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Chemotherapy for peritoneal dissemination is poorly effective owing to limited drug transfer from the blood to the intraperitoneal (i.p.) compartment after intravenous (i.v.) administration. i.p. chemotherapy has been investigated to improve drug delivery to tumors; however, the efficacy continues to be debated. As anticancer drugs have low molecular weight and are rapidly excreted through the peritoneal blood vessels, maintaining the i.p. concentration as high as expected is a challenge. In this study, we examined whether i.p. administration is an efficient route of administration of high-molecular-weight immune checkpoint inhibitors (ICIs) for the treatment of peritoneal dissemination using a model of peritoneal disseminated carcinoma. After i.p. administration, the amount of anti-PD-L1 antibody transferred into i.p. tumors increased by approximately eight folds compared to that after i.v. administration. Intratumoral distribution analysis revealed that anti-PD-L1 antibodies were delivered directly from the i.p. space to the surface of tumor tissue, and that they deeply penetrated the tumor tissues after i.p. administration; in contrast, after i.v. administration, anti-PD-L1 antibodies were only distributed around blood vessels in tumor tissues via the enhanced permeability and retention (EPR) effect. Owing to the enhanced delivery, the therapeutic efficacy of anti-PD-L1 antibody in the peritoneal dissemination models was also improved after i.p. administration compared to that after i.v. administration. This is the first study to clearly demonstrate an EPR-independent delivery of ICIs to i.p. tumors by which ICIs were delivered in a massive amount to the tumor tissue via direct penetration after i.p. administration.

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.

ITD of 64CuCl2 after i.v. and i.p. injection

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.

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.

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

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 < 0.05) or myocardium (0.189 ± 0.07, p < 0.05). Immunostaining showed more macrophages and more TSPO expression in atherosclerotic lesions than in uninjured arteries. TSPO was localized in macrophages, and arterial autoradiography intensity was positively correlated with macrophage concentration (r = 0.64) and TSPO (r = 0.67). TSPO expression in human coronary arteries was higher in AMI cases than in non-cardiac death, or in the vulnerable plaques than in early or stable lesions, respectively. TSPO was localized in macrophages in all aspirated coronary plaques with thrombi. Conclusions: 18F-FEDAC-PET can visualize atherosclerotic lesions, and TSPO-expression may be a marker of highrisk coronary plaques.

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.

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.

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.

Synovial sarcoma (SS) is a rare yet refractory soft-tissue sarcoma that predominantly affects young adults. We show in a mouse model that radioimmunotherapy (RIT) with an α-particle emitting anti-Frizzled homolog 10 (FZD10) antibody, synthesized using the α-emitter radionuclide astatine-211 (211At-OTSA101), suppresses the growth of SS xenografts more efficiently than the corresponding β-particle emitting anti-FZD10 antibody conjugated with the β-emitter yettrium-90 (90Y-OTSA101). In biodistribution analysis, 211At was increased in the SS xenografts but decreased in other tissues up to 1 day after injection as time proceeded, albeit with a relatively higher uptake in the stomach. Single 211At-OTSA101 doses of 25 and 50 μCi significantly suppressed SS tumor growth in vivo, whereas a 50 μCi dose of 90Y-OTSA101 was needed to achieve this. Importantly, 50 μCi of 211At-OTSA101 suppressed tumor growth immediately after injection, whereas this effect required several days in the case of 90Y-OTSA101. Both radiolabeled antibodies at the 50 μCi dosage level significantly prolonged survival. Histopathologically, severe cellular damage accompanied by massive cell death was evident in the SS xenografts at even 1 day after the 211At-OTSA101 injection but these effects were relatively milder with 90Y-OTSA101 at the same timepoint, even though the absorbed doses were comparable (3.3 and 3.0 Gy, respectively). We conclude that α-particle RIT with 211At-OTSA101 is a potential new therapeutic option for SS.

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.

Peritoneal dissemination of pancreatic cancer has a poor prognosis. We have reported that intraperitoneal radioimmunotherapy using a 64Cu-labeled antibody (64Cu-ipRIT) is a promising adjuvant therapy option to prevent this complication. To achieve personalized 64Cu-ipRIT, we developed a new in vitro tumor cell-binding assay (64Cu-TuBA) system with a panel containing nine candidate 64Cu-labeled antibodies targeting seven antigens (EGFR, HER2, HER3, TfR, EpCAM, LAT1, and CD98), which are reportedly overexpressed in patients with pancreatic cancer. We investigated the feasibility of 64Cu-TuBA to select the highest-binding antibody for individual cancer cell lines and predict the treatment response in vivo for 64Cu-ipRIT. 64Cu-TuBA was performed using six human pancreatic cancer cell lines. For three cell lines, an in vivo treatment study was performed with 64Cu-ipRIT using high-, middle-, or low-binding antibodies in each peritoneal dissemination mouse model. The high-binding antibodies significantly prolonged survival in each mouse model, while low-and middle-binding antibodies were ineffective. There was a correlation between in vitro cell binding and in vivo therapeutic efficacy. Our findings suggest that 64Cu-TuBA can be used for patient selection to enable personalized 64Cu-ipRIT. Tumor cells isolated from surgically resected tumor tissues would be suitable for analysis with the 64Cu-TuBA system in future clinical studies.

