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.
Highlights
The use of activatable cell penetrating imaging probes is a promising strategy for the in vivo detection of proteolytic activity in pathological conditions [1,2,3]
The peptides activatable cell penetrating peptides (ACPP)-A, ACPP-B, and ACPP-C with and without SHPP functionality were successfully prepared by Fmoc solid-phase peptide synthesis and in-solution coupling strategies, and purified by reversed phase—HPLC
The calculated volume-of-distribution for ACPP-B is 0.3 L/kg, which is in the same range as for ACPP-2/9, and indicates that the probe is rapidly distributed throughout the extracellular extravascular space [29]. These results indicate that the differences between ACPP-2/9 and ACPP-B activation in the vasculature cannot be attributed to difference in blood kinetics, but are most likely the result of the difference in sensitivity for circulating
Summary
The use of activatable cell penetrating imaging probes is a promising strategy for the in vivo detection of proteolytic activity in pathological conditions [1,2,3]. A radiolabeled activatable cell penetrating peptide (ACPP) sensitive toward matrix metalloproteinases (MMP)-2 and -9 was successfully employed for MMP detection in the course of remodeling post-myocardial infarction in vivo [1]. Besides activation in infarcted heart tissue, the MMP-2/9 sensitive ACPP probe showed a considerable degree of activation in the vascular compartment, leading to background uptake of the activated probe in basically all tissues [1]. Membrane type-1 matrix metalloproteinase (MT1-MMP or MMP-14) has been identified to be such a tissue-specific target. MT1-MMP is involved in several protein modification and biological signaling pathways [4,5]
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