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Photodynamic therapy (PDT) is a minimally invasive form of cancer therapy, and the development of a novel photosensitizer (PS) with optimal properties is important for enhancing PDT efficacy. Folate receptor (FR) membrane protein is frequently overexpressed in 40% of human cancer and a good candidate for tumor-specific targeting. Specific active targeting of PS to FR can be achieved by conjugation with the folate moiety. A folate-linked, near-infrared (NIR)-sensitive probe, folate-Si-rhodamine-1 (FolateSiR-1), was previously developed and is expected to be applicable to NIR-PDT.To investigate the therapeutic efficacy of NIR-PDT induced by FolateSiR-1, a FR-targeted PS, in preclinical cancer models.FolateSiR-1 was developed by conjugating a folate moiety to the Si-rhodamine derivative through a negatively charged tripeptide linker. FR expression in the designated cell lines was examined by western blotting (WB). The selective binding of FolateSiR-1 to FR was confirmed in FR overexpressing KB cells (FR+) and tumors by fluorescence microscopy andHigh FR expression was observed in the KB cells by WB, but not in the OVCAR-3 and A4 cells. Substantial FR-specific binding of FolateSiR-1 was observed byFolateSiR-1 has potential for use in PDT, and FR-targeted NIR-PDT may open a new effective strategy for the treatment of FR-overexpressing tumors.

The platinum-based antineoplastic drug cisplatin is commonly used for chemotherapy in clinics. This work aims to demonstrate a radio-platinum tracer is useful for precisely quantifying small amounts of platinum in pharmacokinetics studies.A cisplatin radiotracer (radio-cisplatin) was synthesized, and a comprehensive evaluation of cisplatin over 7 days after its intravenous injection into nude mice bearing a subcutaneous lung tumor (H460) was conducted.A biphasic retention curve in the whole body and blood was observed [ T1/2 (α) = 1.14 h, T1/2 (β) = 5.33 days for the whole body, and T1/2 (α) = 23.9 min, T1/2 (β) = 4.72 days for blood]. The blood concentration decreased within 1 day after injection. Most of the intact cisplatin was excreted via the kidneys in the early time points, and a small part was distributed in tissues including tumors. The plasma protein binding rate of cisplatin increased rapidly after injection, and the protein-bound cisplatin remained in the blood longer than intact cisplatin. The peak uptake in H460 tumors was 4.7% injected dose per gram at 15 min after injection, and the area under the curve (AUC 0-7 days ) was approximately one-half to one-third of the AUC 0-7 days in the kidneys, liver, and bone, where some toxicity is observed in humans.The radio-platinum tracer revealed the highly quantitative biodistribution of cisplatin, providing insights into the properties of cisplatin, including its adverse effects. The tracer enables a precise evaluation of pharmacokinetics for platinum-based drugs with high sensitivity.

Supplementary Files contain (1) Supplementary Materials and Methods for �V�3 expression analysis, autoradiography and histological analysis, and hematology and hepatorenal function; (2) Supplementary Tables S1-S5; and (3) Supplementary Figures S1-S5. Table S1Effects of 37 MBq (1 nmol) of 64Cu-cyclam-RAFT-c(-RGDfK-)4 {plus minus} GF/Lys on hepatorenal functions of U87MG tumor-bearing mice; Table S2Blood cell counts of U87MG tumor-bearing mice at various time points post-injection of 37 MBq (1 nmol) of 64Cu-cyclam-RAFT-c(-RGDfK-)4 {plus minus} GF/Lys; Table S3Blood cell counts of U87MG tumor-bearing mice at various time points after single dose administrations of 37 and 74 MBq of 64Cu-cyclam-RAFT-c(-RGDfK-)4; Table S4Effects of 74 MBq (2 nmol) of 64Cu-cyclam-RAFT-c(-RGDfK-)4 + GF/Lys on hepatorenal functions of normal mice; Table S5Human absorbed doses extrapolated from the biodistribution data of 64Cu-cyclam-RAFT-c(-RGDfK-)4 in U87MG tumor-bearing mice

