Abstract We0097: Inhibition of Post-Intervention Reatherogenesis Using a Targeted, Drug-Loaded Echogenic Liposomal Formulation

Introduction: We have previously demonstrated efficacy of an ultrasound-enhanced, locally administered pioglitazone-loaded echogenic liposome targeted to atheroma with an anti-ICAM-1 monoclonal antibody in preventing reatherogenesis following percutaneous intervention and stent placement in Yucatan miniswine peripheral arteries. We developed Atheroglitatide (AGT), an analogous product targeted to atheroma with a fibrin-binding peptide for translation to patient use. Hypothesis: Effective inhibition of reatherogenesis by AGT in the miniswine atherosclerosis model can be demonstrated by quantitative immunohistochemical (IHC) and intravascular ultrasound (IVUS) methods. Methods: To produce AGT, pioglitazone-loaded echogenic liposomes containing maleimido phosphatidylethanolamine were conjugated to a fibrin-binding nonapeptide, GPRPPGGGC. After stent placement at the sites of miniswine carotid and iliofemoral atheroma, AGT was administered through an EKOS catheter with or without concomitant IVUS. Four months later, IVUS imaging was performed. Arterial segments proximal and distal to the stent were processed for histological evaluation and IHC for E-selectin, a marker for atheroma-associated inflammation, with a fluorescent secondary antibody conjugated to AlexaFluor 555. Quantitation of IVUS and IHC images was performed. Results: The E-selectin-positive area (RFU/area) in the medial layer of arterial sections proximal to stented atheroma treated with AGT without US (0.00036 ± 0.00028 µm -2 ; n = 5) was greater than in sections treated with AGT+US (0.00004 ± 0.00002 µm -2 ; n = 4; p = 0.064) (Figure). Examination of IVUS images from the same arterial regions supported the IHC data. Conclusions: Efficacy of AGT in preventing reatherogenesis and utility of E-selectin staining for quantitation of atheroma progression are demonstrated in a miniswine model.