Radiopharmaceuticals Research Articles

Nanoparticulate formulations of radiopharmaceuticals: Strategy to improve targeting and biodistribution properties.

Application of nanotechnology principles in drug delivery has created opportunities for treatment of several diseases. Nanotechnology offers the advantage of overcoming the adverse biopharmaceutics or pharmacokinetic properties of drug molecules, to be determined by the transport properties of the particles themselves. Through the manipulation of size, shape, charge, and type of nanoparticle delivery system, variety of distribution profiles may be obtained. However, there still exists greater need to derive and standardize definitive structure property relationships for the distribution profiles of the delivery system. When applied to radiopharmaceuticals, the delivery systems assume greater significance. For the safety and efficacy of both diagnostics and therapeutic radiopharmaceuticals, selective localization in target tissue is even more important. At the same time, the synthesis and fabrication reactions of radiolabelled nanoparticles need to be completed in much shorter time. Moreover, the extensive understanding of the several interesting optical and magnetic properties of materials in nanoscale provides for achieving multiple objectives in nuclear medicine. This review discusses the various nanoparticle systems, which are applied for radionuclides and analyses the important bottlenecks that are required to be overcome for their more widespread clinical adaptation.

Room construction and installation of integrated PET/MR

The integrated PET/MR overcomes the problem of interferences between PET and the strong magnetic field of MRI, realizing the simultaneous acquisition of two modalities, which is a milestone in the field of medical imaging. The use of PET/MR requires the radiopharmaceutical as well as avoids interferences to the homogeneity of main magnetic field and stability of radio-frequency field from surrounding environment. Therefore, the site selection and layout design about integrated PET/MR are more complicated than the single mode system, and the results of installation and debugging should satisfy two imaging modalities (imaging quality and quantitative accuracy). In this paper, the room construction, installation and debugging of integrated PET/MR are discussed, which can supply a reference about key issues in the construction of similar projects. Key words: Facility Design and Construction; Tomography, emission-computed; Magnetic resonance imaging

Toward the Discovery and Development of PSMA Targeted Inhibitors for Nuclear Medicine Applications.

Background: The rising incidence rate of prostate cancer (PCa) has promoted the development of new diagnostic and therapeutic radiopharmaceuticals during the last decades. Promising improvements have been achieved in clinical practice using prostate specific membrane antigen (PSMA) labeled agents, including specific antibodies and small molecular weight inhibitors. Focusing on molecular docking studies, this review aims to highlight the progress in the design of PSMA targeted agents for a potential use in nuclear medicine.Results: Although the first development of radiopharmaceuticals able to specifically recognize PSMA was exclusively oriented to macromolecule protein structure such as radiolabeled monoclonal antibodies and derivatives, the isolation of the crystal structure of PSMA served as the trigger for the synthesis and the further evaluation of a variety of low molecular weight inhibitors. Among the nuclear imaging probes and radiotherapeutics that have been developed and tested till today, labeled Glutamate-ureido inhibitors are the most prevalent PSMA-targeting agents for nuclear medicine applications.Conclusion: PSMA represents for researchers the most attractive target for the detection and treatment of patients affected by PCa using nuclear medicine modalities. [99mTc]MIP-1404 is considered the tracer of choice for SPECT imaging and [68Ga]PSMA-11 is the leading diagnostic for PET imaging by general consensus. [18F]DCFPyL and [18F]PSMA-1007 are clearly the emerging PET PSMA candidates for their great potential for a widespread commercial distribution. After paving the way with new imaging tools, academic and industrial R&Ds are now focusing on the development of PSMA inhibitors labeled with alpha or beta minus emitters for a theragnostic application.

Comparative studies on the potential use of 177Lu-based radiopharmaceuticals for the palliative therapy of bone metastases