Figure S1The treatment outcomes of radiotherapy with 37 MBq (1 nmol) of 64Cu-cyclam-RAFT-c(-RGDfK-)4; Figure S2Toxicity studies in normal mice that were injected with 74 MBq of 64Cu-cyclam-RAFT-c(-RGDfK-)4; Figure S3Preliminary study of U87MG tumors excised at day 13 p.i. of 37 MBq of 64Cu-cyclam-RAFT-c(-RGDfK-)4 for the changes in microvasculature; Figure S4Positive correlation between the tumor volume and the corresponding WBC in U87MG tumor-bearing mice; Figure S5Biodistribution of 64Cu-cyclam-RAFT-c(-RGDfK-)4 at various peptide doses (0.00510 nmol) in U87MG tumor-bearing mice.

The files contain (1) Supplementary Materials and Methods for αVβ3 expression analysis, autoradiography and histological analysis, and hematology and hepatorenal function; (2) Supplementary Tables S1-S5; and (3) Supplementary Figures S1-S5. Table S1â^'Effects of 37 MBq (1 nmole) of 64Cu-cyclam-RAFT-c(-RGDfK-)4 {plus minus} GF/Lys on hepatorenal functions of U87MG tumor-bearing mice; Table S2â^'Blood cell counts of U87MG tumor-bearing mice at various time points post-injection of 37 MBq (1 nmole) of 64Cu-cyclam-RAFT-c(-RGDfK-)4 {plus minus} GF/Lys; Table S3â^'Blood cell counts of U87MG tumor-bearing mice at various time points after single dose administrations of 37 and 74 MBq of 64Cu-cyclam-RAFT-c(-RGDfK-)4; Table S4â^'Effects of 74 MBq (2 nmole) of 64Cu-cyclam-RAFT-c(-RGDfK-)4 + GF/Lys on hepatorenal functions of normal mice; Table S5â^'Human absorbed doses extrapolated from the biodistribution data of 64Cu-cyclam-RAFT-c(-RGDfK-)4 in U87MG tumor-bearing mice; Figure S1â^'The treatment outcomes of radiotherapy with 37 MBq (1 nmole) of 64Cu-cyclam-RAFT-c(-RGDfK-)4; Figure S2â^'Toxicity studies in normal mice that were injected with 74 MBq of 64Cu-cyclam-RAFT-c(-RGDfK-)4; Figure S3â^'Preliminary study of U87MG tumors excised at day 13 p.i. of 37 MBq of 64Cu-cyclam-RAFT-c(-RGDfK-)4 for the changes in microvasculature; Figure S4â^'Positive correlation between the tumor volume and the corresponding WBC in U87MG tumor-bearing mice; Figure S5â^'Biodistribution of 64Cu-cyclam-RAFT-c(-RGDfK-)4 at various peptide doses (0.005â^'10 nmole) in U87MG tumor-bearing mice.

64Cu-RaftRGD-based TRT (toxicity evaluation: hepatorenal functions and gastrointestinal state)

