N-Benzylethanolammonium Ionic Liquids and Molten Salts in the Synthesis of 68Ga- and Al18F-Labeled Radiopharmaceuticals.

Ionic liquids (ILs), due to their structural features, have unique physical and chemical properties and are environmentally friendly. Every year, the number of studies devoted to the use of ILs in medicine and pharmaceutics is growing. In nuclear medicine, the use of ILs with self-buffering capacity in the synthesis of radiopharmaceuticals is extremely important. This research is devoted to obtaining new ionic buffer agents containing N-benzylethanolammonium (BEA) cations and anions of carboxylic acids. A series of new BEA salts was synthesized and identified by NMR (1H, 13C), IR spectroscopy and elemental and thermal analysis. The crystal structures of BEA hydrogen succinate, hydrogen oxalate and oxalate were determined by x-ray diffraction. Newly synthesized compounds were tested as buffer solutions in 68Ga- and Al18F-radiolabeling reactions with a series of bifunctional chelating agents and clinically relevant peptides used for visualization of malignancies by positron emission tomography. The results obtained confirm the promise of using new buffers in the synthesis of 68Ga- and Al18F-labeled radiopharmaceuticals.

Calcium carbonate carriers for combined chemo- and radionuclide therapy of metastatic lung cancer.

Considering the clinical limitations of individual approaches against metastatic lung cancer, the use of combined therapy can potentially improve the therapeutic effect of treatment. However, determination of the appropriate strategy of combined treatment can be challenging. In this study, combined chemo- and radionuclide therapy has been realized using radionuclide carriers (177Lu-labeled core-shell particles, 177Lu-MPs) and chemotherapeutic drug (cisplatin, CDDP) for treatment of lung metastatic cancer. The developed core-shell particles can be effectively loaded with 177Lu therapeutic radionuclide and exhibit good radiochemical stability for a prolonged period of time. In vivo biodistribution experiments have demonstrated the accumulation of the developed carriers predominantly in lungs. Direct radiometry analysis did not reveal an increased absorbance of radiation by healthy organs. It has been shown that the radionuclide therapy with 177Lu-MPs in mono-regime is able to inhibit the number of metastatic nodules (untreated mice = 120 ± 12 versus177Lu-MPs = 50 ± 7). The combination of chemo- and radionuclide therapy when using 177Lu-MPs and CDDP further enhanced the therapeutic efficiency of tumor treatment compared to the single therapy (177Lu-MPs = 50 ± 7 and CDDP = 65 ± 10 versus177Lu-MPs + CDDP = 37 ± 5). Thus, this work is a systematic research on the applicability of the combination of chemo- and radionuclide therapy to treat metastatic lung cancer.

Impact of metallic coating on the retention of 225Ac and its daugthers within core-shell nanocarriers.

Currently, alpha-emitting radionuclide 225Ac is one of the most promising isotopes in alpha therapy due to its high linear energy transfer during four sequential alpha decays. However, the main obstacle preventing the full introduction of 225Ac into clinical practice is the lack of stable retention of radionuclides, leading to free circulation of toxic isotopes in the body. In this work, the surface of silica nanoparticles (SiO2 NPs) has been modified with metallic shells composed of titanium dioxide (TiO2) and gold (Au) nanostructures to improve the retention of 225Ac and its decay products within the developed nanocarriers. In vitro and in vivo studies in healthy mice show that the metallic surface coating of SiO2 NPs promotes an enhanced sequestering of radionuclides (225Ac and its daughter isotopes) compared to non-modified SiO2 NPs for a prolonged period of time. Histological analysis reveals that for the period of 3-10 d after the injections, the developed nanocarriers have no significant toxic effects in mice. At the same time, almost no accumulation of leaked radionuclides can be detected in non-target organs (e.g., in the kidneys). In contrast, non-modified carriers (SiO2 NPs) demonstrate the release of free radionuclides, which are distributed over the whole animal body with the consequent morphological changes in the lung, liver and kidney tissues. These results highlight the potential of the developed nanocarriers to be utilized as radionuclide delivery systems and offer an insight into design rules for the fabrication of new nanotherapeutic agents.

Calcium Carbonate Core-Shell Particles for Incorporation of 225Ac and Their Application in Local α-Radionuclide Therapy.

Actinium-225 (225Ac) radiolabeled submicrometric core-shell particles (SPs) made of calcium carbonate (CaCO3) coated with biocompatible polymers [tannic acid-human serum albumin (TA/HSA)] have been developed to improve the efficiency of local α-radionuclide therapy in melanoma models (B16-F10 tumor-bearing mice). The developed 225Ac-SPs possess radiochemical stability and demonstrate effective retention of 225Ac and its daughter isotopes. The SPs have been additionally labeled with zirconium-89 (89Zr) to perform the biodistribution studies using positron emission tomography-computerized tomography (PET/CT) imaging for 14 days after intratumoral injection. According to the PET/CT analysis, a significant accumulation of 89Zr-SPs in the tumor area is revealed for the whole investigation period, which correlates with the direct radiometry analysis after intratumoral administration of 225Ac-SPs. The histological analysis has revealed no abnormal changes in healthy tissue organs after treatment with 225Ac-SPs (e.g., no acute pathologic findings are detected in the liver and kidneys). At the same time, the inhibition of tumor growth has been observed as compared with control samples [nonradiolabeled SPs and phosphate-buffered saline (PBS)]. The treatment of mice with 225Ac-SPs has resulted in prolonged survival compared to the control samples. Thus, our study validates the application of 225Ac-doped core-shell submicron CaCO3 particles for local α-radionuclide therapy.

