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ImmunoPET/NIRF/Cerenkov multimodality imaging of ICAM-1 in pancreatic ductal adenocarcinoma

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Abstract

Purpose

We dual-labeled an intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody (mAb) and evaluated its effectiveness for lesion detection and surgical navigation in pancreatic ductal adenocarcinoma (PDAC) via multiple noninvasive imaging approaches, including positron emission tomography (PET), near-infrared fluorescence (NIRF), and Cerenkov luminescence imaging (CLI).

Methods

ICAM-1 expression in PDAC cell lines (BxPC-3 and AsPC-1) was assessed via flow cytometry and immunofluorescent staining. An ICAM-1 mAb labeled by IRDye 800CW and radionuclide zirconium-89 (denoted as [89Zr]Zr-DFO-ICAM-1-IR800) was synthesized. Its performance was validated via in vivo comparative PET/NIRF/CLI and biodistribution (Bio-D) studies in nude mice bearing subcutaneous BxPC-3/AsPC-1 tumors or orthotopic BxPC-3 tumor models using nonspecific IgG as an isotype control tracer.

Results

ICAM-1 expression was strong in the BxPC-3 and minimal in the AsPC-1 cell line. Both multimodality imaging and Bio-D data exhibited more prominent uptake of [89Zr]Zr-DFO-ICAM-1-IR800 in BxPC-3 tumors than in AsPC-1 tumors. The uptake of [89Zr]Zr-DFO-IgG-IR800 in BxPC-3 tumors was similar to that of [89Zr]Zr-DFO-ICAM-1-IR800 in AsPC-1 tumors. These results demonstrate the desirable affinity and specificity of [89Zr]Zr-DFO-ICAM-1-IR800 compared to [89Zr]Zr-DFO-IgG-IR800. Orthotopic BxPC-3 tumor foci could also be clearly delineated by [89Zr]Zr-DFO-ICAM-1-IR800. An intermodal match was achieved in the ICAM-1–targeted immunoPET/NIRF/CLI. The positive expression levels of ICAM-1 in BxPC-3 tumor tissue were further confirmed by immunohistopathology.

Conclusion

We successfully developed a dual-labeled ICAM-1–targeted tracer for PET/NIRF/CLI of PDAC that can facilitate better diagnosis and intervention of PDAC upon clinical translation.

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Acknowledgements

We appreciate the Small Animal Imaging Facility (SAIF) at the Wisconsin Institutes for Medical Research (WIMR) in the University of Wisconsin–Madison for acquisition of imaging data.

Funding

This work was supported by the National Key Research and Development Program of China (Grant No. 2020YFA0909000), the University of Wisconsin–Madison, the National Institutes of Health (P30CA014520), the National Natural Science Foundation of China (Program for Young Scholars, Grant No. 81703468 and 82001878), and the Shanghai Rising-Star Program (Grant No. 20QA1406100).

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Author notes

  1. Miao Li and Weijun Wei contributed equally to this work.

Authors and Affiliations

  1. Department of Radiology, the First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Rd, Xi’an, 710061, Shaanxi, China

    Miao Li

  2. Department of Radiology, University of Wisconsin–Madison, Room 7137, 1111 Highland Ave, Madison, WI, 53705, USA

    Miao Li, Weijun Wei, Dawei Jiang, Tianye Cao, Kevin Fan, Weiyu Chen & Weibo Cai

  3. Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Rd, Shanghai, 200127, China

    Weijun Wei & Jianjun Liu

  4. Department of Medical Physics, University of Wisconsin–Madison, Room B1143, 1111 Highland Ave, Madison, WI, 53705, USA

    Todd E. Barnhart, Jonathan W. Engle & Weibo Cai

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  1. Miao Li
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Supplementary Information