Purpose:Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors that are rarely curable. αVβ3 integrin (αVβ3) is overexpressed on tumoral neovessels and frequently on ovarian cancer cells. Here, using two clinically relevant αVβ3-positive OCPM mouse models, we studied the theranostic potential of an αVβ3-specific radiopeptide, 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD), and its intra- and intertumoral distribution in relation to the tumor microenvironment.Experimental Design:αVβ3-expressing peritoneal and subcutaneous models of ovarian carcinoma (IGR-OV1 and NIH:OVCAR-3) were established in nude mice. 64Cu-RaftRGD was administered either intravenously or intraperitoneally. We performed intratumoral distribution (ITD) studies, PET/CT imaging and quantification, biodistribution assay and radiation dosimetry, and therapeutic efficacy and toxicity studies.Results:Intraperitoneal administration was an efficient route for targeting 64Cu-RaftRGD to OCPMs with excellent tumor penetration. Using the fluorescence surrogate, Cy5.5-RaftRGD, in our unique high-resolution multifluorescence analysis, we found that the ITD of 64Cu-RaftRGD was spatially distinct from, but complementary to, that of hypoxia. 64Cu-RaftRGD–based PET enabled clear visualization of multiple OCPM deposits and ascites and biodistribution analysis demonstrated an inverse correlation between tumor uptake and tumor size (1.2–17.2 mm). 64Cu-RaftRGD at a radiotherapeutic dose (148 MBq/0.357 nmol) showed antitumor activities by inhibiting tumor cell proliferation and inducing apoptosis, with negligible toxicity.Conclusions:Collectively, these results demonstrate the all-in-one potential of 64Cu-RaftRGD for imaging guided radiotherapy of OCPM by targeting both tumoral neovessels and cancerous cells. On the basis of the ITD finding, we propose that pairing αVβ3- and hypoxia-targeted radiotherapies could improve therapeutic efficacy by overcoming the heterogeneity of ITD encountered with single-agent treatments.

Table S1-Post-PET biodistribution data of i.v.- and i.p.-administered 64Cu-RaftRGD in IGR-OV1-OCPM mice; Table S2-Biodistribution data of i.p.-administered 64Cu-RaftRGD; Table S3-Inverse regression equations; and Table S4-Estimation of human absorbed doses.

Supplementary Materials and Methods for integrin expression analysis, autoradiography, ITD of Cy5.5-RaftRGD in relation to the tumor microenvironment (in s.c. tumors), PET/CT or PET/CECT imaging and quantification, Ki-67 immunostaining, TUNEL assay, and quantification, survival study, and toxicity evaluation.

This study aims to establish new labeling methods for no-carrier-added radio-Pt (

Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12-18 months. Frizzled homolog 10 (FZD10) is overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of β-radioimmunotherapy (RIT) with the 90Y-labeled anti-FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α-RIT with OTSA101 labeled with the α-emitter 225Ac. Competitive inhibition and cell binding assays showed that specific binding of 225Ac-labeled OTSA101 to SYO-1 synovial sarcoma cells was comparable to that of the imaging agent 111In-labeled OTSA101. Biodistribution studies showed high uptake in SYO-1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of 225Ac-labeled OTSA101 for tumors was 7.8 Bd higher than that of 90Y-labeled OTSA101. 90Y- and 225Ac-labeled OTSA101 decreased tumor volume and prolonged survival. 225Ac-labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. 225Ac-labeled OTSA101 induced a larger amount of necrosis and apoptosis than 90Y-labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment-related mortality or obvious toxicity, except for temporary body weight loss, was observed. 225Ac-labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO-1. RIT with 225Ac-labeled OTSA101 is a promising therapeutic option for synovial sarcoma.

BACKGROUND AND AIMS: This study aimed to investigate whether N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[18F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide (18F-FEDAC), a probe for translocator protein (TSPO), can visualize atherosclerotic lesions in rabbits and whether TSPO is localized in human coronary plaques. METHODS: 18F-FEDAC-PET of a rabbit model of atherosclerosis induced by a 0.5% cholesterol diet and balloon injury of the left carotid artery (n = 7) was performed eight weeks after the injury. The autoradiography intensity of 18F-FEDAC in carotid artery tissue sections was measured, and TSPO expression was evaluated immunohistochemically. TSPO expression was examined in human coronary arteries obtained from autopsy cases (n = 16), and in human coronary plaques (n = 12) aspirated from patients with acute myocardial infarction (AMI). RESULTS: 18F-FEDAC-PET visualized the atherosclerotic lesions in rabbits as high-uptake areas, and the standard uptake value was higher in injured arteries (0.574 ± 0.24) than in uninjured arteries (0.277 ± 0.13, p

