Tumor imaging using radiolabelled matrix metalloproteinase-activated anthrax proteins
<p><strong>Purpose:</strong> 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 MMP...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Journal article |
| Published: |
Society of Nuclear Medicine and Molecular Imaging
2019
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| _version_ | 1797073743647866880 |
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| author | Xavier, M Liu, S Bugge, T Baguna-Torres, J Mosley, M Hopkins, S Allen, P Berridge, G Vendrell, I Fischer, R Kersemans, V Smart, S Leppla, S Cornelissen, B |
| author_facet | Xavier, M Liu, S Bugge, T Baguna-Torres, J Mosley, M Hopkins, S Allen, P Berridge, G Vendrell, I Fischer, R Kersemans, V Smart, S Leppla, S Cornelissen, B |
| author_sort | Xavier, M |
| collection | OXFORD |
| description | <p><strong>Purpose:</strong> 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 <sup>111</sup>In-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).</p> <p><strong>Methods:</strong> 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 <sup>111</sup>In-radiolabelled PA-L1, <sup>111</sup>In-PA-WT<sup>K563C</sup> or <sup>111</sup>In-LF<sup>E687A</sup> (a catalytically inactive LF mutant) in tumour and normal tissues was measured using SPECT/CT imaging in vivo.</p> <p><strong>Results:</strong> 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 <sup>111</sup>In-LF<sup>E687A</sup> was demonstrated, and corroborated using confocal microscopy with fluorescently labelled LF<sup>E687A</sup>. Uptake was blocked by the broad-spectrum MMP inhibitor GM6001. In vivo imaging showed selective accumulation of <sup>111</sup>In-PA-L1 in MDA-MB-231 tumour xenografts (5.7±0.9%ID/g) at 3 h post intravenous administration. <sup>111</sup>In-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).</p> <p><strong>Conclusion:</strong> 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.</p> |
| first_indexed | 2024-03-06T23:26:24Z |
| format | Journal article |
| id | oxford-uuid:6a83a897-50df-4de6-9db0-cfd7b335a27f |
| institution | University of Oxford |
| last_indexed | 2024-03-06T23:26:24Z |
| publishDate | 2019 |
| publisher | Society of Nuclear Medicine and Molecular Imaging |
| record_format | dspace |
| spelling | oxford-uuid:6a83a897-50df-4de6-9db0-cfd7b335a27f2022-03-26T18:58:04ZTumor imaging using radiolabelled matrix metalloproteinase-activated anthrax proteinsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6a83a897-50df-4de6-9db0-cfd7b335a27fSymplectic Elements at OxfordSociety of Nuclear Medicine and Molecular Imaging2019Xavier, MLiu, SBugge, TBaguna-Torres, JMosley, MHopkins, SAllen, PBerridge, GVendrell, IFischer, RKersemans, VSmart, SLeppla, SCornelissen, B<p><strong>Purpose:</strong> 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 <sup>111</sup>In-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).</p> <p><strong>Methods:</strong> 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 <sup>111</sup>In-radiolabelled PA-L1, <sup>111</sup>In-PA-WT<sup>K563C</sup> or <sup>111</sup>In-LF<sup>E687A</sup> (a catalytically inactive LF mutant) in tumour and normal tissues was measured using SPECT/CT imaging in vivo.</p> <p><strong>Results:</strong> 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 <sup>111</sup>In-LF<sup>E687A</sup> was demonstrated, and corroborated using confocal microscopy with fluorescently labelled LF<sup>E687A</sup>. Uptake was blocked by the broad-spectrum MMP inhibitor GM6001. In vivo imaging showed selective accumulation of <sup>111</sup>In-PA-L1 in MDA-MB-231 tumour xenografts (5.7±0.9%ID/g) at 3 h post intravenous administration. <sup>111</sup>In-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).</p> <p><strong>Conclusion:</strong> 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.</p> |
| spellingShingle | Xavier, M Liu, S Bugge, T Baguna-Torres, J Mosley, M Hopkins, S Allen, P Berridge, G Vendrell, I Fischer, R Kersemans, V Smart, S Leppla, S Cornelissen, B Tumor imaging using radiolabelled matrix metalloproteinase-activated anthrax proteins |
| title | Tumor imaging using radiolabelled matrix metalloproteinase-activated anthrax proteins |
| title_full | Tumor imaging using radiolabelled matrix metalloproteinase-activated anthrax proteins |
| title_fullStr | Tumor imaging using radiolabelled matrix metalloproteinase-activated anthrax proteins |
| title_full_unstemmed | Tumor imaging using radiolabelled matrix metalloproteinase-activated anthrax proteins |
| title_short | Tumor imaging using radiolabelled matrix metalloproteinase-activated anthrax proteins |
| title_sort | tumor imaging using radiolabelled matrix metalloproteinase activated anthrax proteins |
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