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Targeting MT1-MMP as an ImmunoPET-Based Strategy for Imaging Gliomas

de Lucas, A G ; Schuhmacher, A J ; Oteo, M ; Romero, E ; Cámara, J A ; de Martino, A ; Arroyo, A G ; Morcillo, M Á ; Squatrito, M ; Martinez-Torrecuadrada, J L ; Mulero, F Ulasov, Ilya

PloS one, 2016-07, Vol.11 (7), p.e0158634-e0158634 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Targeting MT1-MMP as an ImmunoPET-Based Strategy for Imaging Gliomas
Autor: de Lucas, A G ; Schuhmacher, A J ; Oteo, M ; Romero, E ; Cámara, J A ; de Martino, A ; Arroyo, A G ; Morcillo, M Á ; Squatrito, M ; Martinez-Torrecuadrada, J L ; Mulero, F
Ulasov, Ilya
Assuntos: Angiogenesis ; Animal models ; Animals ; Antibodies, Monoclonal - immunology ; Biology and Life Sciences ; Biomarkers ; Biomarkers, Tumor - metabolism ; Blood-brain barrier ; Brain cancer ; Brain Neoplasms - diagnostic imaging ; Brain Neoplasms - enzymology ; Brain research ; Breast cancer ; Breast carcinoma ; Cell Line, Tumor ; Deferoxamine ; Diagnosis ; Genetic aspects ; Glioblastoma ; Glioblastoma - diagnostic imaging ; Glioblastoma - enzymology ; Glioblastoma multiforme ; Glioma ; Gliomas ; Growth factors ; Humans ; Imaging ; Immunoglobulins ; Labelling ; Matrix metalloproteinase ; Matrix Metalloproteinase 14 - immunology ; Matrix Metalloproteinase 14 - metabolism ; Medical diagnosis ; Medical imaging ; Medical prognosis ; Medical research ; Medicine and Health Sciences ; Membrane permeability ; Metalloenzymes ; Metalloproteinase ; Mice ; Mice, Nude ; Monoclonal antibodies ; Neoplasm Transplantation ; Neuroimaging ; Neurospheres ; NMR ; Nuclear magnetic resonance ; Permeability ; PET imaging ; Physiological aspects ; Positron emission ; Positron emission tomography ; Positron-Emission Tomography - methods ; Prognosis ; Radioisotopes ; Research and Analysis Methods ; Tomography ; Tumors ; X-Ray Microtomography ; Xenografts
É parte de: PloS one, 2016-07, Vol.11 (7), p.e0158634-e0158634
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Competing Interests: The authors have declared that no competing interests exist.
Conceived and designed the experiments: AJS MS MAM JLMT FM. Performed the experiments: AJS AGL MO ER JAC. Analyzed the data: AJS MS AM MAM JLMT FM. Contributed reagents/materials/analysis tools: AGA. Wrote the paper: MS AJS MAM AGA JLMT FM.
Descrição: A critical challenge in the management of Glioblastoma Multiforme (GBM) tumors is the accurate diagnosis and assessment of tumor progression in a noninvasive manner. We have identified Membrane-type 1 matrix metalloproteinase (MT1-MMP) as an attractive biomarker for GBM imaging since this protein is actively involved in tumor growth and progression, correlates with tumor grade and is closely associated with poor prognosis in GBM patients. Here, we report the development of an immunoPET tracer for effective detection of MT1-MMP in GBM models. An anti-human MT1-MMP monoclonal antibody (mAb), LEM2/15, was conjugated to p-isothiocyanatobenzyl-desferrioxamine (DFO-NCS) for 89Zr labeling. Biodistribution and PET imaging studies were performed in xenograft mice bearing human GBM cells (U251) expressing MT1-MMP and non-expressing breast carcinoma cells (MCF-7) as negative control. Two orthotopic brain GBM models, patient-derived neurospheres (TS543) and U251 cells, with different degrees of blood-brain barrier (BBB) disruption were also used for PET imaging experiments. 89Zr labeling of DFO-LEM2/15 was achieved with high yield (>90%) and specific activity (78.5 MBq/mg). Biodistribution experiments indicated that 89Zr-DFO-LEM2/15 showed excellent potential as a radiotracer for detection of MT1-MMP positive GBM tumors. PET imaging also indicated a specific and prominent 89Zr-DFO-LEM2/15 uptake in MT1-MMP+ U251 GBM tumors compared to MT1-MMP- MCF-7 breast tumors. Results obtained in orthotopic brain GBM models revealed a high dependence of a disrupted BBB for tracer penetrance into tumors. 89Zr-DFO-LEM2/15 showed much higher accumulation in TS543 tumors with a highly disrupted BBB than in U251 orthotopic model in which the BBB permeability was only partially increased. Histological analysis confirmed the specificity of the immunoconjugate in all GBM models. A new anti MT1-MMP-mAb tracer, 89Zr-DFO-LEM2/15, was synthesized efficiently. In vivo validation showed high-specific-contrast imaging of MT1-MMP positive GBM tumors and provided strong evidence for utility of MT1-MMP-targeted immunoPET as an alternate to nonspecific imaging of GBM.
Editor: United States: Public Library of Science
Idioma: Inglês

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Targeting MT1-MMP as an ImmunoPET-Based Strategy for Imaging Gliomas

de Lucas, A G ; Schuhmacher, A J ; Oteo, M ; Romero, E ; Cámara, J A ; de Martino, A ; Arroyo, A G ; Morcillo, M Á ; Squatrito, M ; Martinez-Torrecuadrada, J L ; Mulero, F Ulasov, Ilya

United States: Public Library of Science

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