We developed a human-scale single-ring OpenPET (SROP) system, which had an open space allowing us access to the subject during measurement. The SROP system consisted of 160 4-layer depth-of-interaction detectors. The open space with the axial width of 430 mm was achieved with the ring axial width of 214 mm and the ring inner diameter of 660 mm. The detectors were axially shifted to each other so that the detector ring was aligned along a plane horizontally tilted by 45° against the axial direction. The system was developed as a mobile scanner to be used not only in clinical positron emission tomography (PET) rooms but also in charged-particle therapy treatment rooms as well as animal experiment rooms. Almost uniform spatial resolution better than 3 mm throughout the entire field of view (FOV) was realized with an iterative image reconstruction method. Peak absolute sensitivity was 3.1%, and there was a region with sensitivity better than 0.8% for a length of more than 700 mm. An in-beam imaging experiment conducted at the heavy ion medical accelerator in Chiba showed that the system was operable even at the highest beam intensity available for heavy-ion therapy. In addition, we conducted entire-body monkey dynamic imaging utilizing the long region inside the gantry by positioning a monkey along the direction having the longest FOV tilted by 45° against the axial direction. We concluded the developed system has a capability to realize versatile PET applications by utilizing its wide-open space and mobility in addition to high spatial resolution with sufficiently good sensitivity. -9mm]Please consider rephrasing the sentence “We concluded the developed system” for clarity.

Auger electrons can induce nanoscale physiochemical damage to DNA. The present study reports a sequential and systematic evaluation of the relationship between DNA damage such as double-strand breaks (DSBs) and the cell cycle for the Auger electron-emitting agent radiolabeled cisplatin with DNA binding ability. For dynamic imaging analysis, we used U2OS-derived cancer cells expressing two fluorescent fusion proteins: tumor-suppressor p53 binding protein 1 with a green fluorescent protein (53BP1-EGFP) and proliferating cell nuclear antigen with a red fluorescent protein (PCNA-DsRed). Time-lapse images of the cells were quantitatively analyzed using the ImageJ software with the deepImageJ plugin and the Google Colaboratory platform. From the middle-to-late G1 phase, around the G1-to-S phase transition, we found increased 53BP1 foci in cells treated with the radio-cisplatin. The radio-cisplatin caused significantly more DSBs than the nonradioactive cisplatin and saline in the G1 phase but not in the other phases. These results indicate that Auger electron-induced DNA damage, including DSBs, depends on the cell cycle. The G1 phase, which is associated with low DNA repair capacity and high radiosensitivity, is a promising target; thus, combining radiolabeled cisplatin with agents that arrest cells in the G1 phase could improve the DNA-damaging effect of Auger electrons and their therapeutic efficacy.

Gastric cancer is a common cause of cancer-related death worldwide, and peritoneal dissemination is the most frequent metastatic pattern of gastric cancer. However, the treatment of this disease condition remains difficult. It has been demonstrated that intraperitoneal radioimmunotherapy (ipRIT) withIn the present study, we examined the efficacy of the combined use of vorinostat, as a radiosensitizer during ipRIT withThe mouse model was treated by ipRIT withCoadministration of ipRIT withOur data suggest that vorinostat is a potentially effective radiosensitizer for use during the treatment of peritoneal dissemination of gastric cancer by ipRIT with

Background In pancreatic cancer surgery, accurate identification and resection of intrapancreatic residual tumors are quite difficult. We have developed a novel open-typed PET system (called 'OpenPET'), which enables high-resolution PET-guided surgery in real time, and demonstrated that OpenPET-guided surgery with intraperitoneally administered 64Cu-labeled anti-epidermal growth factor receptor antibody cetuximab is useful to detect and resect primary pancreatic cancer. Here, we investigated applicability of OpenPET-guided surgery for unexpected residual intrapancreatic tumors and examined its survival benefit over conventional surgery. Methods A mouse model with large (>1 cm) resectable pancreatic cancer of xPA-1-DC cells expressing red fluorescent protein was used. OpenPET-guided surgery was conducted 24 h after intraperitoneal administration of 64Cu-labeled cetuximab (7.4 MBq/mouse). For comparison, similar surgical procedures were conducted, and conventional tumor resection was attempted using only the naked eye (control). Survival rate after OpenPET-guided surgery was compared to that after control operations. Results Intraoperative OpenPET guidance enabled detection and resection of small residual tumors. Ten residual tumor specimens (3-10 mm in diameter) were intraoperatively isolated with OpenPET guidance (n = 7 mice). All isolated specimens showed tumor RFP signals. No resection of tumor tissue was performed in control group because the tumor could not be clearly detected with the naked eye alone. Mice after OpenPET-guided surgery showed significantly longer survival rates than those in control group. Conclusions OpenPET-guided surgery with 64Cu-labeled-cetuximab enabled intraoperative identification and resection of intrapancreatic small residual tumors. This technology could be useful to prevent tumor residuals during surgery and improve pancreatic cancer survival.