Purpose: In recent years, radionuclides like 177Lu have been considered promising material for the creation of therapeutic radiopharmaceuticals. With the therapeutic use of radiopharmaceuticals, the absorbed doses per tumor may exceed 10 Gy. It is extremely important that doses absorbed by healthy organs and tissues do not exceed the threshold for the incidence of deterministic effects.Materials and methods: The potential use of the radionuclide lutetium-177 for the palliative treatment of pain in bone metastases is analyzed. The radionuclide 177Lu is a beta-emitting nuclide with a maximal energy of 0.49 MeV and a half-life of 6.6 days (161 h). Two therapeutic agents were considered: methylene diphosphonate (MDP) and ethylenediamine tetramethylene phosphonic acid (EDTMP). Both drugs contain phosphorus compounds in their composition, which ensures high tropism in bone tissue. For both drugs, biokinetic models of 177Lu’s behavior in the human body are created. A number of studies have shown that the radiochemical stability of these drugs is about 99%: these calculations took into account the presence of a free 177Lu radionuclide in each solution. The absorbed doses in organs and tissues when using the radiopharmaceuticals 177Lu-MDP and 177Lu-EDTMP, as well as the currently used drugs 153Sm-EDTMP and 89SrCl2, are compared. In order to assess the risk of the patient’s exposure to a radiopharmaceutical, the absorbed doses are calculated for each organ where the radioactive label is mainly deposited: the kidneys, red bone marrow, liver and bone surface.Results: The intensity of dose accumulation when using different drugs on the pathological focus is different. The drug 177Lu-MDP is faster than other drugs when it comes to the full realization of the expected dose; therefore, a therapeutic effect is achieved faster when it is used. The slowest absorbed dose accumulates when strontium chloride is used. To compare the effectiveness of preparations based on the 177Lu radionuclide, an analysis of the radiopharmaceuticals currently used for the palliative therapy of bone metastases (89SrCl2 and 153Sm-EDTMP) was performed. For 89Sr, the most vulnerable organs are the kidneys, red bone marrow and liver, while for 153Sm-EDTMP, red marrow bone is most vulnerable. For radiopharmaceuticals based on the 177Lu radionuclide, the most vulnerable organs are the kidneys, liver and red bone marrow. This proves the effectiveness of the 177Lu-MDP and 177Lu-EDTMP radiopharmaceuticals.Conclusions: According to the results of the calculations, 177Lu-EDTMP and 177Lu-MDP demonstrate the best results for the palliative therapy of bone metastases.

Oral Administration of 99mTechnetium-Labeled Heparin in Eosinophilic Esophagitis

ObjectiveTo determine if heparin labeled with 99mTechnetium (99mTc) could be an imaging probe to detect eosinophil-related inflammation in eosinophilic esophagitis and to determine the biodistribution and radiation dosimetry of 99mTc-heparin oral administration using image-based dosimetry models with esophageal modeling. MethodsFreshly prepared 99mTc-heparin was administered orally to 5 research subjects. Radioactivity was measured by whole-body scintigraphy and single-photon emission computed tomography during the 24 hours postadministration. Following imaging, endoscopic examination was performed. The biodistribution of esophageal radioactivity was compared with endoscopic findings, eosinophil counts in biopsy tissues, and immunostaining for eosinophil granule major basic protein-1 (eMBP1). These studies were conducted from July 1, 2013, until April 22, 2017. ResultsOral administration of 99mTc-heparin was well tolerated in all 5 subjects. The entire esophagus could be visualized dynamically during oral administration. Bound esophageal radioactivity marked areas of inflammation as judged by endoscopy scores, by eosinophils per high power field and by localization of eMBP1 using immunostaining. Ninety percent of the radioactivity did not bind to the esophagus and passed through the gastrointestinal tract. ConclusionThe biodistribution of ingested 99mTc-heparin is almost exclusively localized to the gastrointestinal tract. Radiation exposure was highest in the lower gastrointestinal tract and was comparable with other orally administered diagnostic radiopharmaceuticals. The use of swallowed 99mTc-heparin may aid in assessing eosinophil-related inflammation in the esophagus.

Synthesis and properties of Cu- and Pd-complexes of cyclen conjugates with pheophorbide and bacteriopheophorbide

