PROJECT SUMMARY/ABSTRACT Abdominal aortic aneurysm (AAA) is the most common aortic pathology, and accounts for approximately 10,000 deaths annually in the United States. While many preclinical therapeutics have shown great promise, pharmacological interventions have not shown significant inhibition of AAA enlargement. The goal of this proposal is to develop an intravenously administered nanoscale material that will specifically target aneurysmal tissue and serve as the foundation for the development of a nanotherapeutic to prevent and/or regress AAA. Towards this goal, our laboratory has developed and evaluated a novel intravascular targeted technology based on peptide amphiphile (PA) molecules. We have designed and evaluated several PA nanofibers to target features of the aneurysmal microenvironment including matrix metalloproteinase-2 (MMP-2), fragmented elastin, and membrane type 1-matrix metalloproteinase (MT1-MMP). Our results demonstrated excellent targeting for the MMP-2-targeting PA nanofiber. These data are ideal given that a key feature of the pathophysiology of aneurysm formation is the upregulation of MMP-2, and that MMP-2 is overexpressed in both small and large aneurysms. Thus, we hypothesize that PA nanofibers designed to specifically target MMP-2 will bind to aneurysmal tissue and be biocompatible. To investigate this hypothesis, the Specific Aims are to: 1) Characterize and optimize the structural properties and binding kinetics of PA nanofibers targeted to MMP-2 in vitro. An MMP-2-targeting peptide has been incorporated into a PA sequence. We will determine critical parameters for co-assembly with diluent PA to enable nanofiber formation. The resulting AAA-targeting PAs will be characterized for nanofiber formation, structural dimensions, and MMP-2 binding kinetics of the peptide and the co-assembled nanofiber. 2) Evaluate the binding specificity and duration of the MMP-2- targeted PA nanofiber to aneurysmal tissue in vivo. We will induce AAA in the infrarenal aorta of male and female Sprague Dawley rats by exposure to CaCl2 to test targeting capability of our PA nanofibers. We will also determine optimal concentration, dose, and co-assembly ratios. We will then determine the binding duration for the optimal nanofiber dose and co-assembly parameters. 3) Determine the biodistribution, elimination, and safety of the targeted PA nanofiber in vivo. Specifically, blood, bile, urine, and all vital organs will be assessed at multiple time points before/after administration of the targeted PA nanofiber to determine biodistribution, elimination, and safety of the targeted PA nanofiber. Successful completion of this F32 research proposal will result in the development of a nanotechnology specifically targeted to aneurysmal tissue, and serve as the foundation to develop an effective therapy to prevent and/or regress AAA formation. The experience gained from this proposal under the mentorship of Drs. Kibbe and Ikonomidis, both established i...