Pancreatic cancer (PC) has a poor prognosis owing to difficulties in the diagnosis of resectable PC at early stages. Several clinical studies have indicated that the detection and surgery of small resectable PC (64Cu-labeled anti-epidermal growth factor receptor antibody cetuximab was intraperitoneally administered into mice. It clearly identified PC tumors ≥3 mm. In contrast, neither OpenPET with intravenous-administered 64Cu-cetuximab nor intraperitoneal/intravenous-administered 18F-FDG (a traditional PET probe) could detect PC in this model. Immuno-OpenPET-guided surgery accurately resected small PC in mice and achieved significantly prolonged survival. This technology could provide a novel diagnostic and therapeutic strategy for small resectable PC to improve patient survival.

Iodide homeostasis and thyroid hormone metabolism in the brain are potentially related to changes in the activity of the sodium iodide symporter (NIS). No radiotracers are currently available for imaging brain NIS activity. Here, we synthesized 6-[124I]iodo-9-pentylpurine that can noninvasively measure iodide efflux from the brain and showed that the efflux rate of [124I]I- in NIS knockout mice was 84% lower than that of wild-type mice. Thus, 6-[124I]iodo-9-pentylpurine would be useful for imaging brain NIS activity.

Positron-emission tomography (PET) and single-photon-emission computed tomography (SPECT) are well-established nuclear-medicine imaging methods used in modern medical diagnoses. Combining PET with 18F-fluorodeoxyglucose (FDG) and SPECT with an 111In-labelled ligand provides clinicians with information about the aggressiveness and specific types of tumors. However, it is difficult to integrate a SPECT system with a PET system because SPECT requires a collimator. Herein, we describe a novel method that provides simultaneous imaging with PET and SPECT nuclides by combining PET imaging and Compton imaging. The latter is an imaging method that utilizes Compton scattering to visualize gamma rays over a wide range of energies without requiring a collimator. Using Compton imaging with SPECT nuclides, instead of the conventional SPECT imaging method, enables PET imaging and Compton imaging to be performed with one system. In this research, we have demonstrated simultaneous in vivo imaging of a tumor-bearing mouse injected with 18F-FDG and an 111In-antibody by using a prototype Compton-PET hybrid camera. We have succeeded in visualizing accumulations of 18F-FDG and 111In-antibody by performing PET imaging and Compton imaging simultaneously. As simultaneous imaging utilizes the same coordinate axes, it is expected to improve the accuracy of diagnoses.

