RESUMO
Currently, targeted alpha therapy (TAT) is a new therapy involving the administration of a therapeutic drug that combines a substance of α-emitting nuclides that kill cancer cells and a drug that selectively accumulates in cancer cells. It is known to be effective against cancers that are difficult to treat with existing methods, such as cancer cells that are widely spread throughout the whole body, and there are high expectations for its early clinical implementation. The nuclides for TAT, including 149Tb, 211At, 212/213Bi, 212Pb (for 212Bi), 223Ra, 225Ac, 226/227Th, and 230U, are known. However, some nuclides encounter problems with labeling methods and lack sufficient preclinical and clinical data. We labeled the compounds targeting prostate specific membrane antigen (PSMA) with 211At and 225Ac. PSMA is a molecule that has attracted attention as a theranostic target for prostate cancer, and several targeted radioligands have already shown therapeutic effects in patients. The results showed that 211At, which has a much shorter half-life, is no less cytotoxic than 225Ac. In 211At labeling, our group has also developed an original method (Shirakami Reaction). We have succeeded in obtaining a highly purified labeled product in a short timeframe using this method.
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Antígeno Prostático Específico , Neoplasias da Próstata , Radioisótopos , Humanos , Masculino , Meia-Vida , Medicina Nuclear , Neoplasias da Próstata/tratamento farmacológico , Radioisótopos/uso terapêuticoRESUMO
Astatine (211At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the 211At-labeled prostate-specific membrane antigen (PSMA) compound ([211At]PSMA-5) exhibited excellent tumor growth suppression in a xenograft model. We conducted preclinical biodistribution and toxicity studies for the first-in-human clinical trial. [211At]PSMA-5 was administered to both normal male ICR mice (n = 85) and cynomolgus monkeys (n = 2). The mice were divided into four groups for the toxicity study: 5 MBq/kg, 12 MBq/kg, 35 MBq/kg, and vehicle control, with follow-ups at 1 day (n = 10 per group) and 14 days (n = 5 per group). Monkeys were observed 24 h post-administration of [211At]PSMA-5 (9 MBq/kg). Blood tests and histopathological examinations were performed at the end of the observation period. Blood tests in mice indicated no significant myelosuppression or renal dysfunction. However, the monkeys displayed mild leukopenia 24 h post-administration. Despite the high accumulation in the kidneys and thyroid, histological analysis revealed no abnormalities. On day 1, dose-dependent single-cell necrosis/apoptosis was observed in the salivary glands of mice and intestinal tracts of both mice and monkeys. Additionally, tingible body macrophages in the spleen and lymph nodes indicated phagocytosis of apoptotic B lymphocytes. Cortical lymphopenia (2/10) in the thymus and a decrease in the bone marrow cells (9/10) were observed in the 35 MBq/kg group in mice. These changes were transient, with no irreversible toxicity observed in mice 14 days post-administration. This study identified no severe toxicities associated with [211At]PSMA-5, highlighting its potential as a next-generation targeted alpha therapy for prostate cancer. The sustainable production of 211At using a cyclotron supports its applicability for clinical use.