ESM 1

Supplemental Fig. 1 Chromatograms from the assays for quality control of the tracer. Panels: a the ultraviolet–visible (UV–Vis) spectrum of DFO-ICAM-1-IR800 conjugate (1× PBS as blank control for baseline subtraction), with the typical absorption peak of protein at 280 nm and that of 800CW fluorophore at 774 nm in 1× PBS, respectively; b instant thin-layer chromatography (iTLC) for the tests of radiochemical purity and stability of [89Zr]Zr-DFO-ICAM-1-IR800 in 1× PBS solution (baseline offset of the chromatograms at 1 h and 3 h postpurification following the default of iTLC scanner software); radioactive (c) and UV (d; at 280 nm) size exclusion chromatography (SEC) for the test of integrity of [89Zr]Zr-DFO-ICAM-1-IR800. Supplemental Fig. 2 The typical in vivo positron emission tomography (PET) maximum-intensity projections (MIP) of nude mice bearing subcutaneous and orthotopic pancreatic ductal adenocarcinoma (PDAC) tumors (BxPC-3 and AsPC-1) at all time points. Groups: IR800/89Zr dual-labeled ICAM-1 monoclonal antibody ([89Zr]Zr-DFO-ICAM-1-IR800) injected into subcutaneous BxPC-3 model (Group 1); [89Zr]Zr-DFO-ICAM-1-IR800 injected into subcutaneous AsPC-1 model (Group 2); IR800/89Zr dual-labeled IgG control ([89Zr]Zr-DFO-IgG-IR800) injected into subcutaneous BxPC-3 model (Group 3); [89Zr]Zr-DFO-ICAM-1-IR800 injected into orthotopic BxPC-3 model (Group 4). Supplemental Fig. 3 The typical in vivo near-infrared fluorescent (NIRF) images of nude mice bearing subcutaneous and orthotopic pancreatic ductal adenocarcinoma (PDAC) tumors (BxPC-3 and AsPC-1) at all time points. Groups: IR800/89Zr dual-labeled ICAM-1 monoclonal antibody ([89Zr]Zr-DFO-ICAM-1-IR800) injected into subcutaneous BxPC-3 model (Group 1); [89Zr]Zr-DFO-ICAM-1-IR800 injected into subcutaneous AsPC-1 model (Group 2); IR800/89Zr dual-labeled IgG control ([89Zr]Zr-DFO-IgG-IR800) injected into subcutaneous BxPC-3 model (Group 3); [89Zr]Zr-DFO-ICAM-1-IR800 injected into orthotopic BxPC-3 model (Group 4). Supplemental Table 1 The quantitative uptake values withdrawn from the region of interest (ROI) in the in vivo positron emission tomography (PET) images of nude mice bearing subcutaneous and orthotopic pancreatic ductal adenocarcinoma (PDAC) tumors (BxPC-3 and AsPC-1) injected with IR800/89Zr dual-labeled ICAM-1 monoclonal antibody ([89Zr]Zr-DFO-ICAM-1-IR800) or IgG isotype control ([89Zr]Zr-DFO-IgG-IR800) at all time points. Supplemental Table 2 The radioactive ex vivo bio-distribution (Bio-D) of IR800/89Zr dual-labeled ICAM-1 monoclonal antibody ([89Zr]Zr-DFO-ICAM-1-IR800) or IgG control ([89Zr]Zr-DFO-IgG-IR800) in the tumors and major organs of subcutaneous or orthotopic pancreatic ductal adenocarcinoma (PDAC) models (BxPC-3 and AsPC-1) at 120 h postinjection (p.i.). Supplemental Table 3 The quantitative tumor-to-muscle ratio (TMR) of average radiant efficiency withdrawn from the region of interest (ROI) in the in vivo near-infrared fluorescent (NIRF) images of nude mice bearing subcutaneous and orthotopic pancreatic ductal adenocarcinoma (PDAC) tumors (BxPC-3 and AsPC-1) injected with IR800/89Zr dual-labeled ICAM-1 monoclonal antibody ([89Zr]Zr-DFO-ICAM-1-IR800) or IgG isotype control ([89Zr]Zr-DFO-IgG-IR800) at all time points. (DOCX 3290 kb).

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Li, M., Wei, W., Barnhart, T.E. et al. ImmunoPET/NIRF/Cerenkov multimodality imaging of ICAM-1 in pancreatic ductal adenocarcinoma. Eur J Nucl Med Mol Imaging 48, 2737–2748 (2021). https://doi.org/10.1007/s00259-021-05216-3

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