PT  - JOURNAL ARTICLE
AU  - Mary-Ann Elvina Xavier
AU  - Shihui Liu
AU  - Thomas H. Bugge
AU  - Julia Baguña Torres
AU  - Michael Mosley
AU  - Samantha L. Hopkins
AU  - Phillip D. Allen
AU  - Georgina Berridge
AU  - Iolanda Vendrell
AU  - Roman Fischer
AU  - Veerle Kersemans
AU  - Sean Smart
AU  - Stephen H. Leppla
AU  - Bart Cornelissen
TI  - Tumor Imaging Using Radiolabeled Matrix Metalloproteinase–Activated Anthrax Proteins
AID  - 10.2967/jnumed.119.226423
DP  - 2019 Oct 01
TA  - Journal of Nuclear Medicine
PG  - 1474--1482
VI  - 60
IP  - 10
4099  - http://jnm.snmjournals.org/content/60/10/1474.short
4100  - http://jnm.snmjournals.org/content/60/10/1474.full
SO  - J Nucl Med2019 Oct 01; 60
AB  - Increased activity of matrix metalloproteinases (MMPs) is associated with worse prognosis in different cancer types. The wild-type protective antigen (PA-WT) of the binary anthrax lethal toxin was modified to form a pore in cell membranes only when cleaved by MMPs (to form PA-L1). Anthrax lethal factor (LF) is then able to translocate through these pores. Here, we used a 111In-radiolabeled form of LF with the PA/LF system for noninvasive in vivo imaging of MMP activity in tumor tissue by 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-radiolabeled PA-L1, 111In-PA-WTK563C, or 111In-LFE687A (a catalytically inactive LF mutant) in tumor 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 was corroborated using confocal microscopy with fluorescently labeled 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 tumor xenografts (5.7 ± 0.9 percentage injected dose [%ID]/g) at 3 h after intravenous administration. 111In-LFE687A was selectively delivered to MMP-positive MDA-MB-231 tumor 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 noncleavable PA variant control, PA-U7 (2.74 ± 0.24 %ID/g). Conclusion: Taken together, our results indicate that radiolabeled forms of mutated anthrax lethal toxin hold promise for noninvasive imaging of MMP activity in tumor tissue.