioactive form of the PET tracer 3′-deoxy-3′-[ 18 F]fluorothymidine ([ 18 F]FLT) and its known impurities using a conventional CE system, as well as a hybrid-MCE system that we developed, , both using UV absorbance detection, and found the separation efficiency and UV sensitivity to be similar to HPLC.…”

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confidence: 99%

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Integration of High-Resolution Radiation Detector for Hybrid Microchip Electrophoresis

Jones

Barajas

et al. 2020

Anal. Chem.

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For decades, there has been immense progress in miniaturizing analytical methods based on electrophoresis to improve sensitivity and to reduce sample volumes, separation times, and/or equipment cost and space requirements, in applications ranging from analysis of biological samples to environmental analysis to forensics. In the field of radiochemistry, where radiation-shielded laboratory space is limited, there has been great interest in harnessing the compactness, high efficiency, and speed of microfluidics to synthesize short-lived radiolabeled compounds. We recently proposed that analysis of these compounds could also benefit from miniaturization and have been investigating capillary electrophoresis (CE) and hybrid microchip electrophoresis (hybrid-MCE) as alternatives to the typically used highperformance liquid chromatography (HPLC). We previously showed separation of the positron-emission tomography (PET) imaging tracer 3′-deoxy-3′-fluorothymidine (FLT) from its impurities in a hybrid-MCE device with UV detection, with similar separation performance to HPLC, but with improved speed and lower sample volumes. In this paper, we have developed an integrated radiation detector to enable measurement of the emitted radiation from radiolabeled compounds. Though conventional radiation detectors have been incorporated into CE systems in the past, these approaches cannot be readily integrated into a compact hybrid-MCE device. We instead employed a solid-state avalanche photodiode (APD)-based detector for real-time, high-sensitivity β particle detection. The integrated system can reliably separate [ 18 F]FLT from its impurities and perform chemical identification via coinjection with nonradioactive reference standard. This system can quantitate samples with radioactivity concentrations as low as 114 MBq/mL (3.1 mCi/mL), which is sufficient for analysis of radiochemical purity of radiopharmaceuticals.

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Section: ■ Materials and Methodsmentioning

confidence: 99%

“…Operation of the chip was carried out as described previously . Briefly, to load a sample with the new chip design, valves 1, 2, and 3 are closed, while valves 4, 5, and 6 are opened.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Integration of High-Resolution Radiation Detector for Hybrid Microchip Electrophoresis

Jones

Barajas

et al. 2020

Anal. Chem.

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“…Recently, various microfluidic devices have been developed for medical diagnosis [1,2], chemical detection [3][4][5] and biological analysis [6,7], due to the small volume, fast speed and low cost [8]. Nowadays, microfluidics have also made significant progress in the optical field [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Research on liquid flow behavior in deformed microfluidic channels made of PDMS material

Zhang

Luo

et al. 2022

J. Phys.: Conf. Ser.

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In order to improve the application performances of current microfluidic systems, the liquid flow behavior in deformed microfluidic channels made of PDMS material is deeply researched in this study. During the flowing process, liquid pressure features in inelastic and elastic channels are tested and compared respectively, serious channel deformation in elastic PDMS channels is found, and the key influencing factors are summarized and provided, including channel aspect ratio α, top membrane thickness th and channel width w, etc. This study reveals the liquid flow behavior in microfluidic systems made of PDMS material, and provides theoretical and experimental basis for further structural optimization of the systems.