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Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Partículas alfa/uso terapêutico , Astato/farmacocinética , Astato/química , Glutamato Carboxipeptidase II/metabolismo , Macaca fascicularis , Camundongos Endogâmicos ICR , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/química , Distribuição TecidualRESUMO
PURPOSE: Targeted α-therapy (TAT) for prostate-specific membrane antigen (PSMA) is a promising treatment for metastatic castration-resistant prostate cancer (CRPC). Astatine is an α-emitter (half-life=7.2 h) that can be produced by a 30-MeV cyclotron. This study evaluated the treatment effect of 211At-labeled PSMA compounds in mouse xenograft models. METHODS: Tumor xenograft models were established by subcutaneous transplantation of human prostate cancer cells (LNCaP) in NOD/SCID mouse. [211At]PSMA1, [211At]PSMA5, or [211At]PSMA6 was administered to LNCaP xenograft mice to evaluate biodistribution at 3 and 24 h. The treatment effect was evaluated by administering [211At]PSMA1 (0.40 ± 0.07 MBq), [211At]PSMA5 (0.39 ± 0.03 MBq), or saline. Histopathological evaluation was performed for the at-risk organs at 3 and 6 weeks after administration. RESULTS: [211At]PSMA5 resulted in higher tumor retention compared to [211At]PSMA1 and [211At]PSMA6 (30.6 ± 17.8, 12.4 ± 4.8, and 19.1 ± 4.5 %ID/g at 3 h versus 40.7 ± 2.6, 8.7 ± 3.5, and 18.1 ± 2.2%ID/g at 24 h, respectively), whereas kidney excretion was superior in [211At]PSMA1 compared to [211At]PSMA5 and [211At]PSMA6. An excellent treatment effect on tumor growth was observed after [211At]PSMA5 administration. [211At]PSMA1 also showed a substantial treatment effect; however, the tumor size was relatively larger compared to that with [211At]PSMA5. In the histopathological evaluation, regenerated tubules were detected in the kidneys at 3 and 6 weeks after the administration of [211At]PSMA5. CONCLUSION: TAT using [211At]PSMA5 resulted in excellent tumor growth suppression with minimal side effects in the normal organs. [211At]PSMA5 should be considered a new possible TAT for metastatic CRPC, and translational prospective trials are warranted.
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Astato , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Animais , Camundongos , Astato/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Distribuição Tecidual , Estudos Prospectivos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias da Próstata/patologia , Glutamato Carboxipeptidase II/metabolismo , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Compostos Radiofarmacêuticos/uso terapêuticoRESUMO
Targeted alpha therapy (TAT) has garnered significant interest as an innovative cancer therapy. Owing to their high energy and short range, achieving selective α-particle accumulation in target tumor cells is crucial for obtaining high potency without adverse effects. To meet this demand, we fabricated an innovative radiolabeled antibody, specifically designed to selectively deliver 211At (α-particle emitter) to the nuclei of cancer cells. The developed 211At-labeled antibody exhibited a superior effect compared to its conventional counterparts. This study paves the way for organelle-selective drug delivery.
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Neoplasias , Radioisótopos , Humanos , Radioisótopos/uso terapêutico , Sistemas de Liberação de Medicamentos , Núcleo Celular , Neoplasias/tratamento farmacológico , Neoplasias/radioterapiaRESUMO
Fibroblast activation proteins (FAP) are overexpressed in the tumor stroma and have received attention as target molecules for radionuclide therapy. The FAP inhibitor (FAPI) is used as a probe to deliver nuclides to cancer tissues. In this study, we designed and synthesized four novel 211At-FAPI(s) possessing polyethylene glycol (PEG) linkers between the FAP-targeting and 211At-attaching moieties. 211At-FAPI(s) and piperazine (PIP) linker FAPI exhibited distinct FAP selectivity and uptake in FAPII-overexpressing HEK293 cells and the lung cancer cell line A549. The complexity of the PEG linker did not significantly affect selectivity. The efficiencies of both linkers were almost the same. Comparing the two nuclides, 211At was superior to 131I in tumor accumulation. In the mouse model, the antitumor effects of the PEG and PIP linkers were almost the same. Most of the currently synthesized FAPI(s) contain PIP linkers; however, in our study, we found that PEG linkers exhibit equivalent performance. If the PIP linker is inconvenient, a PEG linker is expected to be an alternative.
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Fibroblastos , Polietilenoglicóis , Humanos , Animais , Camundongos , Células HEK293 , Piperazina/farmacologia , Polietilenoglicóis/farmacologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioisótopos de GálioRESUMO
PURPOSE: Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used 64Cu and 225Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter (177Lu)-labelled FAPI-46 and alpha-emitter (225Ac)-labelled FAPI-46 in pancreatic cancer models. METHODS: PET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [18F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [177Lu]FAPI-46 and [225Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [177Lu]FAPI-46 and [225Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq (n = 6), 10 MBq (n = 6), 30 MBq (n = 6), control (n = 4) for [177Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 6), control (n = 7) for [225Ac]FAPI-46. Tumour sizes and body weights were followed. RESULTS: [18F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [177Lu]FAPI-46 and [225Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [177Lu]FAPI-46 and [225Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [177Lu]FAPI-46 were relatively slow but lasted longer than those of [225Ac]FAPI-46. CONCLUSION: This study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly.