Objectives. Chlorin and bacteriochlorin photosensitizers are effective agents for cancer photodynamic therapy and fluorescence imaging. They are also excellent chelators forming stable metal complexes. Besides, 64 Cu and 109 Pd isotopes can serve as emitters for nuclear medicine. Chelation of these metals with cyclen conjugates with chlorin and bacteriochlorin photosensitizers can become a simple and universal strategy for the synthesis of diagnostic and therapeutic radiopharmaceuticals for nuclear medicine. This article reports on the synthesis of similar Cu and Pd complexes of cyclen conjugates with pheophorbide and bacteriopheophorbide and the study of their photophysical properties. Methods. Metalation of cyclen conjugates was carried out with palladium and copper acetates. For bacteriochlorins, 6-O-palmitoyl-L-ascorbic acid was additionally used as a reducing agent. MALDI mass spectrometry, which was carried out on a time-of-flight mass spectrometer Bruker Ultraflex TPF/TOF and a Bruker Daltonics Autoflex II confirmed the structure of the compounds obtained Electronic absorption spectra were obtained on a Shimadzu 3101 spectrophotometer. Fluorescence and phosphorescence spectra were obtained on a FluoTime 300 PicoQuant spectrofluorometer. Results. Photophysical studies of metal complexes showed that the introduction of palladium cations quenches fluorescence and increases the quantum yield of singlet oxygen generation to 0.98 for the chlorin conjugate. Besides, it decreases the quantum yield of fluorescence to 0.10 and increases the quantum yield of singlet oxygen generation to 0.72 for the bacteriochlorin conjugate. Introducing a copper cation to cyclen conjugates with pheophorbide and bacteriopheophorbide leads to photophysical characteristics quenching. Conclusions. Due to the stability of the synthesized metal complexes in acidic media, as well as the short metalation time (5, 20, 10, and 15 minutes) it is reasonable to expect the successful development of effective imaging agents for positron emission tomography and radionuclide therapy. In addition, the residual fluorescence of bacteriochlorins makes it possible to use fluorescence diagnostics in combination with these methods.

A microdosimetry model of kidney by GATE Monte Carlo simulation using a nonuniform activity distribution in digital phantom of nephron.

As the main pathway for the clearance of radiopharmaceutical from the body, kidney is a dose-limiting organ in medical application of radionuclides. Because of its unique physiology, radioactivity is seen to concentrate on kidney nonuniformly. This nonuniformity can be considered in nephron microstructures. A microdosimetry model of kidney is necessary to include the nonuniform distribution in internal radiation dosimetry. Implementing the microdosimetry model requires, first, a geometry phantom of nephrons. Stylized phantoms cannot distribute activities inside nephron compartments nonuniformly. A phantom of nephron was generated by a preliminary three-dimensional graphic model and was converted to a proper format of digital phantom. The phantom was fed to GATE Monte Carlo toolkits. Simulations were performed and S-values for five radionuclides (Tc-99m, In-111, Lu-177, Ac-225 and Bi-212) were calculated and compared with corresponding results published in the literature derived with a stylized phantom of nephron. Activity was distributed nonuniformly according to the kinetics of two mainly used diagnostic tracers (diethylenetriaminepetaacetate and ethylenedicysteine) and absorbed dose of nephron cells were calculated. A good correlation was shown between the generated phantom microdosimetry model and stylized model and revealed the phantom can be used for future microdosimetry studies of kidney to evaluate radiobiological effects of internal radiation from various diagnostic and therapeutic radiopharmaceuticals. Absorbed dose of cells for nonuniform distribution showed that some cells in a nephron compartment receive higher dose than (more than two-fold) that of compartment average dose. Average dose of nephron is not a reliable parameter for nephrotoxicity evaluation.

Full report on a survey of adverse reactions to radiopharmaceuticals from 1975 to 2017 in Japan.

This pharmacovigilance-based survey was aimed at determining the prevalence of, and association between, radiopharmaceuticals and adverse reactions to radiopharmaceuticals from 1975 to 2017 in Japan. The Subcommittee for Safety Issues of Radiopharmaceuticals of the Japan Radioisotope Association's Medical Science and Pharmaceutical Committee mailed a form for reporting adverse reactions to radiopharmaceuticals to all institutes performing nuclear medicine examinations in Japan. This investigation included adverse reactions to diagnostic radiopharmaceuticals labeled with both single-photon- and positron-emitting radionuclides and therapeutic sodium iodide labeled with 131I. Each institute returned the reporting form to the subcommittee each time an adverse reaction occurred. Replies were obtained from 75% of the institutions. In total, 1099 adverse reactions were reported from 46,645,580 radiopharmaceutical administrations, giving a prevalence of 2.4 adverse reactions per 100,000 administrations (95% confidence interval 2.2-2.5). Adverse reactions were most frequently observed for 131I-iodomethylnorcholesterol (230.1/105 administrations), followed by 131I-HSA (76.3/105 administrations), 131I-sodium iodohippurate (31.2/105 administrations), and 99mTc-DTPA (12.0/105 administrations). Comparison of adverse reactions between before and after 1997 revealed that prevalence dropped from 3.7/105 administrations (95% confidence interval 3.5-4.1) to 1.5/105 administrations (95% confidence interval 1.4-1.6). During the study period, vasovagal reactions accounted for 50.3% of adverse reactions, fever for 7.5%, allergic reactions for 25.7%, and other for 16.5%; 3.7% of all adverse reactions were considered severe but none were lethal. A definite, probable, possible, less likely, and uncertain causal relationship with radiopharmaceuticals was observed in 13.1%, 33.7%, 39.9%, 6.2%, and 7.1% of adverse reactions, respectively. These results suggest that nuclear medicine staff must be aware of the possibility of adverse reactions from radiopharmaceuticals, despite their rarity.

