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J Nucl Med. 2019 Apr 6. pii: jnumed.119.226423. doi: 10.2967/jnumed.119.226423. [Epub ahead of print]

Tumor imaging using radiolabelled matrix metalloproteinase-activated anthrax proteins.

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Department of Oncology, University of Oxford, United Kingdom.
Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, NIH, United States.
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, United Kingdom.
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, United States.


Purpose: Increased activity of matrix metalloproteinases (MMPs) is associated with worse prognosis in different cancer types. The protective antigen (PA-WT) of the binary anthrax lethal toxin was modified to form a pore in cell membranes only when cleaved by MMPs (PA-L1). Anthrax lethal factor (LF) is then able to translocate through these pores. Here, we used an 111In-radiolabelled form of LF with the PA/LF system for non-invasive in vivo imaging of MMP activity in tumour tissue by single photon emission computed tomography (SPECT). Methods: MMP-mediated activation of PA-L1 was correlated to anthrax receptor expression and MMP activity in a panel of cancer cells (HT1080, MDA-MB-231, B8484 and MCF7). Uptake of 111In-radiolabelled PA-L1, 111In-PA-WTK563C or 111In-LFE687A (a catalytically inactive LF mutant) in tumour and normal tissues was measured using SPECT/CT imaging in vivo. Results: Activation of PA-L1 in vitro correlated with anthrax receptor expression and MMP activity (HT1080>MDA-MB-231>B8484>MCF7). PA-L1-mediated delivery of 111In-LFE687A was demonstrated, and corroborated using confocal microscopy with fluorescently labelled LFE687A Uptake was blocked by the broad-spectrum MMP inhibitor GM6001. In vivo imaging showed selective accumulation of 111In-PA-L1 in MDA-MB-231 tumour xenografts (5.7±0.9%ID/g) at 3 h post intravenous administration. 111In-LFE687A was selectively delivered to MMP-positive MDA-MB-231 tumour tissue by MMP-activatable PA-L1 (5.98±0.62%ID/g), but not by furin cleavable PA-WT (1.05±0.21%ID/g), or a non-cleavable PA variant control, PA-U7 (2.74 ± 0.24%ID/g). Conclusion: Taken together, our results indicate that radiolabelled forms of mutated anthrax lethal toxin hold promise for non-invasive imaging of MMP activity in tumour tissue.


Animal Imaging; Anthrax lethal toxin; Cancer; MMP; Molecular Imaging; Oncology: Breast; Other; Pretargeting; Radiopharmaceuticals; SPECT


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