Purpose This study aimed to evaluate the potential of podoplanin (PDPN)-targeted alpharadiotherapy (RIT) for treating malignant mesothelioma.Methods A newly developed anti-PDPN antibody, NZ-16, and a previous anti-PDPN antibody, NZ-12, were assessed. The in vitro properties of radiolabeled antibodies were evaluated by cell binding and competitive inhibition assays using PDPN-expressing NCI-H226 (H226) mesothelioma cells. The biodistribution of 111 In-labeled antibodies was studied in tumorbearing mice. Tumor volumes and body weights of mice treated with 90 Y- and 225 Ac-labeled NZ-16 were measured for 56 days. The absorbed doses were estimated on the basis of the biodistribution data. Pathologic analysis of tumors and organs was conducted.Results The radiolabeled NZ-16 specifically bound to H226 cells with higher affinity than NZ12. The biodistribution studies showed higher tumor uptake of radiolabeled NZ-16 compared with NZ-12. RIT with 225 Ac-labeled NZ-16 (11.1 and 18.5 kBq) had a significantly higher antitumor effect than RIT with 90 Y-labeled NZ-16 (3.7 MBq; P < 0.01). 225 Ac-labeled NZ-16 induced more necrosis compared with 90 Y-labeled NZ-16, but the Ki-67 index and apoptosis rate were similar. The estimated absorbed doses were expected to be tolerable in mice. Temporary body weight loss occurred, but recovered within several days. No visible damage to major organs was detected.Conclusion The novel anti-PDPN antibody NZ-16 was a more effective RIT agent than NZ12. Radiolabeled NZ-16, especially 225 Ac-labeled NZ-16, markedly suppressed tumor growth and prolonged survival without inducing severe adverse effects. RIT with radiolabeled NZ-16 is a promising therapeutic option for malignant mesothelioma.

The α-emitter 211At-labeled meta-astatobenzylguanidine (211At-MABG) has a strong antitumor effect on pheochromocytoma xenograft tumors and holds great promise as a new therapeutic option for malignant pheochromocytoma. To evaluate the acute radiation-related toxicity of 211At-MABG, we conducted biodistribution and dosimetry studies of 211At-MABG in ICR mice to estimate the doses absorbed by organs. We determined the maximum tolerated doses (MTD) of 211At-MABG on the basis of body weight loss and assessed the acute radiation-related toxicity induced by MTD administration on the basis of organ weights, histologic features, hematologic indices, and biochemical indices. The biodistribution and dosimetry studies of α-emitting 211At-MABG revealed high doses absorbed by most organs except the brain in ICR mice. The administration of 1.1, 2.2, and 3.3 MBq of 211At-MABG induced transient body weight loss, and 4.4 MBq of 211At-MABG induced unrecoverable body weight loss; thus, the MTD was 3.3 MBq for ICR mice. Although by day 5 the administration of 3.3 MBq had induced some radiation-related toxicity symptoms—such as body weight loss and leucopenia, which are generally observed in radiation therapy including β−-emitting radiopharmaceuticals—the mice had recovered by day 28. We observed no unexpected severe toxicity in ICR mice despite the high absorbed doses in most organs, especially the thyroid, heart, stomach, and adrenal glands. Our findings suggest that therapeutic treatments with appropriate doses of 211At-MABG estimated by dosimetry in each patient could be tolerated, although lower doses may initially be necessary to ensure patient safety in the first-in-human study.

Podoplanin is a type I transmembrane sialomucin-like glycoprotein that is highly expressed in malignant mesothelioma. The rat-human chimeric antibody NZ-12 has high affinity for human podoplanin and antibody-dependent cellular cytotoxicity and is applicable for radioimmunotherapy (RIT) to enhance the antitumor effect. In the present study, we evaluated the in vivo and in vitro properties of radiolabeled NZ-12 and the antitumor effect of RIT with 90 Y-labeled NZ-12 in an NCI-H226 (H226) malignant mesothelioma xenograft mouse model. 111 In-labeled NZ-12 bound specifically to H226 cells with high affinity, and accumulation was high in H226 tumors but low in major organs. RIT with 90 Y-labeled NZ-12 significantly suppressed tumor growth and prolonged survival without body weight loss and obvious adverse effects. Higher podoplanin expression levels were observed in human mesothelioma specimens, suggesting higher tumor accumulation of 90 Y-labeled NZ-12 in patients compared with the H226 tumor xenografts. Our findings suggest that 90 Y-labeled NZ-12 is a promising RIT agent as a new therapeutic option for malignant mesothelioma that warrants further clinical studies to evaluate the dosimetry and efficacy in patients.

