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Synthesis and In Vivo Evaluation of a Site-specifically Labeled Radioimmunoconjugate for Dual-Modal (PET/NIRF) Imaging of MT1-MMP in Sarcomas

Lookup NU author(s): Dr Toni Pringle, Dr Corey ChanORCiD, Dr Saimir LuliORCiD, Dr Helen Blair, Dr Kenneth RankinORCiD, Dr James KnightORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

Bone sarcomas are devastating primary bone cancers that mostly affect children, young adults, and the elderly. These aggressive tumors are associated with poor survival, and surgery remains the mainstay of treatment. Surgical planning is increasingly informed by positron emission tomography (PET), and tumor margin identification during surgery is aided by near-infrared fluorescence (NIRF) imaging, yet these investigations are confounded by probes that lack specificity for sarcoma biomarkers. We report the development of a dual-modal (PET/NIRF) immunoconjugate ([⁸⁹Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW) that targets MT1-MMP, a matrix metalloproteinase overexpressed in high-grade sarcomas. [⁸⁹Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW was synthesized via site-specific chemoenzymatic glycan modification, characterized, and isolated in high specific activity and radiochemical purity. Saturation binding and immunoreactivity assays indicated only minor perturbation of binding properties. A novel mouse model of dedifferentiated chondrosarcoma based on intrafemoral inoculation of HT1080 WT or KO cells (high and low MT1-MMP expression, respectively) was used to evaluate target binding and biodistribution. Fluorescence and Cerenkov luminescence images of [⁸⁹Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW showed preferential uptake in HT1080 WT tumors. Ex vivo gamma counting revealed that uptake in MT1-MMP-positive tumors was significantly higher than that in control groups. Taken together, [⁸⁹Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW is a promising dual-modal sarcoma imaging agent for pre-operative surgical planning and intraoperative surgical guidance.

Publication metadata

Author(s): Pringle TA, Chan CD, Luli S, Blair HJ, Rankin KS, Knight JC

Publication type: Article

Publication status: Published

Journal: Bioconjugate Chemistry

Year: 2022

Volume: 33

Issue: 8

Pages: 1564-1573

Print publication date: 17/08/2022

Online publication date: 22/07/2022

Acceptance date: 11/07/2022

Date deposited: 01/08/2022

ISSN (print): 1043-1802

ISSN (electronic): 1520-4812

Publisher: American Chemical Society

URL: https://doi.org/10.1021/acs.bioconjchem.2c00306

DOI: 10.1021/acs.bioconjchem.2c00306

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