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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 < 0.01; 0.39 ± 0.08 vs 1.88 ± 0.09 with 370 k Bq/m L ^(90) Y-ITGA6 B4 exposure, P < 0.01) 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 < 0.05), and for 41 d when compared with the BEZ235 treatment alone(1.8 ± 0.7 vs 3.14 ± 1.19 at Day 41, P < 0.05). Tumors from treatment groups showed reduction in volumes, dec

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

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Folate receptor-targeted near-infrared photodynamic therapy for folate receptor-overexpressing tumors

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World Journal of Clinical Oncology 2022年第11期13卷 880-895页

作者： winn aung Atsushi B Tsuji Kenjiro Hanaoka Tatsuya Higashi Department of Molecular Imaging and Theranostics Institute for Quantum Medical ScienceNational Institutes for Quantum and Radiological Science and TechnologyChiba 263-8555Japan Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences Keio UniversityTokyo 105-8512Japan

BACKGROUND 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 *** receptor(FR)membrane protein is frequently overexpressed in 40%of human cancer and a good candidate for tumor-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 *** To investigate the therapeutic efficacy of NIR-PDT induced by FolateSiR-1,a FRtargeted PS,in preclinical cancer *** FolateSiR-1 was developed by conjugating a folate moiety to the Si-rhodamine derivative through a negatively charged tripeptide *** 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 and in vivo fluorescence *** FR expressing OVCAR-3 and A4 cell lines were used as negative controls(FR-).The NIR light(635±3 nm)-induced phototoxic effect of FolateSiR-1 was evaluated by cell viability imaging *** time-dependent distribution of FolateSiR-1 and its specific accumulation in KB tumors was determined using in vivo longitudinal fluorescence *** PDT effect of FolateSiR-1 was evaluated in KB tumor bearing mice divided into four experimental groups:(1)FolateSiR-1(100μmol/L)alone;(2)FolateSiR-1(100μmol/L)followed by NIR irradiation(50 J/cm2);(3)NIR irradiation(50 J/cm2)alone;and(4)no *** volume measurement and immunohistochemical(IHC)and histological examinations of the tumors were performed to analyze the effect of *** High FR expression was observed in the KB cells by WB,but not in the OVCAR-3 and A4 *** FR-specific binding of FolateSiR-1 was observed by in vitro an

关键词： Photodynamic therapy Near-infrared Photosensitizer Folate receptor Fluorescence Cancer

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Imaging assessment of photosensitizer emission induced by radionuclide-derived Cherenkov radiation using charge-coupled device optical imaging and long-pass filters

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World Journal of Radiology 2023年第11期15卷 315-323页

作者： winn aung Atsushi B Tsuji Kazuaki Rikiyama Fumihiko Nishikido Satoshi Obara Tatsuya Higashi Department of Molecular Imaging and Theranostics Institute for Quantum Medical ScienceNational Institutes for Quantum Science and TechnologyChiba 263-8555Japan Department of Advanced Nuclear Medicine Sciences Institute for Quantum Medical ScienceNational Institutes for Quantum Science and TechnologyChiba 263-8555Japan

BACKGROUND Radionuclides produce Cherenkov radiation(CR),which can potentially activate photosensitizers(PSs)in *** groups have studied Cherenkov energy transfer to PSs using optical imaging;however,cost-effectively identifying whether PSs are excited by radionuclide-derived CR and detecting fluorescence emission from excited PSs remain a *** laboratories face the need for expensive dedicated *** To cost-effectively confirm whether PSs are excited by radionuclide-derived CR and distinguish fluorescence emission from excited *** The absorbance and fluorescence spectra of PSs were measured using a microplate reader and fluorescence spectrometer to examine the photo-physical properties of *** mitigate the need for expensive dedicated equipment and achieve the aim of the study,we developed a method that utilizes a chargecoupled device optical imaging system and appropriate long-pass filters of different wavelengths(manual sequential application of long-pass filters of 515,580,645,700,750,and 800 nm).Tetrakis(4-carboxyphenyl)porphyrin(TCPP)was utilized as a model *** doses of copper-64(^(64)CuCl_(2))(4,2,and 1 mCi)were used as CR-producing *** and data acquisition were performed 0.5 h after sample *** image analysis was conducted by using ImageJ software(National Institutes of Health)to visually evaluate TCPP *** The maximum absorbance of TCPP was at 390-430 nm,and the emission peak was at 670 *** CR and CRinduced TCPP emissions were observed using the optical imaging system and the high-transmittance long-pass filters described *** emission spectra of TCPP with a peak in the 645-700 nm window were obtained by calculation and subtraction based on the serial signal intensity(total flux)difference between^(64)CuCl_(2)+TCPP and^(64)CuCl_(2).Moreover,the differential fluorescence images of TCPP were obtained by subtracting the^(64)CuCl_(2)image from the^

关键词： Tetrakis(4-carboxyphenyl)porphyrin Photosensitizer emission Radionuclide Cherenkov radiation Optical imaging Long-pass filters

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