Radiolabeled somatostatin analogues for the diagnosis and therapy of NETs: upcoming new strategies

Octreotide is the progenitor of the somatostatin analogues (SSA) family, which includes radiopharmaceuticals suitable for SPECT, PET and radionuclide therapy, within an effective theragnostic model. Nowadays, PET/CT performed using DOTA peptides radiolabeled with Gallium-68 is considered the best molecular imaging procedure in staging and restaging of neuroendocrine tumors (NETs), while new SSA are being successfully developed for Peptide Receptor Radionuclide Therapy (PRRT). Technological developments both in the area of PET and MRI are likely to open new avenues for the optimization of the diagnostic workup of NETs. The aim of this paper is to present an up-to-date overview of the role of diagnostic 68Ga-SSA/PET hybrid imaging with MRI or CT, for the workup of NETs, as well as the perspectives arising from the use of therapeutic SSA radiopharmaceuticals either alone or in combination with cold SSA. A literature review of the most relevant papers in the field of radiolabeled SSA used for diagnosis or therapy demonstrates that PET/MRI as compared to PET/CT has a slightly higher diagnostic accuracy in detecting liver metastases but a lower accuracy in detecting pulmonary secondary lesions. In the present scenario, PET/CT remains the most cost-effective choice, integrated with an abdominal MRI when needed. Concurrently with the growth of PRRT performed with Lutetium-177 or Yttrium-90 DOTA peptides, new strategies to improve the therapeutic outcome are being sought with combined treatments using radioactively labeled SSA along with cold SSA. Interesting perspectives are opened by the availability of PET/MRI and full digital PET/CT due to the improved detector sensitivity and spatial resolution. At the same time, new strategies will be sought based on the association of PRRT with old and/or newer oncologic therapeutic strategies, or on the use of radionuclide cocktails. An intriguing future can be envisaged due to the commercial availability of radiopharmaceuticals labeled with alpha emitting radionuclides, which may allow better results compared to beta-emitters, likely due to the bystander and/or abscopal effect.

Targeted Alpha Therapy with Thorium-227.

Targeted alpha therapy (TAT) can deliver high localized burden of radiation selectively to cancer cells as well as the tumor microenvironment, while minimizing toxicity to normal surrounding cell. Radium-223 (223Ra), the first-in-class α-emitter approved for bone metastatic castration-resistant prostate cancer has shown the ability to prolong patient survival. Targeted Thorium-227 (227Th) conjugates represent a new class of therapeutic radiopharmaceuticals for TAT. They are comprised of the α-emitter 227Th complexed to a chelator conjugated to a tumor-targeting monoclonal antibody. In this review, the authors will focus out interest on this therapeutic agent. In recent studies 227Th-labeled radioimmunoconjugates showed a relevant stability both in serum and vivo conditions with a significant antigen-dependent inhibition of cell growth. Unlike 223Ra, the parent radionuclide 227Th can form highly stable chelator complexes and is therefore amenable to targeted radioimmunotherapy. The authors discuss the future potential role of 227Th TAT in the treatment of several solid as well as hematologic malignancies.

