A Glucose-Responsive Glucagon-Micelle for the Prevention of Hypoglycemia.

While glucose-responsive insulin delivery systems are in widespread clinical use to treat insulin insufficiency, the on-demand supplementation of glucagon for acute hypoglycemia treatment remains understudied. A self-regulated glucagon release material is highly desired to mitigate the potential risks of severe insulin-induced hypoglycemia. Here, we describe a glucose-responsive polymeric nanosystem with glucagon covalently grafted to the end-group.

A humanized monoclonal antibody targeting an ectonucleotidase rescues cardiac metabolism and heart function after myocardial infarction.

Myocardial infarction (MI) results in aberrant cardiac metabolism, but no therapeutics have been designed to target cardiac metabolism to enhance heart repair. We engineer a humanized monoclonal antibody against the ectonucleotidase ENPP1 (hENPP1mAb) that targets metabolic crosstalk in the infarcted heart. In mice expressing human ENPP1, systemic administration of hENPP1mAb metabolically reprograms myocytes and non-myocytes and leads to a significant rescue of post-MI heart dysfunction.

Rapid Concentration of Ga-68 and Proof-of-Concept Microscale Labeling of [Ga]Ga-PSMA-11 in a Droplet Reactor.

The radiometal gallium-68 (Ga-68) has garnered significant interest due to its convenient production via compact and widely available generators and the high performance of Ga-labeled compounds for positron-emission tomography (PET) imaging for cancer diagnosis and management of patients undergoing targeted radionuclide therapy. Given the short half life of Ga-68 (68 min), microfluidic-based radiosynthesis is a promising avenue to establish very rapid, efficient, and routine radiolabeling with Ga-68; however, the typical elution volume of Ga-68 from a generator (4-10 mL) is incompatible with the microliter reaction volumes of microfluidic devices. To bridge this gap, we developed a microscale cartridge-based approach to concentrate Ga-68.

Scalable droplet-based radiosynthesis of [F]fluorobenzyltriphenylphosphonium cation ([F]FBnTP) a "numbering up" approach.

The [F]fluorobenzyltriphenylphosphonium cation ([F]FBnTP) has emerged as a highly promising positron emission tomography (PET) tracer for myocardial perfusion imaging (MPI) due to its uniform distribution in the myocardium and favorable organ biodistribution demonstrated in preclinical studies. However, a complex and low-efficiency radiosynthesis procedure has significantly hindered its broader preclinical and clinical explorations. Recently, Zhang developed a pinacolyl arylboronate precursor, enabling a one-step synthesis process that greatly streamlines the production of [F]FBnTP.

Proof-of-concept optimization of a copper-mediated F-radiosynthesis of a novel MAGL PET tracer on a high-throughput microdroplet platform and its macroscale translation.

Copper-mediated radiofluorination has demonstrated remarkable potential in forming aromatic C-F bonds of radioligands for positron emission tomography (PET). Achieving optimal results often requires optimization efforts, requiring a substantial amount of radiolabeling precursor and time, severely limiting the experimental throughput. Recently, we successfully showcased the feasibility of performing and optimizing Cu-mediated radiosynthesis on a high-throughput microdroplet platform using the well-known and clinically used radioligand [F]FDOPA as an illustrative example.

Accelerating radiochemistry development: Automated robotic platform for performing up to 64 droplet radiochemical reactions in a morning.

The growing discovery and development of novel radiopharmaceuticals and radiolabeling methods requires an increasing capacity for radiochemistry experiments. However, such studies typically rely on radiosynthesizers designed for clinical batch production rather than research, greatly limiting throughput. Two general solutions are being pursued to address this: developing new synthesis optimization algorithms to minimize how many experiments are needed, and developing apparatus with enhanced experiment throughput.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development.

Main Body: This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals.

Conclusion: Trends in radiochemistry and radiopharmacy are highlighted.

Detrimental impact of aqueous mobile phases on 18F-labelled radiopharmaceutical analysis radio-TLC.

The list of new positron-emission tomography (PET) tracers has rapidly grown in the past decade, following discoveries of new biological targets and therapeutic strategies, with several compounds garnering recent regulatory approval for clinical use. During the development of synthesis methods and production of new tracers for imaging, analytical methods for radio-high performance liquid chromatography (radio-HPLC) and radio-thin layer chromatography (radio-TLC) separations need to be developed to assess radiochemical compositions. Radio-TLC is often faster, simpler, and sometimes more accurate than radio-HPLC (as there is no underestimation of [F]fluoride when analyzing F-labeled radiopharmaceuticals).