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Neoplasias Pancreáticas , Animais , Fibroblastos/patologia , Humanos , Camundongos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/radioterapia , Quinolinas , Compostos Radiofarmacêuticos , Distribuição TecidualRESUMO
This study confirmed the effect of sodium/iodine symporter (NIS) expression on existing drugs by in vitro and in vivo tests using cultured cell lines. The tumor growth inhibitory effect of sodium astatide ([211At]NaAt) was evaluated by in vitro and in vivo tests using human thyroid cancer cells (K1, K1/NIS and K1/NIS-DOX). NIS expression in cancer cells was controlled using the Tet-On system. [131I]NaI was used as control existing drug. From the results of the in vitro studies, the mechanism of [211At]NaAt uptake into thyroid cancer cells is mediated by NIS, analogous to [131I]NaI, and the cellular uptake rate correlates with the expression level of NIS. [211At]NaAt's ability to inhibit colony formation was more than 10 times that of [131I]NaI per becquerel (Bq), and [211At]NaAt's DNA double-strand breaking (DSB) induction was more than ten times that of [131I]NaI per Bq, and [211At]NaAt was more than three times more cytotoxic than [131I]NaI (at 1000 kBq each). In vivo studies also showed that the tumor growth inhibitory effect of [211At]NaAt depended on NIS expression and was more than six times that of [131I]NaI per Bq.
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Compostos de Iodo , Simportadores , Neoplasias da Glândula Tireoide , Humanos , Simportadores/genética , Simportadores/metabolismo , Radioisótopos do Iodo/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismoRESUMO
Recent introduction of alpha-emitting radionuclides in targeted radionuclide therapy has stimulated the development of new radiopharmaceuticals. Preclinical evaluation using an animal experiment with an implanted tumor model is frequently used to examine the efficiency of the treatment method and to predict the treatment response before clinical trials. Here, we propose a mathematical model for evaluation of the tumor response in an implanted tumor model and apply it to the data obtained from the previous experiment of 211At treatment in a thyroid cancer mouse model. The proposed model is based on the set of differential equations, describing the kinetics of radiopharmaceuticals, the tumor growth, and the treatment response. First, the tumor growth rate was estimated from the control data without injection of 211At. The kinetic behavior of the injected radionuclide was used to estimate the radiation dose profile to the target tumor, which can suppress the tumor growth in a dose-dependent manner. An additional two factors, including the time delay for the reduction of tumor volume and the impaired recovery of tumor regrowth after the treatment, were needed to simulate the temporal changes of tumor size after treatment. Finally, the parameters obtained from the simulated tumor growth curve were able to predict the tumor response in other experimental settings. The model can provide valuable information for planning the administration dose of radiopharmaceuticals in clinical trials, especially to determine the starting dose at which efficacy can be expected with a sufficient safety margin.
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Neoplasias , Compostos Radiofarmacêuticos , Camundongos , Animais , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias/radioterapia , Neoplasias/tratamento farmacológico , Radioisótopos/uso terapêutico , Modelos TeóricosRESUMO
Astatine (211At) is an alpha-emitter with a better treatment efficacy against differentiated thyroid cancer compared with iodine (131I), a conventional beta-emitter. However, its therapeutic comparison has not been fully evaluated. In this study, we compared the therapeutic effect between [211At]NaAt and [131I]NaI. In vitro analysis of a double-stranded DNA break (DSB) and colony formation assay were performed using K1-NIS cells. The therapeutic effect was compared using K1-NIS xenograft mice administered with [211At]NaAt (0.4 MBq (n = 7), 0.8 MBq (n = 9), and 1.2 MBq (n = 4)), and [131I]NaI (1 MBq (n = 4), 3 MBq (n = 4), and 8 MBq (n = 4)). The [211At]NaAt induced higher numbers of DSBs and had a more reduced colony formation than [131I]NaI. In K1-NIS mice, dose-dependent therapeutic effects were observed in both [211At]NaAt and [131I]NaI. In [211At]NaAt, a stronger tumour-growth suppression was observed, while tumour regrowth was not observed until 18, 25, and 46 days after injection of 0.4, 0.8, and 1.2 MBq of [211At]NaAt, respectively. While in [131I]NaI, this was observed within 12 days after injection (1, 3, and 8 MBq). The superior therapeutic effect of [211At]NaAt suggests the promising clinical applicability of targeted alpha therapy using [211At]NaAt in patients with differentiated thyroid cancer refractory to standard [131I]NaI treatment.
