IAEA Contribution to Nanosized Targeted Radiopharmaceuticals for Drug Delivery.

The rapidly growing interest in the application of nanoscience in the future design of radiopharmaceuticals and the development of nanosized radiopharmaceuticals in the late 2000's, resulted in the creation of a Coordinated Research Project (CRP) by the International Atomic Energy Agency (IAEA) in 2014. This CRP entitled 'Nanosized delivery systems for radiopharmaceuticals' involved a team of expert scientist from various member states. This team of scientists worked on a number of cutting-edge areas of nanoscience with a focus on developing well-defined, highly effective and site-specific delivery systems of radiopharmaceuticals. Specifically, focus areas of various teams of scientists comprised of the development of nanoparticles (NPs) based on metals, polymers, and gels, and their conjugation/encapsulation or decoration with various tumor avid ligands such as peptides, folates, and small molecule phytochemicals. The research and development efforts also comprised of developing optimum radiolabeling methods of various nano vectors using diagnostic and therapeutic radionuclides including Tc-99m, Ga-68, Lu-177 and Au-198. Concerted efforts of teams of scientists within this CRP has resulted in the development of various protocols and guidelines on delivery systems of nanoradiopharmaceuticals, training of numerous graduate students/post-doctoral fellows and publications in peer reviewed journals while establishing numerous productive scientific networks in various participating member states. Some of the innovative nanoconstructs were chosen for further preclinical applications-all aimed at ultimate clinical translation for treating human cancer patients. This review article summarizes outcomes of this major international scientific endeavor.

Potential Theranostic Boron Neutron Capture Therapy Agents as Multimodal Radiopharmaceuticals.

Boron neutron capture therapy (BNCT) has been extant for decades and continues to be practiced in many centers around the globe. Most of the active clinical trials utilize boronophenylalanine as the drug containing boron atoms. The important aspect that has been added to the BNCT practice is the use of an F-18 radiolabeled analog for ascertaining targeting and monitoring follow-up studies. The recent widespread application of therapeutic radiopharmaceuticals, especially peptides (somatostatin analogs), prostate-specific antigen-binding ligands, or immunomolecules, offers the ambit for invention of new tumor-specific BNCT agents, especially for BNCT-susceptible tumors, that is, locoregional cancers such as head and neck cancer. Such BNCT agents, when radiolabeled, can enable simultaneous imaging and/or therapeutic applications (depending on the radionuclide used) through multimodal approaches. Development of boron-rich moieties such as sodium borocaptate and neutral carboranes combined with tumor-targeting moieties can lead to a new horizon in BNCT. The review covers various aspects of drug design, tumor targeting, and possible future radiopharmaceutical development for multimodal theranostic application in humans.

IAEA Activities on 67Cu, 186Re, 47Sc Theranostic Radionuclides and Radiopharmaceuticals.

Despite interesting properties, the use of 67Cu, 186Re and 47Sc theranostic radionuclides in preclinical studies and clinical trials is curtailed by their limited availability due to a lack of widely established production methods. An IAEA Coordinated Research Project (CRP) was initiated to identify important technical issues related to the production and quality control of these emerging radionuclides and related radiopharmaceuticals, based on the request from IAEA Member States. The international team worked on targetry, separation, quality control and radiopharmaceutical aspects of the radionuclides obtained from research reactors and cyclotrons leading to preparation of a standard recommendations for all Member States. The CRP was initiated in 2016 with fourteen participants from thirteen Member States from four continents. Extraordinary results on the production, quality control and preclinical evaluation of selected radionuclides were reported in this project that was finalized in 2020. The outcomes, outputs and results of this project achieved by participating Member States are described in this minireview.

Copper-64 based radiopharmaceuticals for brain tumors and hypoxia imaging.

INTRODUCTION: The most common and aggressive primary malignancy of the central nervous system is Glioblastoma that, as a wide range of malignant solid tumor, is characterized by extensive hypoxic regions. A great number of PET radiopharmaceuticals have been developed for the identification of hypoxia in solid tumors, among these, we find copper-based tracers. The aim of the current review paper was to provide an overview of radiocopper compounds applied for preclinical and clinical research in brain tumors and hypoxia imaging or therapy. EVIDENCE ACQUISITION: Copper offers a wide variety of isotopes, useful for nuclear medicine applications, but only 64Cu and 67Cu are under the spotlight of the scientific community since being good candidates for theranostic applications. Between the two, 64Cu availability and production cost have attracted more interest of the scientific community. EVIDENCE SYNTHESIS: In order to better understand the application of copper-bis thiosemicarbazones in hypoxia imaging, an overview of the role of hypoxia in cancer, existing non-imaging and imaging techniques for hypoxia identification and promising future avenues regarding hypoxia is necessary. Different proposed uptake mechanisms of [64Cu][Cu(ATSM)] inside the cell will be discussed and other 64Cu-based tracers for brain tumors described. CONCLUSIONS: Among radio copper compounds [64Cu][Cu(ATSM)] is the most studied radiopharmaceutical for imaging and treatment of brain tumors. Experimental evidence suggested that [64Cu][Cu(ATSM)] could be more appropriately considered as a marker of over-reduced intracellular state rather than a pure hypoxia agent. Moreover, preliminary clinical data suggested that [64Cu]CuCl2 can be a potentially useful diagnostic agent for malignancies of the central nervous system (CNS).

IAEA contribution to the development of 64Cu radiopharmaceuticals for theranostic applications.

Copper-64 is a very attractive radioisotope with unique nuclear properties that allow using it as both a diagnostic and therapeutic agent, thus providing an almost ideal example of a theranostic radionuclide. A characteristic of Cu-64 stems from the intrinsic biological nature of copper ions that play a fundamental role in a large number of cellular processes. Cu-64 is a radionuclide that reflects the natural biochemical pathways of Cu-64 ions, therefore, can be exploited for the detection and therapy of certain malignancies and metabolic diseases. Beside these applications of Cu-64 ions, this radionuclide can be also used for radiolabelling bifunctional chelators carrying a variety of pharmacophores for targeting different biological substrates. These include peptide-based substrates and immunoconjugates as well as small-molecule bioactive moieties. Fueled by the growing interest of Member States (MS) belonging to the International Atomic Energy Agency (IAEA) community, a dedicated Coordinated Research Project (CRP) was initiated in 2016, which recruited thirteen participating MS from four continents. Research activities and collaborations between the participating countries allowed for collection of an impressive series of results, particularly on the production, preclinical evaluation and, in a few cases, clinical evaluation of various 64Cu-radiopharmaceuticals that may have potential impact on future development of the field. Since this CRP was finalized at the beginning of 2020, this short review summarizes outcomes, outputs and results of this project with the purpose to propagate to other MS and to the whole scientific community, some of the most recent achievements on this novel class of theranostic 64Cu-pharmaceuticals.