Rapid Purification and Formulation of Radiopharmaceuticals via Thin-Layer Chromatography.

Before formulating radiopharmaceuticals for injection, it is necessary to remove various impurities via purification. Conventional synthesis methods involve relatively large quantities of reagents, requiring high-resolution and high-capacity chromatographic methods (e.g.

A rapid and systematic approach for the optimization of radio thin-layer chromatography resolution.

Radiopharmaceutical analysis is limited by conventional methods. Radio-HPLC may be inaccurate for some compounds (e.g.

Microliter-scale reaction arrays for economical high-throughput experimentation in radiochemistry.

The increasing number of positron-emission tomography (PET) tracers being developed to aid drug development and create new diagnostics has led to an increased need for radiosynthesis development and optimization. Current radiosynthesis instruments are designed to produce large-scale clinical batches and are often limited to performing a single synthesis before they must be decontaminated by waiting for radionuclide decay, followed by thorough cleaning or disposal of synthesizer components. Though with some radiosynthesizers it is possible to perform a few sequential radiosyntheses in a day, none allow for parallel radiosyntheses.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development.

Results: This commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals and also a contribution in relation to MRI-agents is included.

Conclusion: Trends in (radio)chemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

Economical Production of Radiopharmaceuticals for Preclinical Imaging Using Microdroplet Radiochemistry.

The short-lived radiolabeled "tracers" needed for performing whole body imaging in animals or patients with positron-emission tomography (PET) are generally produced via automated "radiosynthesizers". Most current radiosynthesizers are designed for routine production of relatively large clinical batches and are very wasteful when only a small batch of a tracer is needed, such as is the case for preclinical in vivo PET imaging studies. To overcome the prohibitively high cost of producing small batches of PET tracers, we developed a droplet microreactor system that performs radiochemistry at the 1-10μL scale instead of the milliliter scale of conventional technologies.

Economical droplet-based microfluidic production of [F]FET and [F]Florbetaben suitable for human use.

Current equipment and methods for preparation of radiopharmaceuticals for positron emission tomography (PET) are expensive and best suited for large-scale multi-doses batches. Microfluidic radiosynthesizers have been shown to provide an economic approach to synthesize these compounds in smaller quantities, but can also be scaled to clinically-relevant levels. Batch microfluidic approaches, in particular, offer significant reduction in system size and reagent consumption.

Optimization of Radiochemical Reactions using Droplet Arrays.

Current automated radiosynthesizers are designed to produce large clinical batches of radiopharmaceuticals. They are not well suited for reaction optimization or novel radiopharmaceutical development since each data point involves significant reagent consumption, and contamination of the apparatus requires time for radioactive decay before the next use. To address these limitations, a platform for performing arrays of miniature droplet-based reactions in parallel, each confined within a surface-tension trap on a patterned polytetrafluoroethylene-coated silicon "chip", was developed.

Cerenkov Luminescence Imaging in the Development and Production of Radiopharmaceuticals.

Over the past several years there has been an explosion of interest in exploiting Cerenkov radiation to enable and intraoperative optical imaging of subjects injected with trace amounts of radiopharmaceuticals. At the same time, Cerenkov luminescence imaging (CLI) also has been serving as a critical tool in radiochemistry, especially for the development of novel microfluidic devices for producing radiopharmaceuticals. By enabling microfluidic processes to be monitored non-destructively , CLI has made it possible to literally watch the activity distribution as the synthesis occurs, and to quantitatively measure activity propagation and losses at each step of synthesis, paving the way for significant strides forward in performance and robustness of those devices.

High-Efficiency Production of Radiopharmaceuticals via Droplet Radiochemistry: A Review of Recent Progress.

New platforms are enabling radiochemistry to be carried out in tiny, microliter-scale volumes, and this capability has enormous benefits for the production of radiopharmaceuticals. These droplet-based technologies can achieve comparable or better yields compared to conventional methods, but with vastly reduced reagent consumption, shorter synthesis time, higher molar activity (even for low activity batches), faster purification, and ultra-compact system size. We review here the state of the art of this emerging direction, summarize the radiotracers and prosthetic groups that have been synthesized in droplet format, describe recent achievements in scaling up activity levels, and discuss advantages and limitations and the future outlook of these innovative devices.