An investigation of calcium carbonate core-shell particles for incorporation of 225Ac and sequester of daughter radionuclides: in vitro and in vivo studies.

Alpha therapy provides an outstanding prospect in the treatment of recalcitrant and micrometastatic cancers. However, side effects on the normal tissues and organs (especially, kidneys) due to the release of daughter isotopes from α-emitters remain a bottleneck. In this work, calcium carbonate core-shell particles of different sizes were considered as isotope carriers for encapsulation of 225Ac (highly powerful alpha-emitter that generates 4 net alpha particle isotopes in a short decay chain) in order to achieve in vitro and in vivo retention of 225Ac and its daughter isotopes. According to the in vitro studies, the developed calcium carbonate core-shell particles were able to retain 225Ac and its daughter isotopes (221Fr and 213Bi) exhibited good stability in biological media and dose-dependent biocompatibility (over 30 d). The SPECT imaging demonstrated the size-dependent distribution of 225Ac-doped core-shell particles. Further, in vivo studies confirmed the high retention efficiency of calcium carbonate core-shell particles, which was demonstrated in normal Wistar rats (up to 10 d). Interestingly, the radioactivity accumulation in kidney and urine was significantly less for encapsulated 225Ac than in case of non-encapsulated form of 225Ac (225Ac conjugated with albumin), indicating the absence of radioisotope leakage from the developed particles. Thus, our study validates the application of 225Ac-doped core-shell particles to sequester α-emitter (225Ac) and its decay products in order to reduce their systemic toxicity during alpha therapy.

On the consensus nomenclature rules for radiopharmaceutical chemistry - Reconsideration of radiochemical conversion.

Radiochemical conversion is an important term to be included in the "Consensus nomenclature rules for radiopharmaceutical chemistry". Radiochemical conversion should be used to define reaction efficiency by measuring the transformation of components in a crude reaction mixture at a given time, whereas radiochemical yield is better suited to define the efficiency of an entire reaction process including, for example, separation, isolation, filtration, and formulation.

Radiolabeling Strategies of Micron- and Submicron-Sized Core-Shell Carriers for In Vivo Studies.

Core-shell particles made of calcium carbonate and coated with biocompatible polymers using the Layer-by-Layer technique can be considered as a unique drug-delivery platform that enables us to load different therapeutic compounds, exhibits a high biocompatibility, and can integrate several stimuli-responsive mechanisms for drug release. However, before implementation for diagnostic or therapeutic purposes, such core-shell particles require a comprehensive in vivo evaluation in terms of physicochemical and pharmacokinetic properties. Positron emission tomography (PET) is an advanced imaging technique for the evaluation of in vivo biodistribution of drug carriers; nevertheless, an incorporation of positron emitters in these carriers is needed. Here, for the first time, we demonstrate the radiolabeling approaches of calcium carbonate core-shell particles with different sizes (CaCO3 micron-sized core-shell particles (MicCSPs) and CaCO3 submicron-sized core-shell particles (SubCSPs)) to precisely determine their in vivo biodistribution after intravenous administration in rats. For this, several methods of radiolabeling have been developed, where the positron emitter (68Ga) was incorporated into the particle's core (co-precipitation approach) or onto the surface of the shell (either layer coating or adsorption approaches). According to the obtained data, radiochemical bounding and stability of 68Ga strongly depend on the used radiolabeling approach, and the co-precipitation method has shown the best radiochemical stability in human serum (96-98.5% for both types of core-shell particles). Finally, we demonstrate the size-dependent effect of core-shell particles' distribution on the specific organ uptake, using a combination of imaging techniques, PET, and computerized tomography (CT), as well as radiometry of separate organs. Thus, our findings open up new perspectives of CaCO3-radiolabeled core-shell particles for their further implementation into clinical practice.

Tetrabutylammonium tosylate as inert phase-transfer catalyst: The key to high efficiency SN2 radiofluorinations.

Here we describe use of the tetrabutylammonium p-toluenesulfonate (TBAOTs) as an inert phase transfer catalyst allowing high efficient aliphatic radiofluorination of labeling precursors for the preparation of common radiotracers using only 0.2-1.2 mg of the substrates. With operational convenience (no need for azeotropic drying) and compatibility with the common types of strong anion-exchange cartridges (QMA), this method has a high potential for routine application in various automated synthesizers and offers significant costs reductions due to less precursors used.

Use of capillary electrophoresis for the determination of impurities in preparations of fluorine-18 labelled PET radiopharmaceuticals.

Fluorine-18 labelled radiotracers are the most common diagnostic agents employed in positron emission tomography (PET). Despite well-established quality control (QC) procedures, introduction of new synthetic methods demands continuous development of analytical methodology. Here we propose capillary electrophoresis (CE) as a simple, fast and cost-efficient analytical method, allowing for the evaluation of potentially toxic impurities, including transition metals, in the formulated preparations. Method developed was applied in routine QC procedures for several clinically relevant radiotracers.