Keisuke Tsuda

In Vivo SPECT Imaging with 111In-DOTA-c(RGDfK) to Detect Early Pancreatic Cancer in a Hamster Pancreatic Carcinogenesis Model

Early detection of pancreatic cancer is key to overcoming its poor prognosis. αvβ3-integrin is often overexpressed in pancreatic tumor cells, whereas it is scarcely expressed in normal pancreatic cells. In this study, we investigated the usefulness of SPECT imaging with 111In-1,4,7,10-tetraazacylododecane-N,N′,N″,N′′′-tetraacetic acid-cyclo-(Arg-Gly-Asp-d-Phe-Lys) [111In-DOTA-c(RGDfK)], an imaging probe of αvβ3-integrin, for the early detection of pancreatic cancer in a hamster pancreatic carcinogenesis model. Methods: Hamsters were subcutaneously injected with the pancreatic duct carcinogen N-nitrosobis(2-oxopropyl)amine to induce pancreatic cancer. N-nitrosobis(2-oxopropyl)amine–treated hamsters underwent in vivo SPECT with 111In-DOTA-c(RGDfK). After imaging, the tumor-to-normal pancreatic tissue radioactivity ratios in excised pancreatic samples were measured with autoradiography (ARG) and compared with the immunopathologic findings for αvβ3-integrin. In a mouse model in which inflammation was induced with turpentine, the uptake of 111In-DOTA-c(RGDfK) in inflammatory regions was evaluated with ARG and compared with that of 18F-FDG. Results: 111In-DOTA-c(RGDfK) was clearly visualized in pancreatic cancer lesions as small as 3 mm in diameter. ARG analysis revealed high tumor-to-normal pancreatic tissue radioactivity ratios (4.6 ± 1.0 [mean ± SD] in adenocarcinoma and 3.3 ± 1.4 in atypical hyperplasia). The uptake of 111In-DOTA-c(RGDfK) strongly correlated with αvβ3-integrin expression. In the inflammatory model, inflammation-to-muscle ratios for 18F-FDG and 111In-DOTA-c(RGDfK) were 8.37 ± 4.37 and 1.98 ± 0.60, respectively. These results imply that 111In-DOTA-c(RGDfK) has a lower rate of false-positive tumor detection than 18F-FDG. Conclusion: Our findings suggest that SPECT with 111In-DOTA-c(RGDfK) has great potential for the early and accurate detection of pancreatic cancer.

Abstract 4325: The requisites for in vivo clear visualization of intratumoral heterogeneity by a SPECT/CT scanner dedicated for small animal imaging

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Objectives: Although even conventional nuclear medicine tests could successfully detect tumor masses in vivo, they did not always visualize heterogeneous interiors of tumor masses. The clear visualization of intratumoral heterogeneity in vivo will give us additional information about the choice of cancer therapy. Recently developed single photon emission computed tomography (SPECT) scanners dedicated for small animal imaging show excellent spatial resolution (< 1 mm) and they are expected to visualize intratumoral heterogeneity in vivo even for mouse tumors. But, little studies have revealed the requisites for this purpose. In this study, we considered the conditions to image intratumoral heterogeneity in vivo. Materials and Methods: A small animal SPECT/CT scanner with four detectors equipped with 9-pinhole collimators (1.0 mm or 1.4 mm of pinholes, Bioscan, Washington, D.C.) was used. First, phantom experiments with 111In of similar radioactivity that is commonly used in mouse imaging studies were performed to evaluate the optimal conditions to obtain best spatial resolution and concentration linearity. Then, mouse tumors were imaged. 111In-labeled liposomes with high specific activity and high concentration were injected to Sarcoma180 bearing ddY mice. In vivo SPECT images and ex vivo autoradiograms were compared and the radioactivity distribution in tumors and other tissues was measured. Results: In phantom experiments with 111In, the best spatial resolution under the current experimental conditions simulating in vivo small animal imaging was 1.1 mm (1.4 mmϕ, 5 MBq/mL, 120 min of total acquisition), although they greatly depended on total acquisition counts or total radioactivity. The good linearity between the concentration and SPECT values was obtained under the condition of 0.5-1.5 MBq/mL. 111In-labeled liposomes (15-20 MBq/mouse) were strongly accumulated in the tumor (1-2 MBq/g, 10-15% of injected dose/g), predominantly in the marginal regions of tumors. And, SPECT clearly visualized this heterogeneous intratumoral localization in vivo with good spatial resolution with the acquisition time of 60 min at 24h after the injection. The threshold to clearly visualize the tumor heterogeneity was about 0.5 MBq/g. Ex vivo autoradiograms of excised tumors demonstrated that the small animal SPECT scanner could successfully image the heterogeneous intratumoral accumulation of liposomes. Conclusion: The SPECT/CT scanner dedicated for small animal imaging successfully visualized the tumor heterogeneity in vivo using radioactive probes with rather high specific radioactivity and high concentration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4325.