A simple and efficient automated microvolume radiosynthesis of [F]Florbetaben.

Background: Current automated radiosynthesizers are generally optimized for producing large batches of PET tracers. Preclinical imaging studies, however, often require only a small portion of a regular batch, which cannot be economically produced on a conventional synthesizer. Alternative approaches are desired to produce small to moderate batches to reduce cost and the amount of reagents and radioisotope needed to produce PET tracers with high molar activity.

Multi-GBq production of the radiotracer [F]fallypride in a droplet microreactor.

Microfluidics offers numerous advantages for the synthesis of short-lived radiolabeled imaging tracers: performing F-radiosyntheses in microliter-scale droplets has exhibited high efficiency, speed, and molar activity as well as low reagent consumption. However, most reports have been at the preclinical scale. In this study we integrate a [F]fluoride concentrator and a microdroplet synthesizer to explore the possibility of synthesizing patient doses and multi-patient batches of clinically-acceptable tracers.

Green and efficient synthesis of the radiopharmaceutical [F]FDOPA using a microdroplet reactor.

From an efficiency standpoint, microdroplet reactors enable significant improvements in the preparation of radiopharmaceuticals due to the vastly reduced reaction volume. To demonstrate these advantages, we adapt the conventional (macroscale) synthesis of the clinically-important positron-emission tomography tracer [F]FDOPA, following the nucleophilic diaryliodonium salt approach, to a newly-developed ultra-compact microdroplet reaction platform. In this first microfluidic implementation of [F]FDOPA synthesis, optimized via a high-throughput multi-reaction platform, the radiochemical yield (non-decay-corrected) was found to be comparable to macroscale reports, but the synthesis consumed significantly less precursor and organic solvents, and the synthesis process was much faster.

Integration of High-Resolution Radiation Detector for Hybrid Microchip Electrophoresis.

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 high-performance liquid chromatography (HPLC).

Rapid, efficient, and economical synthesis of PET tracers in a droplet microreactor: application to O-(2-[F]fluoroethyl)-L-tyrosine ([F]FET).

Background: Conventional scale production of small batches of PET tracers (e.g. for preclinical imaging) is an inefficient use of resources.

High-throughput radio-TLC analysis.

Introduction: Radio thin layer chromatography (radio-TLC) is commonly used to analyze purity of radiopharmaceuticals or to determine the reaction conversion when optimizing radiosynthesis processes. In applications where there are few radioactive species, radio-TLC is preferred over radio-high-performance liquid chromatography due to its simplicity and relatively quick analysis time. However, with current radio-TLC methods, it remains cumbersome to analyze a large number of samples during reaction optimization.

In vivo characterization of [F]AVT-011 as a radiotracer for PET imaging of multidrug resistance.

Purpose: Multidrug resistance (MDR) impedes cancer treatment. Two efflux transporters from the ATP-binding cassette (ABC) family, ABCB1 and ABCG2, may contribute to MDR by restricting the entry of therapeutic drugs into tumor cells. Although a higher expression of these transporters has been correlated with an unfavorable response to chemotherapy, transporter expression does not necessarily correlate with function.

On-demand radiosynthesis of -succinimidyl-4-[F]fluorobenzoate ([F]SFB) on an electrowetting-on-dielectric microfluidic chip for F-labeling of protein.

An all-electronic, droplet-based batch microfluidic device, operated using the electrowetting on dielectric (EWOD) mechanism was developed for on-demand synthesis of -succinimidyl-4-[F]fluorobenzoate ([F]SFB), the most commonly used F-prosthetic group for biomolecule labeling. In order to facilitate the development of peptides, and proteins as new diagnostic and therapeutic agents, we have diversified the compact EWOD microfluidic platform to perform the three-step radiosynthesis of [F]SFB starting from the no carrier added [F]fluoride ion. In this report, we established an optimal microliter droplet reaction condition to obtain reliable yields and synthesized [F]SFB with sufficient radioactivity for subsequent conjugation to the anti-PSCA cys-diabody (A2cDb) and for small animal imaging.