Abstract 272: Targeted Activatable Cell-Penetrating Peptides Identify Atherosclerotic Plaques in Mice with Noninvasive Magnetic Resonance Imaging

Abstract

Atherosclerotic plaque progression from stable lesions to advanced plaques that can spontaneously disrupt is promoted by numerous enzymes, including thrombin and extracellular matrix metalloproteases (MMPs). Assessing the activity of these enzymes in vivo by noninvasive MRI could be a valuable tool for the risk assessment of plaque disruption and a powerful method for monitoring the effectiveness of therapies. Novel thrombin- and MMP-targeted activatable cell-penetrating peptides (ACPPs) have a mechanism for activation and retention at sites of high enzymatic activity and show great promise for plaque detection due to incorporation of gadolinium (Gd), an MR active agent. In addition to the morphological information that is traditionally provided by MRI, both ACPPs also allow for a functional assessment of plaque. We hypothesized that these new targeted ACPPs would provide enhanced contrast at a smaller dosage and improve the sensitivity and specificity of plaque detection. The aorta of fat fed male ApoE knockout mice were imaged with a T1-weighted spin echo sequence before and after the administration of a substandard dose of non-targeted Gd-DTPA (2.5 μmol/kg, compared to the standard dose of 0.1-0.2 mol/kg). Administration of a comparable dose of thrombin- or MMP-targeted ACPP yielded a great increase in contrast around the aortic plaques (Figure 1). In conclusion, administration of the targeted ACPP achieved superior contrast and, therefore, demonstrates the potential to achieve high detection power of plaques with a much lower and safer dose of Gd.