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Adenocarcinoma , Astato , Neoplasias da Glândula Tireoide , Adenocarcinoma/tratamento farmacológico , Animais , Astato/uso terapêutico , Humanos , Radioisótopos do Iodo/uso terapêutico , Camundongos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Transplante HeterólogoRESUMO
α-Methyl-l-tyrosine (AMT) has a high affinity for the cancer-specific l-type amino acid transporter 1 (LAT1). Therefore, we established an anti-cancer therapy, with 211 At-labeled α-methyl-l-tyrosine (211 At-AAMT) as a carrier of 211 At into tumors. 211 At-AAMT had high affinity for LAT1, inhibited tumor cell growth, and induced DNA double-stranded breaks in vitro. We evaluated the accumulation of 211 At-AAMT in vivo and the role of LAT1. Treatment with 0.4 MBq/mouse 211 At-AAMT inhibited tumor growth in the PANC-1 tumor model and 1 MBq/mouse 211 At-AAMT inhibited metastasis in the lung of the B16F10 metastasis model. Our results suggested that 211 At would be useful for anti-cancer therapy and that LAT1 is suitable as a target for radionuclide therapy.
Assuntos
Partículas alfa/uso terapêutico , Astato/administração & dosagem , Portadores de Fármacos/farmacologia , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Neoplasias/radioterapia , alfa-Metiltirosina/farmacologia , Animais , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Modelos Animais de Doenças , Estudos de Viabilidade , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Neoplasias/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: 211At is a high-energy α-ray emitter with a relatively short half-life and a high cytotoxicity for cancer cells. Its dispersion can be imaged using clinical scanners, and it can be produced in cyclotrons without the use of nuclear fuel material. This study investigated the biodistribution and the antitumor effect of 211At-labeled gold nanoparticles (211At-AuNP) administered intratumorally. RESULTS: AuNP with a diameter of 5, 13, 30, or 120 nm that had been modified with poly (ethylene glycol) methyl ether (mPEG) thiol and labeled with 211At (211At-AuNP-S-mPEG) were incubated with tumor cells, or intratumorally administered to C6 glioma or PANC-1 pancreatic cancers subcutaneously transplanted into rodent models. Systemic and intratumoral distributions of the particles in the rodents were then evaluated using scintigraphy and autoradiography, and the changes in tumor volumes were followed for about 40 days. 211At-AuNP-S-mPEG was cytotoxic when it was internalized by the tumor cells. After intratumoral administration, 211At-AuNP-S-mPEG became localized in the tumor and did not spread to systemic organs during a time period equivalent to 6 half-lives of 211At. Tumor growth was strongly suppressed for both C6 and PANC-1 by 211At-AuNP-S-mPEG. In the C6 glioma model, the strongest antitumor effect was observed in the group treated with 211At-AuNP-S-mPEG with a diameter of 5 nm. CONCLUSIONS: The intratumoral single administration of a simple nanoparticle, 211At-AuNP-S-mPEG, was shown to suppress the growth of tumor tissue strongly in a particle size-dependent manner without radiation exposure to other organs caused by systemic spread of the radionuclide.