[目的]がんの初期治療によって誘発される組織修復過程では、テネイシンC (TNC)が誘導される。誘導されたTNCを標的とすることで、修復反応が起こっている場所に、薬剤を集中的に運搬できるかどうかを検証した。[方法]In-111標識抗TNC抗体3種類及びcontrol抗体を、放射線照射(30Gy)または非照射担がんマウスに投与し、体内動態、SPECT/CT、ARGを実施した。[結果]体内動態試験で、抗TNC抗体3-6でのみ、照射された腫瘍への取込が投与1日後に2倍上昇することが観察された。SPECT/CTでも腫瘍集積の有意な上昇が確認された。ARGより、非照射腫瘍では腫瘍集積が限局的だったが、照射腫瘍では腫瘍内全体に高い集積を認めた。control抗体では照射群でも低いシグナルが観察されたのみであった。[結論]抗TNC抗体3-6を利用することで、初期治療を受けた後に修復反応が起こっている場所に、RIを含む薬剤を2倍以上運搬できることが明らかとなった。今後、治療効果を検証する必要がある。, 第61回日本核医学会学術総会

Objective: Photoimmunotherapy (PIT) is an upcoming potential cancer treatment modality. Meanwhile, due to the limited therapeutic effect of PIT alone, the combination of anticancer agents with PIT is an option to improve the therapeutic outcome. PIT causes a super-enhanced permeability and retention (SUPR) effect. The selection of drug molecule sizes that are suitable for enhanced permeability is also important for optimizing therapeutic efficacy. Thus, a method that supports to investigate the drug delivery of varying molecular weights coupled with PIT is desirable. Here, we evaluated the SUPR effect using radiolabeled drugs of varying molecular weights ( 18F-5FU, 111In-DTPA, 99mTc-HSA-D, and 111In-IgG) to determine the appropriate drug size. Methods: PIT was conducted with an indocyanine green-labeled anti-HER2 antibody and an 808-nm laser irradiation. Mice were subcutaneously inoculated with HER2-positive cells in both legs. The tumor on one side was treated with PIT, and the contralateral side was not treated. The differences between tumor accumulations were quantitatively evaluated using positron emission tomography (PET) or single-photon emission computed tomography (SPECT). In this study, we used the four radionuclide imaging probes: 18F-5FU, a low-molecular-weight (148 Da) PET probe; 111In-DTPA, a low-molecular-weight (504 Da) SPECT probe, 99mT- HSA-D, a medium-molecular-weight (66492 Da) SPECT probe, and 111In-IgG, a high-molecular-weight (147111 Da) SPECT probe to quantify the SUPR effect induced by PIT. high-molecular-weight (147111 Da) SPECT probe to quantify the SUPR effect induced by PIT. Results: PIT-treated tumors showed significantly increased uptake of 18F-5FU (P < 0.001), 111In-DTPA (P < 0.05), and 99mTc-HSA-D (P < 0.02). A tendency toward increased accumulation of 111In-IgG was observed. These findings suggest that low- and medium-molecular-weight agents are promising candidates for combined PIT, and so are macromolecules; hence, administration after PIT could enhance their efficacy. Conclusion: The radionuclide imaging approach is elucidated for the PIT-mediated SUPR effect and can help in optimizing therapeutic measures by means of the feasibility of selecting a drug size and monitoring its distribution. Our findings encourage further preclinical and clinical studies to develop a combination therapy of PIT with conventional anticancer drugs., World Molecular Imaging Congress

[目的]がんの初期治療によって誘発される組織修復過程では、テネイシンC (TNC)が誘導される。誘導されたTNCを標的とすることで、修復反応が起こっている場所に、薬剤を集中的に運搬できるかどうかを検証した。[方法]In-111標識抗TNC抗体3種類及びcontrol抗体を、放射線照射(30Gy)または非照射担がんマウスに投与し、体内動態、SPECT/CT、ARGを実施した。[結果]体内動態試験で、抗TNC抗体3-6でのみ、照射された腫瘍への取込が投与1日後に2倍上昇することが観察された。SPECT/CTでも腫瘍集積の有意な上昇が確認された。ARGより、非照射腫瘍では腫瘍集積が限局的だったが、照射腫瘍では腫瘍内全体に高い集積を認めた。control抗体では照射群でも低いシグナルが観察されたのみであった。[結論]抗TNC抗体3-6を利用することで、初期治療を受けた後に修復反応が起こっている場所に、RIを含む薬剤を2倍以上運搬できることが明らかとなった。今後、治療効果を検証していく予定である。, 第16回小動物インビボイメージング研究会

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.