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“…Ideally, it does not rely on cleaning procedures and aligns with the state-of-the art approach of single-use disposables. To date, efforts in this direction have focused on development of microfluidic approaches for radiopharmaceutical manufacturing (Amaraesekera et al 2013; Audrain 2007; Awasthi et al 2014; Bejot et al 2010; Bouvet et al 2011; Bouvet et al 2012; Bouvet and Wuest 2013; Chen et al 2014; Collier et al 2010, 2017; De Leonardis et al 2010, 2011; Gaja et al 2012; Gillies et al 2006; Lu and Pike 2007; Lu and Pike 2010; Elizarov 2009; Elizarov et al 2010; Fortt and Gee 2013; Kealey et al 2011; Keng et al 2012b; Keng and van Dam 2015; Lee et al 2005; Liow et al 2005; Liu et al 2011; Liu et al 2013; Lu et al 2004, 2009, 2010; Matesic et al 2017; Miller 2009; Miller et al 2010, 2011; Pascali et al 2010, 2011, 2013; Pascali and Salvadori 2016; Rensch et al 2012, 2013; Selivanova et al 2012; Simms et al 2012; Steel et al 2007; Ungersboeck et al 2011, 2012a, 2012b; Voccia et al 2009; Wang et al 2010; Wang et al 2019; Wester et al 2009; Wheeler et al 2010; Yokell et al 2012; Zeng et al 2013), as well as purification/reformulation (Chao et al 2017) and quality control (QC) testing (Ha et al 2017; Taggart et al 2016; Ly et al 2018). While the benefits of microreactors for radiopharmaceutical synthesis have been well documented in this multitude of literature precedent, and they have been used to prepare radiopharmaceuticals for clinical use (Lebedev et al 2013; Liang et al 2014a, 2014b; Rensch et al 2014), there are continuing challenges that have prevented them from commercialization and really transitioning into widespread use to date (Chiu et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Development and implementation of ISAR, a new synthesis platform for radiopharmaceutical production

Frank

Ciulli

Rensei

et al. 2019

EJNMMI radiopharm. chem.

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Background PET radiopharmaceutical development and the implementation of a production method on a synthesis module is a complex and time-intensive task since new synthesis methods must be adapted to the confines of the synthesis platform in use. Commonly utilized single fluid bus architectures put multiple constraints on synthesis planning and execution, while conventional microfluidic solutions are limited by compatibility at the macro-to-micro interface. In this work we introduce the ISAR synthesis platform and custom-tailored fluid paths leveraging up to 70 individually addressable valves on a chip-based consumable. The ISAR synthesis platform replaces traditional stopcock valve manifolds with a fluidic chip that integrates all fluid paths (tubing) and valves into one consumable and enables channel routing without the single fluid bus constraint. ISAR can scale between the macro- (10 mL), meso- (0.5 mL) and micro- (≤0.05 mL) domain seamlessly, addressing the macro-to-micro interface challenge and enabling custom tailored fluid circuits for a given application. In this paper we demonstrate proof-of-concept by validating a single chip design to address the challenge of synthesizing multiple batches of [13N]NH3 for clinical use throughout the workday. Results ISAR was installed at an academic PET Center and used to manufacture [13N]NH3 in > 96% radiochemical yield. Up to 9 batches were manufactured with a single consumable chip having parallel paths without the need to open the hot-cell. Quality control testing confirmed the ISAR-based [13N]NH3 met existing clinical release specifications, and utility was demonstrated by imaging a rodent with [13N]NH3 produced on ISAR. Conclusions ISAR represents a new paradigm in radiopharmaceutical production. Through a new system architecture, ISAR integrates the principles of microfluidics with the standard volumes and consumables established in PET Centers all over the world. Proof-of-concept has been demonstrated through validation of a chip design for the synthesis of [13N]NH3 suitable for clinical use.

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Toward miniaturized analysis of chemical identity and purity of radiopharmaceuticals via microchip electrophoresis

Cited by 15 publications

References 42 publications

Integration of High-Resolution Radiation Detector for Hybrid Microchip Electrophoresis

Integration of High-Resolution Radiation Detector for Hybrid Microchip Electrophoresis

Research on liquid flow behavior in deformed microfluidic channels made of PDMS material

Development and implementation of ISAR, a new synthesis platform for radiopharmaceutical production

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