2026-06-14T03:29:48Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/52092024-11-29T23:29:59Zcom_20.500.12105_19604com_20.500.12105_2051com_20.500.12105_2173col_20.500.12105_19605col_20.500.12105_19597
Repisalud
author
de Lucas, A. G.
author
Schuhmacher, A. J.
author
Oteo, M.
author
Romero, E.
author
Camara, J. A.
author
de Martino, A.
author
Arroyo, Alicia G
author
Morcillo, M. A.
author
Squatrito, Massimo
author
Martinez Torrecuadrada, Jorge Luis
author
Mulero, Francisca
funder
Fundación Española para la Ciencia y la Tecnología
funder
Comunidad de Madrid (España)
funder
Fundación BBVA
funder
Madrid-MIT M+Visión Consortium
funder
Fundación Seve Ballesteros
2017-10-30T13:15:41Z
2017-10-30T13:15:41Z
2016
PLoS One. 2016; 11(7):e0158634
10.1371/journal.pone.0158634
1932-6203
Plos One
27462980
http://hdl.handle.net/20.500.12105/5209
Background 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. Methods An anti-human MT1-MMP monoclonal antibody (mAb), LEM2/15, was conjugated to p-isothiocyanatobenzyl-desferrioxamine (DFO-NCS) for Zr-89 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. Results Zr-89 labeling of DFO-LEM2/ 15 was achieved with high yield (>90\%) and specific activity (78.5 MBq/mg). Biodistribution experiments indicated that Zr-89-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 Zr-89-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. Zr-89-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. Conclusion A new anti MT1-MMP-mAb tracer, Zr-89-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.
eng
P-ISOTHIOCYANATOBENZYL-DESFERRIOXAMINE
TYPE-1 MATRIX-METALLOPROTEINASE
GLIOBLASTOMA-MULTIFORME
MONOCLONAL-ANTIBODIES
1-MATRIX METALLOPROTEINASE
ADJUVANT TEMOZOLOMIDE
BIFUNCTIONAL CHELATE
ENDOTHELIAL-CELLS
BRAIN-TUMORS
IN-VIVO
Targeting MT1-MMP as an ImmunoPET-Based Strategy for Imaging Gliomas
journal article
URL
https://repisalud.isciii.es/bitstreams/fb59579f-e421-45bf-9b02-004ca88c9799/download
File
MD5
1f0debbd5f1be7d5320d5487761f0df3
5083894
application/pdf
TargetingMT1-MMPasAnImmunoPET-Based_2016
URL
https://repisalud.isciii.es/bitstreams/8543ca92-c33b-4a47-937c-21d80551c863/download
File
MD5
e7cd0ce966098c98dca862ab64434feb
67388
text/plain
TargetingMT1-MMPasAnImmunoPET-Based_2016.txt