The role of lymphoscintigraphy in the diagnosis of lymphedema

Introduction. Lymphedema is a chronic disease of the lymphatic system that often remains undiagnosed or poorly diagnosed and can lead to severe and disabling swelling of the extremities. The aim of this paper was to review the literature on lymphoscintigraphy as a nuclear medicine imaging technique in the diagnosis of lymphedema, as well as to present clinical cases where lymphoscintigraphy was performed due to edema of unknown origin. Material and Methods. A literature review was performed using PubMed and manual search. Additionally, characteristics of diagnostic radiopharmaceuticals, methodological aspects of lymphoscintigraphy and interpretation criteria used in our department were presented in two clinical cases. Results. Literature data analysis showed that in the diagnosis of lymphedema, lymphoscintigraphy is a reliable diagnostic method in evaluation of the functional capacity of the lymphatic system, with a sensitivity of up to 96% and a specificity of 100%. In the presented clinical cases, lymphoscintigraphy diagnosed functional dysfunction/ obstruction of the lymphatic pathways in the lower extremities. Conclusion. Lymphoscintigraphy is a safe and reliable method in the diagnostic algorithm of patients with lymphedema, also valuable in monitoring the condition after the applied therapeutic modalities.

Inclusion of Radiopharmaceuticals in the Indian Pharmacopeia: A Step Forward.

Pharmacopeia is the national collection of quality standards of pharmaceutical products. It is an important instrument for drug safety. The inclusion of radiopharmaceuticals (RPs) in the Indian Pharmacopeia is a step-in right direction as the adaptation of provision of pharmacopeia will reduce the unwanted adverse effects and ensure the effectiveness of RPs.

The main issues of quality assurance of radiopharmaceuticals

One of the prerequisites for successful application of nuclear medicine technologies is the production and clinical use of radiopharmaceuticals (RPs) of a reliably high quality. The aim of the review is to discuss specific properties of RPs, which stipulate specific approaches to their production (or preparation) and quality control. The decisive requirement for the management of RPs at all stages of their life cycle is the observance of the radiation safety rules and regulations. The paper considers the main approaches to assessing the risks of medical radiation exposure to patients and radiation protection of nuclear medicine staff. The choice of a particular quality parameter and the corresponding analytical procedure should be made taking into account the duration of the test, which, like the production time, should be comparable with the radionuclide half-life. The feasibility of the analytical procedure should also be taken into account, given the high radioactivity of the samples tested. Now that theranostics has caught on, new approaches are being developed all over the world concerning regulatory aspects of transition from preclinical studies of RPs to clinical trials, because, according to experts, this is becoming a key condition for rapid implementation of nuclear medicine achievements. The results and conclusions of the present study can be used in the development and expert review of monographs and other specifications required for RP marketing and use. The results of the analysis suggest that it is necessary to develop specific requirements and guidelines for RP testing and evaluation for their successful promotion on the EAEU market.

Targeted Alpha Therapy with anti-HER2 Thorium-227 Antibody-chelator Conjugates (HER2-TTCs) in Mouse Xenograft Models with Varying Levels of HER2 Expression and Resistance to Current State-of-the-art Therapies

Targeted thorium conjugates (TTCs) represent a new class of therapeutic radiopharmaceuticals for the targeted alpha therapy (TAT) of cancer. The human epidermal growth factor receptor 2 (HER2) is overexpressed in several cancers and is a validated target for the treatment of breast and gastric cancer, also serving as a prognostic and predictive biomarker. During treatment, many patients become resistant or are not eligible for these therapies, due to low expression levels of the target (∼55%). Therefore there exists a high unmet medical need for new drugs with alternative mechanisms of action targeting HER2. We describe an antibody conjugate capable of delivering thorium-227 (227Th) to cancer cells expressing the human epidermal growth factor receptor 2 (HER2). The preclinical pharmacological in vivo characterization of the HER2-TTC, with a focus on trastu¬zumab and T-DM1 (trastuzumab-DM1)-resistant and HER2 low expressing mouse xenograft models, are presented.

177Lu-PSMA-I&T automated radiolabeling and preclinical prostate cancer targeting research

