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Near-infrared photoimmunotherapy of pancreatic cancer using an indocyanine green-labeled anti-tissue factor antibody

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world Journal of Gastroenterology 2018年第48期24卷 5491-5504页

作者： winn aung Atsushi B Tsuji Aya Sugyo Hiroki Takashima Masahiro Yasunaga Yasuhiro Matsumura Tatsuya Higashi Department of Molecular Imaging and Theranostics National Institute of Radiological SciencesNational Institutes for Quantum and Radiological Science and Technology (QST-NIRS) Division of Developmental Therapeutics Exploratory Oncology Research and Clinical Trial CenterNational Cancer Center

AIM To investigate near-infrared photoimmunotherapeutic effect mediated by an anti-tissue factor(TF) antibody conjugated to indocyanine green(ICG) in a pancreatic cancer *** 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 IgG2 b 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-PITinduced 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 NIRPIT, 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 antiTF 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

关键词： Pancreatic cancer Anti-tissue factor antibody Indocyanine green Photoimmunotherapy Near-infrared

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Combined treatment of pancreatic cancer xenograft with 90Y-ITGA6B4-mediated radioimmunotherapy and PI3k/m TOR inhibitor

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world Journal of Gastroenterology 2017年第42期23卷 7551-7562页

作者： winn aung Atsushi B Tsuji Hitomi Sudo Aya Sugyo Yoshinori Ukai katsushi kouda Yoshikazu kurosawa Takako Furukawa Tsuneo Saga Tatsuya Higashi Department of Molecular Imaging and Theranostics National Institute of Radiological SciencesNational Institutes for Quantum and Radiological Science and Technology(QST-NIRS) Perseus Proteomics Inc. Innovation Center for Advanced Medicine Fujita Health University Department of Radiological and Medical Laboratory Sciences Nagoya University Graduate School of Medicine Department of Diagnostic Radiology Kyoto University Hospital

AIM To investigate the therapeutic effect of combined integrin α6β4-targeted radioimmunotherapy(RIT) and PI3 k/m TOR inhibitor BEZ235 in a pancreatic cancer *** Phosphorylation of Akt, m TOR, the downstream effectors eukaryotic initiation factor 4 E binding protein 1(4 EBP1) and S6 ribosomal protein(S6) were evaluated in Bx PC-3 human pancreatic cancer cells treated with Yttrium-^(90)(^(90) Y) labeled anti-integrin α6β4 antibody(ITGA6 B4) and BEZ235 by western blotting. The cytotoxic effect of BEZ235 was investigated using a colony formation assay. Therapeutic efficacy enhancement by oral BEZ235 administration was assessed using mice bearing Bx PC-3 xenograft tumors. Tumor volume measurements and immunohistochemical analyses(cell proliferation marker ki-67, DNA damage marker p-H2 AX and p-4 EBP1 staining) of tumors were performed for evaluation of combined treatment with ^(90) Y-ITGA6 B4 plus BEZ235, or each arm *** we found that phosphorylation of Akt(p-Akt), 4 EBP1(p-4 EBP1) and S6(p-S6) was inhibited by BEZ235. Colony formation in Bx PC-3 cells was additively suppressed by the combination of ^(90) Y-ITGA6 B4 and BEZ235. Pretreatment with BEZ235 before ^(90) Y-ITGA6 B4 exposure resulted in significant reduction of cells plating efficiency(PE)(0.54 ± 0.11 vs 2.81 ± 0.14 with 185 k Bq/m L ^(90) Y-ITGA6 B4 exposure, P with 370 k Bq/m L ^(90) Y-ITGA6 B4 exposure, P when 5 × 10~3 cells per dish were plated. In vivo, the combined treatment with ^(90) Y-ITGA6 B4 plus BEZ235 enhanced the inhibition of tumor growth and statistically significant differences of relative tumor volume were observed for 27 d after the treatment start date when compared with the ^(90) Y-ITGA6 B4 single injection treatment(1.03 ± 0.38 vs 1.5 ± 0.15 at Day 27, P when compared with the BEZ235 treatment alone(1.8 ± 0.7 vs 3.14 ± 1.19 at Day 41, P wed reduction in volumes, dec

关键词： Radioimmunotherapy Pancreatic cancer Anti-integrin α6β4 antibody Yttrium-90 NVP-BEZ235

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