The high therapeutic effect of targeted radioisotope/radionuclide therapy (TRT) using α-emitters, especially 225Ac, is attracting attention worldwide. However, the only 225Ac production method that has been put into practical use is extraction from a 229Th generator derived from the nuclear fuel 233U, and it is unlikely that this method alone is able to meet future global medical demand. Development towards new 225Ac production methods is in progress. These new 225Ac production methods require the irradiation of 232Th or 226Ra using an accelerator or a nuclear reactor. Global competition has already begun in the race to secure a reliable supply of 232Th and 226Ra, as well as 229Th for the conventional production method. Japan is a “resource-poor country” that depends on foreign countries for most of its needs. As such, it is difficult for Japan to secure raw materials such as 232Th and 226Ra for medical application. In this paper, we look back on our research at the National Institutes for Quantum Science and Technology (QST) in the fields of 225Ac production and 225Ac-labeled pharmaceutical development. We present the history and details of our research from 2011, as well as the development of a collaboration between QST and Nihon Medi-Physics that focuses on research into 225Ac production via 226Ra(p,2n)225Ac reaction using an accelerator. Furthermore, we review the valuable discussion at the 2018 Joint IAEA-JRC Workshop—“Supply of Actinium-225”, an international conference that we participated in. Overall, the statuses of external 225Ac supply, domestic production, and distribution are discussed, as are the latest developments in 225Ac production methods, 225Ac pharmaceuticals, and future prospects for the domestic production of 225Ac in Japan, a country lacking natural resources for medical applications.

AIM To investigate near-infrared photoimmunotherapeutic effect mediated by an anti-tissue factor (TF) antibody conjugated to indocyanine green (ICG) in a pancreatic cancer model. METHODS Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that utilizes an antibody-photosensitizer conjugate administration, followed by NIR light exposure. Anti-TF antibody 1849-ICG conjugate was synthesized by labeling of rat IgG2b anti-TF monoclonal antibody 1849 (anti-TF 1849) to a NIR photosensitizer, ICG. The expression levels of TF in two human pancreatic cancer cell lines were examined by western blotting. Specific binding of the 1849-ICG to TF-expressing BxPC-3 cells was examined by fluorescence microscopy. NIR-PIT-induced cell death was determined by cell viability imaging assay. In vivo longitudinal fluorescence imaging was used to explore the accumulation of 1849-ICG conjugate in xenograft tumors. To examine the effect of NIR-PIT, tumor-bearing mice were separated into 5 groups: (1) 100 μg of 1849-ICG i.v. administration followed by NIR light exposure (50 J/cm2) on two consecutive days (Days 1 and 2); (2) NIR light exposure (50 J/cm2) only on two consecutive days (Days 1 and 2); (3) 100 μg of 1849-ICG i.v. administration; (4) 100 μg of unlabeled anti-TF 1849 i.v. administration; and (5) the untreated control. Semiweekly tumor volume measurements, accompanied with histological and immunohistochemical (IHC) analyses of tumors, were performed 3 d after the 2nd irradiation with NIR light to monitor the effect of treatments. RESULTS High TF expression in BxPC-3 cells was observed via western blot analysis, concordant with the observed preferential binding with intracellular localization of 1849-ICG via fluorescence microscopy. NIR-PIT-induced cell death was observed by performing cell viability imaging assay. In contrast to the other test groups, tumor growth was significantly inhibited by NIR-PIT with a statistically significant difference in relative tumor volumes for 27 d after the treatment start date [2.83 ± 0.38 (NIR-PIT) vs 5.42 ± 1.61 (Untreated), vs 4.90 ± 0.87 (NIR), vs 4.28 ± 1.87 (1849-ICG), vs 4.35 ± 1.42 (anti-TF 1849), at Day 27, P < 0.05]. Tumors that received NIR-PIT showed evidence of necrotic cell death-associated features upon hematoxylin-eosin staining accompanied by a decrease in Ki-67-positive cells (a cell proliferation marker) by IHC examination. CONCLUSION The TF-targeted NIR-PIT with the 1849-ICG conjugate can potentially open a new platform for treatment of TF-expressing pancreatic cancer.