Objective To synthesis 177Lu-prostate specific membrane antigen (PSMA)-I&T with automated module, evaluate the biodistribution and pharmacokinetics in mice and study the targeting property in human prostate cancer cell line LNCaP Clone FGC. Methods The iQS-TS automated module was applied in labeling 177Lu-PSMA-I&T. Radiochemical purity and stability were determined with high performance liquid chromatography (HPLC). The biodistribution was observed in normal ICR mice and U-SPECT/CT imaging was performed in LNCaP Clone FGC tumor-bearing mice. Independent-sample t test was used to analyze the data. Results 177Lu-PSMA-I&T was stable in vitro and in vivo, with the radiolabeled yield of (91.5±4.9)% and radiochemical purity >99%. The half maximal inhibitory concentration (IC50) of 177Lu-PSMA-I&T binding to LNCaP Clone FGC cells was (26.74±3.53) nmol/L. The uptake of 177Lu-PSMA-I&T by LNCaP Clone FGC cells increased with time and significantly decreased after the inhibitor addition (t values: 4.301-27.483, all P<0.05). 177Lu-PSMA-I&T was cleared from blood rapidly and predominantly excreted by kidneys. Significant radioactive uptake was observed in tumors with a long retention time. Conclusion 177Lu-PSMA-I&T can be produced in a convenient and efficient procedure using iQS-TS automated module, with good biological properties and excellent affinity and targeting property towards prostate cancer cells, which making it a potential radiopharmaceutical for prostate cancer therapy. Key words: Prostatic neoplasms; Prostate-specific membrane antigen; Isotope labeling; Lutetium; Chemical synthesis; Tumor cells, cultured; Mice, nude

Imaging DNA Damage Repair In Vivo After 177Lu-DOTATATE Therapy.

Molecular radiotherapy using 177Lu-DOTATATE is a most effective treatment for somatostatin receptor–expressing neuroendocrine tumors. Despite its frequent and successful use in the clinic, little or no radiobiologic considerations are made at the time of treatment planning or delivery. On positive uptake on octreotide-based PET/SPECT imaging, treatment is usually administered as a standard dose and number of cycles without adjustment for peptide uptake, dosimetry, or radiobiologic and DNA damage effects in the tumor. Here, we visualized and quantified the extent of DNA damage response after 177Lu-DOTATATE therapy using SPECT imaging with 111In-anti-γH2AX-TAT. This work was a proof-of-principle study of this in vivo noninvasive biodosimeter with β-emitting therapeutic radiopharmaceuticals. Methods: Six cell lines were exposed to external-beam radiotherapy (EBRT) or 177Lu-DOTATATE, after which the number of γH2AX foci and the clonogenic survival were measured. Mice bearing CA20948 somatostatin receptor–positive tumor xenografts were treated with 177Lu-DOTATATE or sham-treated and coinjected with 111In-anti-γH2AX-TAT, 111In-IgG-TAT control, or vehicle. Results: Clonogenic survival after external-beam radiotherapy was cell-line–specific, indicating varying levels of intrinsic radiosensitivity. Regarding in vitro cell lines treated with 177Lu-DOTATATE, clonogenic survival decreased and γH2AX foci increased for cells expressing high levels of somatostatin receptor subtype 2. Ex vivo measurements revealed a partial correlation between 177Lu-DOTATATE uptake and γH2AX focus induction between different regions of CA20948 xenograft tumors, suggesting that different parts of the tumor may react differentially to 177Lu-DOTATATE irradiation. Conclusion: 111In-anti-γH2AX-TAT allows monitoring of DNA damage after 177Lu-DOTATATE therapy and reveals heterogeneous damage responses.

Radiolabeling efficiency and stability study on Lutetium-177 labeled bombesin peptide

Bombesin is a 14-amino-acid peptide having the ability to specifically bind gastrin releasing peptide receptors (GRPR) which show over-expression in many types of cancer cells. Therefore, bombesin analogs have been complexed with radionuclides and reported as radiopharmaceuticals for cancer diagnosis and therapy. Lutetium-177 (Lu-177) is a beta emitting radionuclide that decays with a half-life of 6.65 days. The medium beta energy and the relatively long half-life of Lu-177 make it one of the ideal radionuclides used in targeted radionuclide therapy. As the oxidation state of this radioisotope is 3+, it requires multidentate chelators such as DOTA to form stable complex. In this work, the commercially available conjugated peptide, DOTA-[Pro1, Tyr4]-bombesin, was labeled with Lu-177 for preliminary formulation as a therapeutic radiopharmaceutical. The aim was to evaluate the radiolabeling efficiency using various amounts of the peptide and the stability in human serum for 7 days. The radiolabeling was performed in sterile water for injection with 5 mCi of Lu-177, adjusted to pH 5.5 to 6.0 by 0.5 M sodium acetate, and incubated at 100°C for 30 min. It was found that the radiochemical yield was more than 99% when using 20 µg of the peptide, and the complex was stable for a week. Moreover, human serum was used to simulate in vivo condition. The results showed high complex stability with more than 98% remaining intact after 7 days.