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.

Cadherin-17 (CDH17) is a transmembrane protein that mediates cell-cell adhesion and is frequently expressed in adenocarcinomas, including gastric cancer. CDH17 may be an effective diagnostic marker for the staging of gastric cancer. Here, we developed an In-labeled anti-CDH17 monoclonal antibody (Mab) as an imaging tracer and performed biodistribution and single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging studies using mice with CDH17-positive gastric cancer xenografts. CDH17 expression in gastric cancer specimens was also analyzed.

Pancreatic cancer (PC) has a very poor prognosis. Surgery is the primary treatment for patients with resectable PC; however, local recurrence, hepatic metastasis, and peritoneal dissemination often occur even after extensive surgery. Adjuvant chemotherapy, typically with gemcitabine, has been used clinically but with only a modest survival benefit. To achieve a better outcome, we investigated the efficacy of 64Cu-intraperitoneal radioimmunotherapy (ipRIT) with 64Cu-labeled antiepidermal growth factor receptor antibody cetuximab as an adjuvant treatment after PC surgery using an orthotopic xenografted mouse model. Methods: The efficacy of adjuvant 64Cu-ipRIT was investigated in a human PC mouse model harboring orthotopic xenografts of xPA-1-DC cells. To reproduce the clinical situation, PC xenografts were surgically resected when pancreatic tumors were readily visible but not metastatic tumors. Increasing doses of 64Cu-cetuximab were intraperitoneally injected, and the mice were monitored for toxicity to determine the safe therapeutic dose. For adjuvant 64Cu-ipRIT, the day after tumor resection, the mice were intraperitoneally administered 22.2 MBq of 64Cu-PCTA-cetuximab and the survival was compared with that in surgery-only controls. For comparison, adjuvant chemotherapy with gemcitabine was also examined using the same model. Results: The mouse model not only developed primary tumors in the pancreas but also subsequently reproduced local recurrence, hepatic metastasis, and peritoneal dissemination after surgery, which is similar to the manifestations that occur with human PC. Adjuvant 64Cu-ipRIT with 64Cu-labeled cetuximab after surgery effectively suppressed local recurrence, hepatic metastasis, and peritoneal dissemination in this model. Significant improvement of the survival with minimal toxicity was achieved by adjuvant 64Cu-ipRIT compared with that in control mice that underwent surgery only. Adjuvant chemotherapy with gemcitabine nominally prolonged the survival, but the effect was not statistically significant. Conclusion: 64Cu-ipRIT with cetuximab can be an effective adjuvant therapy after PC surgery.

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.

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.

We have successfully developed 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD) as a multimeric RGD-based radiopeptide for specifically targeting the transmembrane cell adhesion receptor, alphaVbeta3 integrin (aVb3). Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors. Despite advances in surgical cytoreduction and drug development, the 5-year survival rate for OCPM patients remains as low as, SNMMI2021 Annual Meeting

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-.

CD137 is an attractive target for cancer immunotherapy, but its expression in normal tissues induces some adverse effects in patients receiving CD137-targeted therapy. To overcome this issue, we developed a switch antibody, STA551, that binds to CD137 only under high ATP concentrations around cells. This study quantified biodistribution of murine switch antibodies in human CD137 knock-in mice to show the viability of the switch antibody concept in vivo. We utilized four antibodies: Sta-MB, Ure-MB, Sta-mIgG, and KLH-MB. Sta-MB is a switch antibody having the variable region of STA551. The MB is a murine Fc highly binding to murine Fcγ receptor II. Ure-MB has a variable region mimicking the clinically available anti-CD137 agonist antibody urelumab, binding to CD137 regardless of ATP concentration. Sta-mIgG has the same variable region as Sta-MB but has the standard murine constant region. KLH-MB binds to keyhole limpet hemocyanin. The four antibodies were radiolabeled with In-111, SPECT/CT imaging was conducted in human CD137 knock-in mice, and the uptake in regions of interest was quantified. In-labeled Sta-MB and Sta-mIgG showed high uptake in tumors but low uptake in the lymph nodes and spleen in human CD137 knock-in mice. On the other hand, Ure-MB highly accumulated not only in tumors but also in the lymph nodes and spleen. KLH-MB showed low uptake in the tumors, lymph nodes, and spleen. The present study provides evidence that the switch antibody concept works in vivo. Our findings encourage further clinical imaging studies to evaluate the biodistribution of STA551 in patients.

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