Due to their short range (2–500 nm), Auger electrons (Auger e-) have the potential to induce nano-scale physiochemical damage to biomolecules. Although DNA is the primary target of Au-ger e-, it remains challenging to maximize the interaction between Auger e- and DNA. To assess the DNA-damaging effect of Auger e- released as close as possible to DNA without chemical damage, we radio-synthesized no-carrier-added (n.c.a.) [189, 191Pt]cisplatin and evaluated both its in vitro properties and DNA-damaging effect. Cellular uptake, intracellular distribution, and DNA binding were investigated, and DNA double-strand breaks (DSBs) were evaluated by im-munofluorescence staining of γH2AX and gel electrophoresis of plasmid DNA. Approximately 20% of intracellular radio-Pt was in a nucleus, and about 2% of intra-nucleus radio-Pt bound to DNA, although uptake of n.c.a. radio-cisplatin was low (0.6% incubated dose after 25-h incuba-tion), resulting in the frequency of cells with γH2AX foci was low (1%). Nevertheless, some cells treated with radio-cisplatin had γH2AX aggregates unlike non-radioactive cisplatin. These findings suggest n.c.a. radio-cisplatin binding to DNA causes severe DSBs by release of Auger e- very close to DNA without chemical damage by carriers. Efficient radio-drug delivery to DNA is necessary for successful clinical application of Auger e-.

This study aimed to investigate whether N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[

In treatment-refractory cancers, tumor tissues damaged by therapy initiate the repair response, therefore, tumor tissues must be exposed to an additional burden before successful repair. We hypothesized that an agent recognizing a molecule that responds to anticancer treatment-induced tissue injury could deliver an additional antitumor agent including a radionuclide to damaged cancer tissues during repair. We selected the extracellular matrix glycoprotein tenascin-C (TNC) as such a molecule, and three antibodies recognizing human and murine TNC were employed to evaluate X-irradiation-induced changes in TNC uptake by subcutaneous tumors. TNC expression was assessed by immunohistochemical staining of BxPC-3 tumors treated with or without X-irradiation (30 Gy) for 7 days. Antibodies against TNC (3&ndash, 6, 12&ndash, 2&ndash, 7, TDEAR) and a control antibody were radiolabeled with 111In and injected into nude mice having BxPC-3 tumors 7 days after X-irradiation, and temporal uptake was monitored for an additional 4 days by biodistribution and single-photon emission computed tomography with computed tomography (SPECT/CT) studies. Intratumoral distribution was analyzed by autoradiography. The immunohistochemical signal for TNC expression was faint in nontreated tumors but increased and expanded with time until day 7 after X-irradiation. Biodistribution studies revealed increased tumor uptake of all three 111In-labeled antibodies and the control antibody. However, a statistically significant increase in uptake was evident only for 111In-labeled 3&ndash, 6 (35% injected dose (ID)/g for 30 Gy vs. 15% ID/g for 0 Gy at day 1, p &lt, 0.01), whereas limited changes in 111In-labeled TDEAR2, 12&ndash, 27, and control antibody were observed (several % ID/g for 0 and 30 Gy). Serial SPECT/CT imaging with 111In-labeled 3&ndash, 6 or control antibody provided consistent results. Autoradiography revealed noticeably stronger signals in irradiated tumors injected with 111In-labeled 3&ndash, 6 compared with each of the nonirradiated tumors and the control antibody. The signals were observed in TNC-expressing stroma. Markedly increased uptake of 111In-labeled 3&ndash, 6 in irradiated tumors supports our concept that an agent, such as an antibody, that recognizes a molecule involved in tissue injury repair, such as TNC, could enhance drug delivery to tumor tissues that have undergone therapy. The combination of antibody 3&ndash, 6 coupled to a tumoricidal drug and conventional therapy has the potential to achieve better outcomes for patients with refractory cancer.