Изучение фармакокинетики нового радиофармацевтического препарата на основе меченной технецием-99m производной глюкозы

Purpose: To study the features of the distribution and removal of a new radiopharmaceutical (RPH) on the basis of a labeled 99mTc glucose derivative for radionuclide diagnostics of oncological diseases in the body of experimental animals.&#x0D; Material and methods: The main stage of the study was performed on 65 mature conventional outbred white rats and 9 rabbits of the Soviet Chinchilla breed. To study the dynamics of changes in the concentration of the studied RPH in the blood plasma and its distribution in the main organs and tissues, as well as to study the metabolic features of the drug and its excretion, the RPH studied was administered intravenously, once in activity of 20 MBq. Multiple introduction of the RPH was performed in order to study the cumulative properties of the study drug, and to elucidate the possibilities of predicting the cumulation processes from the data obtained with a single administration of RPH. For this purpose, intravenous RPH was administered at the same time 1 time / day for 5 days, at a dose of 20 MBq. To confirm the theory of linearity of the pharmacokinetics of the RFP studied, three groups of laboratory animals received the drug in three activity levels – 10, 20 and 40 MBq were used. After euthanasia, the animals were autopsied and removed the necessary organs and tissues. The prepared and washed organs were placed in tubes for further radiometry in order to study the concentrations of the RPH in the bioassay.&#x0D; Results: It has been established that the RPH being studied practically does not accumulate in the main organs and tissues, accumulating mainly in the kidneys and bladder. The main organs of elimination of the test drug are the kidneys, and the main excreta are urine. The half-life of the drug from the blood was 10 minutes. Pharmacokinetics of the drug is linear and does not depend on the administered activity, and the drug itself does not possess cumulative properties.&#x0D; Conclusion: A study of the pharmacokinetics of the RPH 99mTc-1-Thio-D-glucose showed that the preparation possesses optimal properties for the diagnostic agent. The drug stably does not accumulate in the main organs and tissues, which allows it to be reused, for example at the stages of dynamic observation of cancer patients.

Synergistic Effect of a HER2 Targeted Thorium-227 Conjugate in Combination with Olaparib in a BRCA2 Deficient Xenograft Model.

Targeted thorium-227 conjugates (TTCs) represent a novel class of therapeutic radiopharmaceuticals for the treatment of cancer. TTCs consist of the alpha particle emitter thorium-227 complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the alpha particles induce potent and selective anti-tumor activity driven by the induction of DNA damage in the target cell. Methods: The efficacy of human epidermal growth factor receptor 2 (HER2)-TTC was tested in combination in vitro and in vivo with the poly ADP ribose polymerase (PARP) inhibitor (PARPi), olaparib, in the human colorectal adenocarcinoma isogenic cell line pair DLD-1 and the knockout variant DLD-1 BRCA2 -/- Results: The in vitro combination effects were determined to be synergistic in DLD-1 BRCA2 -/- and additive in DLD-1 parental cell lines. Similarly, the in vivo efficacy of the combination was determined to be synergistic only in the DLD-1 BRCA2 -/- xenograft model, with statistically significant tumor growth inhibition at a single TTC dose of 120 kBq/kg body weight (bw) and 50 mg/kg bw olaparib (daily, i.p. for 4 weeks), demonstrating comparable tumor growth inhibition to a single TTC dose of 600 kBq/kg bw. Conclusions: This study supports the further investigation of DNA damage response inhibitors in combination with TTCs as a new strategy for the effective treatment of mutation-associated cancers.

Appraisement of 186/188Re-HEDP, a new compositional radiopharmaceutical

Undoubtedly radionuclide therapy is the next phase of nuclear medicine development. 188Re-HEDP and 186Re-HEDP are therapeutic radiopharmaceuticals which have been used to treat bone metastases. With regard to their complementary features, in this study, as new idea their combined effects have been investigated with preparing the cocktail of 188/186Re-HEDP with radiochemical purity nearly 99%. The 188/186Re-HEDP biodistribution was checked in rats’ tissues up to 72 h. The produced 188/186Re-HEDP properties suggest a new bone palliative radiopharmaceutical to overcome bone metastases.