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

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), a...

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Bibliographic Details
Published in:Bioconjugate chemistry 2022-08, Vol.33 (8), p.1564-1573
Main Authors: Pringle, Toni A., Chan, Corey D., Luli, Saimir, Blair, Helen J., Rankin, Kenneth S., Knight, James C.
Format: Article
Language:English
Subjects:
Binding
Biomarkers
Bone imaging
Bone tumors
Chondrosarcoma
Fluorescence
Glycan
Immunoreactivity
Infrared imaging
Inoculation
Matrix metalloproteinase
Matrix metalloproteinases
Medical imaging
Metalloproteinase
Perturbation
Positron emission
Positron emission tomography
Radiochemistry
Sarcoma
Surgery
Tomography
Tumors
Young adults
Zirconium isotopes
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Summary: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.
ISSN:1043-1802
1520-4812
DOI:10.1021/acs.bioconjchem.2c00306