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Astato/uso terapêutico , Ouro/uso terapêutico , Nanopartículas/química , Nanopartículas/uso terapêutico , Coloração e Rotulagem/métodos , Animais , Astato/química , Glioma , Ouro/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , Polietilenoglicóis , Cintilografia/métodos , Ratos , Distribuição TecidualRESUMO
We report the first ionization potentials (IP1) of the heavy actinides, fermium (Fm, atomic number Z = 100), mendelevium (Md, Z = 101), nobelium (No, Z = 102), and lawrencium (Lr, Z = 103), determined using a method based on a surface ionization process coupled to an online mass separation technique in an atom-at-a-time regime. The measured IP1 values agree well with those predicted by state-of-the-art relativistic calculations performed alongside the present measurements. Similar to the well-established behavior for the lanthanides, the IP1 values of the heavy actinides up to No increase with filling up the 5f orbital, while that of Lr is the lowest among the actinides. These results clearly demonstrate that the 5f orbital is fully filled at No with the [Rn]5f147s2 configuration and that Lr has a weakly bound electron outside the No core. In analogy to the lanthanide series, the present results unequivocally verify that the actinide series ends with Lr.
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BACKGROUND: L-type amino acid transporter 1 (LAT1) is overexpressed in various cancers; therefore, radiohalogen-labeled amino acid derivatives targeting LAT1 have emerged as promising candidates for cancer radiotheranostics. However, 211At-labeled amino acid derivatives exhibit instability against deastatination in vivo, making it challenging to use 211At for radiotherapy. In this study, radiohalogen-labeled amino acid derivatives with high dehalogenation stability were developed. RESULTS: We designed and synthesized new radiohalogen-labeled amino acid derivatives ([211At]At-NpGT, [125I]I-NpGT, and [18F]F-NpGT) in which L-tyrosine was introduced into the neopentyl glycol (NpG) structure. The radiolabeled amino acid derivatives were recognized as substrates of LAT1 in the in vitro studies using C6 glioma cells. In a biodistribution study using C6 glioma-bearing mice, these agents exhibited high stability against in vivo dehalogenation and similar biodistributions. The similarity of [211At]At-NpGT and [18F]F-NpGT indicated that these pairs of radiolabeled compounds would be helpful in radiotheranostics. Moreover, [211At]At-NpGT exhibited a dose-dependent inhibitory effect on the growth of C6 glioma-bearing mice. CONCLUSIONS: [211At]At-NpGT exhibited a dose-dependent inhibitory effect on the tumor growth of glioma-bearing mice, and its biodistribution was similar to that of other radiohalogen-labeled amino acid derivatives. These findings suggest that radiotheranostics using [18F]F-NpGT and [123/131I]I-NpGT for diagnostic applications and [211At]At-NpGT and [131I]I-NpGT for therapeutic applications are promising.
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BACKGROUND: The alpha emitter astatine-211 (211At) is garnering attention as a novel targeted alpha therapy for patients with refractory thyroid cancer resistant to conventional therapy using beta emitter radioiodine (131I). Herein, we aimed to establish a robust method for the manufacturing and quality control of [211At]NaAt solution for intravenous administration under the good manufacturing practice guidelines for investigational products to conduct an investigator-initiated clinical trial. RESULTS: 211At was separated and purified via dry distillation using irradiated Bi plates containing 211At obtained by the nuclear reaction of 209Bi(4He, 2n)211At. After purification, the 211At trapped in the cold trap was collected in a reaction vessel using 15 mL recovery solution (1% ascorbic acid and 2.3% sodium hydrogen carbonate). After stirring the 211At solution for 1 h inside a closed system, the reaction solution was passed through a sterile 0.22 µm filter placed in a Grade A controlled area and collected in a product vial to prepare the [211At]NaAt solution. According to the 3-lot tests, decay collected radioactivity and radiochemical yield of [211At]NaAt were 78.8 ± 6.0 MBq and 40 ± 3%, respectively. The radiochemical purity of [211At]At- obtained via ion-pair chromatography at the end of synthesis (EOS) was 97 ± 1%, and remained > 96% 6 h after EOS; it was detected at a retention time (RT) 3.2-3.3 min + RT of I-. LC-MS analysis indicated that this principal peak corresponded with an astatide ion (m/z = 210.988046). In gamma-ray spectrometry, the 211At-related peaks were identified (X-ray: 76.9, 79.3, 89.3, 89.8, and 92.3 keV; γ-ray: 569.7 and 687.0 keV), whereas the peak at 245.31 keV derived from 210At was not detected during the 22 h continuous measurement. The target material, Bi, was below the 9 ng/mL detection limit in all lots of the finished product. The pH of the [211At]NaAt solution was 7.9-8.6; the concentration of ascorbic acid was 9-10 mg/mL. Other quality control tests, including endotoxin and sterility tests, confirmed that the [211At]NaAt solution met all quality standards. CONCLUSIONS: We successfully established a stable method of [211At]NaAt solution that can be administered to humans intravenously as an investigational product.
