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Tatiana A Slastnikova,1,* Andrey A Rosenkranz,1,2,* Natalia B Morozova,3 Maria S Vorontsova,3 Vasiliy M Petriev,4,5 Tatiana N Lupanova,1 Alexey V Ulasov,1 Michael R Zalutsky,6 Raisa I Yakubovskaya,3 Alexander S Sobolev1,2 1Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 2Department of Biophysics, Biological Faculty, Lomonosov Moscow State University, 3Department of Anticancer Therapy Modifiers and Protectors, Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, Moscow, 4National Medical Research Radiological Center, Russian Ministry of Health Care, Obninsk, Moscow Region, 5Department of Nuclear Medicine, National Research Nuclear University MEPhI (Moscow Engineering Physics Institute), Moscow, Russia; 6Department of Radiology, Duke University Medical Center, Durham, NC, USA *These authors contributed equally to this work Purpose: Modular nanotransporters (MNTs) are a polyfunctional platform designed to achieve receptor-specific delivery of short-range therapeutics into the cell nucleus by receptor-mediated endocytosis, endosome escape, and targeted nuclear transport. This study evaluated the potential utility of the MNT platform in tandem with Auger electron emitting 111In for cancer therapy.Methods: Three MNTs developed to target either melanocortin receptor-1 (MC1R), folate receptor (FR), or epidermal growth factor receptor (EGFR) that are overexpressed on cancer cells were modified with p-SCN-Bn-NOTA and then labeled with 111In in high specific activity. Cytotoxicity of the 111In-labeled MNTs was evaluated on cancer cell lines bearing the appropriate receptor target (FR: HeLa, SK-OV-3; EGFR: A431, U87MG.wtEGFR; and MC1R: B16-F1). In vivo micro-single-photon emission computed tomography/computed tomography imaging and antitumor efficacy studies were performed with intratumoral injection of MC1R-targeted 111In-labeled MNT in B16-F1 melanoma tumor-bearing mice.Results: The three NOTA-MNT conjugates were labeled with a specific activity of 2.7 GBq/mg with nearly 100% yield, allowing use without subsequent purification. The cytotoxicity of 111In delivered by these MNTs was greatly enhanced on receptor-expressing cancer cells compared with 111In nontargeted control. In mice with B16-F1 tumors, prolonged retention of 111In by serial imaging and significant tumor growth delay (82% growth inhibition) were found.Conclusion: The specific in vitro cytotoxicity, prolonged tumor retention, and therapeutic efficacy of MC1R-targeted 111In-NOTA–MNT suggest that this Auger electron emitting conjugate warrants further evaluation as a locally delivered radiotherapeutic, such as for ocular melanoma brachytherapy. Moreover, the high cytotoxicity observed with FR- and EGFR-targeted 111In-NOTA–MNT suggests further applications of the MNT delivery strategy should be explored. Keywords: nuclear delivery, cancer, melanoma, radionuclide therapy, Auger electrons

Nuclear medicine presents one of the most promising modalities for efficient non-invasive treatment of a variety of cancers, but the application of radionuclides in cancer therapy and diagnostics is severely limited by their nonspecific tissue accumulation and poor biocompatibility. Here, we explore the use of nanosized metal-organic frameworks (MOFs) as carriers of radionuclides to order to improve their delivery to tumour. To demonstrate the concept, we prepared polymer-coated MIL-101(Cr)-NH 2 MOFs and conjugated them with clinically utilized radionuclide 188 Re. The nanoparticles demonstrated high loading efficacy of radionuclide reaching specific activity of 49 MBq mg -1 . Pharmacokinetics of loaded MOFs was investigated in mice bearing colon adenocarcinoma. The biological half-life of the radionuclide in blood was (20.9 ± 1.3) h, and nanoparticles enabled it to passively accumulate and retain in the tumour. The radionuclide delivery with MOFs led to a significant decrease of radioactivity uptake by the thyroid gland and stomach as compared with perrhenate salt injection, which is beneficial for reducing the side toxicity of nuclear therapy. The reported data on the functionalization and pharmacokinetics of MIL-101(Cr)-NH 2 for radionuclide delivery unveils the promising potential of these MOFs for nuclear medicine., (© 2023 IOP Publishing Ltd.)

The aim of this study was to verify the applicability of high-concentration collagen-based bioink with MSC (ADSC) and decellularized ECM granules for the formation of cartilage tissue de novo after subcutaneous implantation of the scaffolds in rats. The printability of the bioink (4% collagen, 2.5% decellularized ECM granules, derived via 280 μm sieve) was shown. Three collagen-based compositions were studied: (1) with ECM; (2) with MSC; (3) with ECM and MSC. It has been established that decellularized ECM granules are able to stimulate chondrogenesis both in cell-free and MSC-laden scaffolds. Undesirable effects have been identified: bone formation as well as cartilage formation outside of the scaffold area. The key perspectives and limitations of ECM granules (powder) application have been discussed.

We studied the biodistribution of 68 Ga-NODA-aminoglucose ( 68 Ga-NODA-AG) in normal mice and mice with experimental model of colon adenocarcinoma tumor. It was shown that 68 Ga-NODA-aminoglucose was retained in the tumor for 3 h after injection and demonstrated high level of accumulation in the tumor. Rapid clearance of radioactivity from other organs was observed. The results suggest that 68 Ga-NODA-aminoglucose is a promising agent for tumor visualization by positron emission tomography.

We analyzed biodistribution of 68 Ga-labeled hydroxyethylidenediphosphonic acid ( 68 Ga-HEDP) and diethylenetriaminepentakis(methylenephosphonic acid) ( 68 Ga-DTPMP) in Wistar rats with experimental model of bone callus. It was shown that the content of 68 Ga-DTPMP and 68 Ga-HEDP in bone callus was ~1.5-fold higher than in intact femur. 68 Ga-DTPMP was characterized by higher stability in vivo, higher uptake in the bone tissue, and lower uptake in others visceral organs in comparison with 68 Ga-HEDP. Thus, 68 Ga-DTPMP had more suitable pharmacokinetic properties than 68 Ga-HEDP.

We investigate biodistribution of gallium-labeled hydroxyethylidenediphosphonic acid ( 68 Ga-HEDP) and diethylenetriaminepentakis(methylenephosphonic acid) ( 68 Ga-DTPMP) in intact Wistar rats. It was shown that 68 Ga-DTPMP accumulated mainly in the bone tissue providing high femur/blood and femur/muscle ratios and had high stability in vivo. In contrast, 68 Ga-HEDP was characterized by low stability and high uptake of radioactivity in blood throughout the study. So 68 Ga-DTPMP can be considered as a new prospective radiotracer in oncology for imaging bone tissue metastasis by positron emission tomography.

Nuclear nanomedicine, with its targeting ability and heavily loading capacity, along with its enhanced retention to avoid rapid clearance as faced with molecular radiopharmaceuticals, provides unique opportunities to treat tumors and metastasis. Despite these promises, this field has seen limited activities, primarily because of a lack of suitable nanocarriers, which are safe, excretable and have favorable pharmacokinetics to efficiently deliver and retain radionuclides in a tumor. Here, we introduce biodegradable laser-synthesized Si nanoparticles having round shape, controllable low-dispersion size, and being free of any toxic impurities, as highly suitable carriers of therapeutic 188 Re radionuclide. The conjugation of the polyethylene glycol-coated Si nanoparticles with radioactive 188 Re takes merely 1 hour, compared to its half-life of 17 hours. When intravenously administered in a Wistar rat model, the conjugates demonstrate free circulation in the blood stream to reach all organs and target tumors, which is radically in contrast with that of the 188 Re salt that mostly accumulates in the thyroid gland. We also show that the nanoparticles ensure excellent retention of 188 Re in tumor, not possible with the salt, which enables one to maximize the therapeutic effect, as well as exhibit a complete time-delayed conjugate bioelimination. Finally, our tests on rat survival demonstrate excellent therapeutic effect (72% survival compared to 0% of the control group). Combined with a series of imaging and therapeutic functionalities based on unique intrinsic properties of Si nanoparticles, the proposed biodegradable complex promises a major advancement in nuclear nanomedicine.

Gamma-ray emitting 111 In, which is extensively used for imaging, is also a source of short-range Auger electrons (AE). While exhibiting negligible effect outside cells, these AE become highly toxic near DNA within the cell nucleus. Therefore, these radionuclides can be used as a therapeutic anticancer agent if delivered precisely into the nuclei of tumor target cells. Modular nanotransporters (MNTs) designed to provide receptor-targeted delivery of short-range therapeutic cargoes into the nuclei of target cells are perspective candidates for specific intracellular delivery of AE emitters. The objective of this study was to evaluate the in vitro and in vivo efficacy of 111 In attached MNTs to kill human bladder cancer cells overexpressing epidermal growth factor receptor (EGFR). The cytotoxicity of 111 In delivered by the EGFR-targeted MNT ( 111 In-MNT) was greatly enhanced on EJ-, HT-1376-, and 5637-expressing EGFR bladder cancer cell lines compared with 111 In non-targeted control. In vivo microSPECT/CT imaging and antitumor efficacy studies revealed prolonged intratumoral retention of 111 In-MNT with t ½ = 4.1 ± 0.5 days as well as significant dose-dependent tumor growth delay (up to 90% growth inhibition) after local infusion of 111 In-MNT in EJ xenograft-bearing mice.

Purpose: Modular nanotransporters (MNTs) are a polyfunctional platform designed to achieve receptor-specific delivery of short-range therapeutics into the cell nucleus by receptor-mediated endocytosis, endosome escape, and targeted nuclear transport. This study evaluated the potential utility of the MNT platform in tandem with Auger electron emitting 111 In for cancer therapy., Methods: Three MNTs developed to target either melanocortin receptor-1 (MC1R), folate receptor (FR), or epidermal growth factor receptor (EGFR) that are overexpressed on cancer cells were modified with p-SCN-Bn-NOTA and then labeled with 111 In in high specific activity. Cytotoxicity of the 111 In-labeled MNTs was evaluated on cancer cell lines bearing the appropriate receptor target (FR: HeLa, SK-OV-3; EGFR: A431, U87MG.wtEGFR; and MC1R: B16-F1). In vivo micro-single-photon emission computed tomography/computed tomography imaging and antitumor efficacy studies were performed with intratumoral injection of MC1R-targeted 111 In-labeled MNT in B16-F1 melanoma tumor-bearing mice., Results: The three NOTA-MNT conjugates were labeled with a specific activity of 2.7 GBq/mg with nearly 100% yield, allowing use without subsequent purification. The cytotoxicity of 111 In delivered by these MNTs was greatly enhanced on receptor-expressing cancer cells compared with 111 In nontargeted control. In mice with B16-F1 tumors, prolonged retention of 111 In by serial imaging and significant tumor growth delay (82% growth inhibition) were found., Conclusion: The specific in vitro cytotoxicity, prolonged tumor retention, and therapeutic efficacy of MC1R-targeted 111 In-NOTA-MNT suggest that this Auger electron emitting conjugate warrants further evaluation as a locally delivered radiotherapeutic, such as for ocular melanoma brachytherapy. Moreover, the high cytotoxicity observed with FR- and EGFR-targeted 111 In-NOTA-MNT suggests further applications of the MNT delivery strategy should be explored., Competing Interests: The authors report no conflicts of interest in this work.

About 10.7% cases of prostate cancer were registered in Russia in 2011 (40,000 patients). More than half of cancer cases were revealed in advanced (III-IV) stages when metastases inevitably developed quickly. Clinical problem of early diagnostics and treatment of metastatic prostate cancer is still not solved. Anatomical imaging techniques have low sensitivity and specificity for the detection of this disease. Metabolic visualization methods which use prostate specific antigen (PSA) as a marker are also ineffective. This article describes prostate-specific membrane antigens (PSMA) that are proposed as a marker for diagnostics and therapy of prostate cancer. The most promising PSMA-based radiopharmaceutical agent for diagnostics has been developed and clinically tested in the European countries. These pharmaceuticals are based on small peptide molecules modified with urea, and have the highest affinity to PSMA. Favorable phannacokinetics, rapid accumulation in the tumor and rapid excretion from the body are beneficial features of these pharmaceuticals.

Results of the study of absorbed dose formed in organs and tissues of mice after administration of new therapeutic radiopharmaceutical on the base of 103Pd and albumin microspheres (MSA) are presented. Pharmacokinetic parameters of preparation distribution in the body of animals were experimentally determined and then absorbed doses were calculated using MCNP code for the developed mathematical model of mouse. It was shown that absorption of 103Pd-MSA in tumor, physical properties of 103Pd and daughter radionuclide 103mRh provide a targeted irradiation of tumor as compared with the adjusting tissues and critical organs. In administration to tumor muscle tissue of the leg of experimental animals after 15 days following the injection of 103Pd-MSA the accumulated absorbed dose was 15 times less than corresponding one in tumor. In a critical organ (kidneys) the accumulated absorbed dose was 20 times less than in tumor. The work performed as a stage of pre-clinical testing of the radiopharmaceutical.

The effects of whole-body gamma-irradiation in different doses on the distribution of (188)Re-labeled mesenchymal stem cells obtained by culturing of the rat bone marrow cells were studied in different organs and tissues of animals after intravenous (systemic) injection. Irradiation stimulated homing of (188)Re-labeled mesenchymal stem cells in organs and tissues of animals in comparison with this process in intact non-irradiated rats. The intensity of homing increased with increasing the irradiation dose and decreased with prolongation of the period between irradiation and systemic transplantation. It was hypothesized that increased migration of transplanted mesenchymal stem cells into irradiated organs and tissues can be caused by developing cell death processes. It seems that systemic transplantation of mesenchymal stem cells shortly after irradiation can be used for stimulation of reparative processes in damaged tissues.

Intraarterial selective injection of serum albumin microspheres into the kidney resulted in embolization of the vessels with microspheres of different sizes. In vivo radiometry made it possible to improve the localization of microspheres and their distribution in the animals' bodies at varying time of observation. Pathomorphological investigations showed optimum sizes of microspheres causing prolonged retention of microparticles at the site of injection without considerable morphological changes of body tissues. The method of using microspheres as a radionuclide carrier was shown to hold promise for therapeutic purposes.

Distribution of 57Co-bleomycin was studied in mice with Lewis carcinoma implanted into different parts of the body. It was found that organ distribution of the labeled antibiotic did not depend on the tumor localization. The accumulation level of 57Co-bleomycin in Lewis carcinoma implanted subcutaneously into the pad foot was 3 times higher than that in the healthy pad. Resection of the primary tumor stimulated metastasis to the lungs resulting in relatively selective accumulation of the antibiotic in the lungs. The levels of 57Co-bleomycin in the lungs the main part of which was affected with metastases were 3--7 times higher than the respective control values.

Distribution of 57Co-bleomycetin in organs and tissues of rats with experimental short-term hyperglycemia was studied. Hyperglycemia was induced by intraperitoneal administration of 40 per cent glucose solution in doses of 1 to 10.4 g/kg. The labeled antitumor antibiotic was also administered intraperitoneally (0.2-0.8 MBq per animal). The data on both the external radiometry in the area under the animal limb and the radiometry of separate organs and tissues showed that hyperglycemia markedly altered pharmacokinetics of the labeled antibiotic and retarded its elimination. With respect to the lungs it even increased the drug tropism and accumulation. This information may be useful in radionuclide diagnosis and therapy in particular of lung cancer. The time course of glucose concentration in blood was not an adequate criterion of hyperglycemia influence since the influence of hyperglycemia on retarding the drug elimination was also observed when the level of glucose in blood did not differ from the initial one.

The effect of 57Co-bleomycin on the immune response induced by sheep red cells was studied on mice. It was found that the immune response was not suppressed when the labeled antibiotic was used in a single dose of 5-20 mg/kg. By the 5th day the level of 57Co-bleomycin in the skin, thymus and blood was 3-10 times higher than that of 57CoCl2 and in the spleen it was 1.3-1.5 times higher.

Pharmacokinetics of 57Co-bleomycetin was studied on mice with lymphosarcoma LIO-1. It was found that at early periods of intravenous administration of the labeled antibiotic, i.e. within the period from 5 minutes to 1 hour its higher levels are detected in the liver, kidneys, blood serum, lungs, intestine and tumor. At later periods the drug levels in the organs and tissues gradually decrease and by the 72nd hour the concentration of 57Co-bleomycetin in the blood serum appears to be 30 times lower as that after 5 minutes. In the muscles and tumor its concentrations by that period are 15 and 2 times lower respectively. Radiometry of the animals showed that within the first 24 hours more than 85 per cent of 57Co-bleomycetin was excreted from the mice.

The authors presented the results of experiments on 14 random bred dogs in whom fragmentary osteotomy of the maxilla at the level of 7 perpendicular 7 teeth was performed with subsequent investigation of the volumetric blood flow rate in soft and osseous tissues of the osteotomized fragment using labeled albumin microspheres. The animals were divided into 4 groups (the study group and control groups). The volumetric blood flow rate was investigated over time with the monitoring of the CV system 1 (the 2nd group), 6 (the 3rd group) and 24 h (the 4th group) after operation. The total reduction of the blood flow in the tissues of the osteotomized fragment as compared to that of the control group was 54.5% (in the 1st group), 39.3% (in the 2nd group) and 41% (in the 3rd group). The results of the study showed correlation between the blood flow rate reduction in the soft tissue structures and osseous tissue.

Experimental studies on rats with sarcoma 45 showed that antitumor efficacy of bleomycetin could be markedly increased by inducing short-term hyperglycemia. It was noted that the theoretical value of the additive effect of these factors was lower than the experimental one. This is in favour of the synergistic mechanism of bleomycetin action under conditions of hyperglycemia.