title: Development of Radiolabeled Membrane Type-1 Matrix Metalloproteinase Activatable Cell Penetrating Peptide Imaging Probes.
abstract: Membrane type-1 matrix metalloproteinase (MT1-MMP or MMP-14) plays an important role in adverse cardiac remodelling. Here, we aimed to develop radiolabeled activatable cell penetrating peptides (ACPP) sensitive to MT1-MMP for the detection of elevated MT1-MMP levels in adverse cardiac remodelling. Three ACPP analogs were synthesized and the most potent ACPP analog was selected using MT1-MMP sensitivity and enzyme specificity assays. This ACPP, called ACPP-B, showed high sensitivity towards MT1-MMP, soluble MMP-2, and MT2-MMP, while limited sensitivity was measured for other members of the MMP family. In in vitro cell assays, radiolabeled ACPP-B showed efficient cellular uptake upon activation. A pilot in vivo study showed increased uptake of the radiolabeled probe in regions of infarcted myocardium compared to remote myocardium, warranting further in vivo evaluation.
authors.affiliation: Department of Biomedical Engineering, Eindhoven University of Technology, High Tech Campus 11, Eindhoven 5656 AE, The Netherlands. sander_van_duijnhoven@outlook.com.|Department of Oncology Solutions, Philips Research, High Tech Campus 11, Eindhoven 5656 AE, The Netherlands. sander_van_duijnhoven@outlook.com.
authors.forename: Sander M J
authors.initials: SM
authors.lastname: van Duijnhoven
authors.affiliation: Tagworks Pharmaceuticals, High Tech Campus 11, Eindhoven 5656 AE, The Netherlands. marc.robillard@tagworkspharma.com.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Robillard
authors.affiliation: Department of Biomedical Engineering, Eindhoven University of Technology, High Tech Campus 11, Eindhoven 5656 AE, The Netherlands. k.nicolay@tue.nl.
authors.forename: Klaas
authors.initials: K
authors.lastname: Nicolay
authors.affiliation: Department of Biomedical Engineering, Eindhoven University of Technology, High Tech Campus 11, Eindhoven 5656 AE, The Netherlands. h.gruell@tue.nl.|Department of Oncology Solutions, Philips Research, High Tech Campus 11, Eindhoven 5656 AE, The Netherlands. h.gruell@tue.nl.
authors.forename: Holger
authors.initials: H
authors.lastname: Grüll
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D051379:Mice; D015335:Molecular Probes; D011868:Radioisotopes / Q000378:metabolism*; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: D057846:Cell-Penetrating Peptides; D015335:Molecular Probes; D011868:Radioisotopes; D053511:Matrix Metalloproteinase 14
keywords: activatable cell penetrating peptide; matrix metalloproteinase-14; membrane type-1 matrix metalloproteinase; molecular imaging; myocardial infarction; peptide chemistry; radiolabeling