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The reduction behavior of mendelevium (Md) was studied using a flow electrolytic chromatography apparatus. By application of the appropriate potentials on the chromatography column, the more stable Md(3+) is reduced to Md(2+). The reduction potential of the Md(3+) + e(-) â Md(2+) couple was determined to be -0.16 ± 0.05 V versus a normal hydrogen electrode.
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In targeted radionuclide therapy, determining the absorbed dose of the ligand distributed to the whole body is vital due to its direct influence on therapeutic and adverse effects. However, many targeted alpha therapy drugs present challenges for in vivo quantitative imaging. To address this issue, we developed a planar imaging system equipped with a cadmium telluride semiconductor detector that offers high energy resolution. This system also comprised a 3D-printed tungsten collimator optimized for high sensitivity to astatine-211, an alpha-emitting radionuclide, and adequate spatial resolution for mouse imaging. The imager revealed a spectrum with a distinct peak for X-rays from astatine-211 owing to the high energy resolution, clearly distinguishing these X-rays from the fluorescent X-rays of tungsten. High collimator efficiency (4.5 × 10-4) was achieved, with the maintenance of the spatial resolution required for discerning mouse tissues. Using this system, the activity of astatine-211 in thyroid cancer tumors with and without the expression of the sodium iodide symporter (K1-NIS/K1, respectively) was evaluated through in vivo imaging. The K1-NIS tumors had significantly higher astatine-211 activity (sign test, p = 0.031, n = 6) and significantly decreased post-treatment tumor volume (Student's t-test, p = 0.005, n = 6). The concurrent examination of intratumor drug distribution and treatment outcome could be performed with the same mice.
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Glypican-1 (GPC1) is overexpressed in several solid cancers and is associated with tumor progression, whereas its expression is low in normal tissues. This study aimed to evaluate the potential of an anti-GPC1 monoclonal antibody (GPC1 mAb) labeled with 89Zr or 211At as a theranostic target in pancreatic ductal adenocarcinoma. Methods: GPC1 mAb clone 01a033 was labeled with 89Zr or 211At with a deferoxamine or decaborane linker, respectively. The internalization ability of GPC1 mAb was evaluated by fluorescence conjugation using a confocal microscope. PANC-1 xenograft mice (n = 6) were intravenously administered [89Zr]GPC1 mAb (0.91 ± 0.10 MBq), and PET/CT scanning was performed for 7 d. Uptake specificity was confirmed through a comparative study using GPC1-positive (BxPC-3) and GPC1-negative (BxPC-3 GPC1-knockout) xenografts (each n = 3) and a blocking study. DNA double-strand breaks were evaluated using the γH2AX antibody. The antitumor effect was evaluated by administering [211At]GPC1 mAb (â¼100 kBq) to PANC-1 xenograft mice (n = 10). Results: GPC1 mAb clone 01a033 showed increased internalization ratios over time. One day after administration, a high accumulation of [89Zr]GPC1 mAb was observed in the PANC-1 xenograft (SUVmax, 3.85 ± 0.10), which gradually decreased until day 7 (SUVmax, 2.16 ± 0.30). The uptake in the BxPC-3 xenograft was significantly higher than in the BxPC-3 GPC1-knockout xenograft (SUVmax, 4.66 ± 0.40 and 2.36 ± 0.36, respectively; P = 0.05). The uptake was significantly inhibited in the blocking group compared with the nonblocking group (percentage injected dose per gram, 7.3 ± 1.3 and 12.4 ± 3.0, respectively; P = 0.05). DNA double-strand breaks were observed by adding 150 kBq of [211At]GPC1 and were significantly suppressed by the internalization inhibitor (dynasore), suggesting a substantial contribution of the internalization ability to the antitumor effect. Tumor growth suppression was observed in PANC-1 mice after the administration of [211At]GPC1 mAb. Internalization inhibitors (prochlorperazine) significantly inhibited the therapeutic effect of [211At]GPC1 mAb, suggesting an essential role in targeted α-therapy. Conclusion: [89Zr]GPC1 mAb PET showed high tumoral uptake in the early phase after administration, and targeted α-therapy using [211At]GPC1 mAb showed tumor growth suppression. GPC1 is a promising target for future applications for the precise diagnosis of pancreatic ductal adenocarcinoma and GPC1-targeted theranostics.