@article{c99f81c9e3d148eaa14d07a322eafbb8,
title = "Peptide Amphiphile Supramolecular Nanofibers Designed to Target Abdominal Aortic Aneurysms",
abstract = "An abdominal aortic aneurysm (AAA) is a localized dilation of the aorta located in the abdomen that poses a severe risk of death when ruptured. The cause of AAA is not fully understood, but degradation of medial elastin due to elastolytic matrix metalloproteinases is a key step leading to aortic dilation. Current therapeutic interventions are limited to surgical repair to prevent catastrophic rupture. Here, we report the development of injectable supramolecular nanofibers using peptide amphiphile molecules designed to localize to AAA by targeting fragmented elastin, matrix metalloproteinase 2 (MMP-2), and membrane type 1 matrix metalloproteinase. We designed four targeting peptide sequences from X-ray crystallographic data and incorporated them into PA molecules via solid phase peptide synthesis. After coassembling targeted and diluent PAs at different molar ratios, we assessed their ability to form nanofibers using transmission electron microscopy and to localize to AAA in male and female Sprague-Dawley rats using light sheet fluorescence microscopy. We found that three formulations of the PA nanofibers were able to localize to AAA tissue, but the MMP-2 targeting PA substantially outperformed the other nanofibers. Additionally, we demonstrated that the MMP-2 targeting PA nanofibers had an optimal dose of 5 mg (12 mg/kg). Our results show that there was not a significant difference in targeting between male and female Sprague-Dawley rats. Given the ability of the MMP-2 targeting PA nanofiber to localize to AAA tissue, future studies will investigate potential diagnostic and targeted drug delivery applications for AAA. ",
keywords = "abdominal aortic aneurysm, matrix metalloproteinases, peptide amphiphile, self-assembly, targeted nanomaterials",
author = "Ledford, {Benjamin T.} and Akerman, {Adam W.} and Kui Sun and Gillis, {David C.} and Weiss, {Jenna M.} and Johnny Vang and Smaranda Willcox and Clemons, {Tristan D.} and Hiroaki Sai and Ruomeng Qiu and Karver, {Mark R.} and Griffith, {Jack D.} and Tsihlis, {Nick D} and Stupp, {Samuel I.} and Ikonomidis, {John S.} and Kibbe, {Melina Rae}",
note = "Funding Information: This study was supported, in part, by funding from the University of North Carolina School of Medicine. T.D.C. acknowledges funding support from an American Australian Association Fellowship and the Center for Regenerative Nanomedicine at the Simpson Querrey Institute for BioNanotechnology at Northwestern University. The authors would like to acknowledge technical support provided by several core facilities at UNC Chapel Hill including: the UNC Microscopy Services Lab, the Small Animal Imaging Facility at the Biomedical Research Imaging Center, the R. L. Juliano Bioinformatics Core facility, and the Neuroscience Microscopy Core. The TEM studies were supported by a grant to J.D.G. from the National Institutes of Health (5R0)-ES031635. The Microscopy Services Laboratory, Department of Pathology and Laboratory Medicine, is supported in part by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. Research reported in this publication was supported in part by the North Carolina Biotech Center Institutional Support Grant 2016-IDG-1016. MST and CD spectroscopy experiments were conducted at the UNC Macromolecular Interactions Facility, which is supported by the National Cancer Institute of the National Institutes of Health under award number P30CA016086. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. X-ray experiments were carried out at the DuPont-Northwestern-Dow Collaborative Access Team (DND-CAT) located at Sector 5 of the Advanced Photon Source (APS). DND-CAT is supported by Northwestern University, E.I. DuPont de Nemours & Co., and The Dow Chemical Company. Use of APS, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357. The authors would like to personally thank M. Seniw at the Simpson Querrey Institute for BioNanotechnology for peptide amphiphile nanofiber illustration design. Peptide amphiphile synthesis was performed in the Peptide Synthesis Core Facility of the Simpson Querrey Institute at Northwestern University. The U.S. Army Research Office, the U.S. Army Medical Research and Materiel Command, and Northwestern University provided funding to develop this facility, and ongoing support is being received from the Soft and Hybrid Nanotechnology Experimental (SHyNE) (NSF ECCS-2025633). Publisher Copyright: {\textcopyright} 2022 American Chemical Society.",
year = "2021",
doi = "10.1021/acsnano.1c06258",
language = "English (US)",
journal = "ACS Nano",
issn = "1936-0851",
publisher = "American Chemical Society",
}