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Animais , Camundongos , Glipicanas/metabolismo , Tomografia por Emissão de Pósitrons , Medicina de Precisão , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Linhagem Celular Tumoral , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/terapia , DNA , ZircônioRESUMO
Alpha-particle radiotherapy has gained considerable attention owing to its potent anti-cancer effect. 211At, with a relatively short half-life of 7.2 h, emits an alpha particle within a few cell diameters with high kinetic energy, which damages cancer cells with high biological effectiveness. In this study, we investigated the intravenous injection of 211At-labeled gold nanoparticles (AuNPs) for targeted alpha-particle therapy (TAT). Different kinds of surface-modified gold nanoparticles can be labeled with 211At in high radiochemical yield in 5 min, and no purification is necessary. The in vivo biodistribution results showed the accumulation of 5 nm 211At-AuNPs@mPEG at 2.25% injection dose per gram (% ID/g) in tumors within 3 h via the enhanced permeability and retention (EPR) effect. Additionally, we observed a long retention time in tumor tissues within 24 h. This is the first study to demonstrate the anti-tumor efficacy of 5 nm 211At-AuNPs@mPEG that can significantly suppress tumor growth in a pancreatic cancer model via intravenous administration. AuNPs are satisfactory carriers for 211At delivery, due to simple and efficient synthesis processes and high stability. The intravenous administration of 5 nm 211At-AuNPs@mPEG has a significant anti-tumor effect. This study provides a new framework for designing nanoparticles suitable for targeted alpha-particle therapy via intravenous injection.
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For radiological diagnosis and radionuclide therapy, X-ray and gamma-ray imaging technologies are essential. Single-photon emission tomography (SPECT) and positron emission tomography (PET) play essential roles in radiological diagnosis, such as the early detection of tumors. Radionuclide therapy is also rapidly developing with the use of these modalities. Nevertheless, a limited number of radioactive tracers are imaged owing to the limitations of the imaging devices. In a previous study, we developed a hybrid Compton camera that conducts simultaneous Compton and pinhole imaging within a single system. In this study, we developed a system that simultaneously realizes three modalities: Compton, pinhole, and PET imaging in 3D space using multiple hybrid Compton cameras. We achieved the simultaneous imaging of Cs-137 (Compton mode targeting 662 keV), Na-22 (PET mode targeting 511 keV), and Am-241 (pinhole mode targeting 60 keV) within the same field of view. In addition, the imaging of Ga-67 and In-111, which are used in various diagnostic scenarios, was conducted. We also verified that the 3D distribution of the At-211 tracer inside a mouse could be imaged using the pinhole mode.
RESUMO
OBJECTIVE: Astatine (211At) is a promising alpha emitter as an alternative to iodine (131I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [211At]NaAt to determine the FIH dose. METHODS: [211At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups. RESULTS: No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [211At]NaAt. CONCLUSIONS: In the extended single-dose toxicity study of [211At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial.