Peptide Amphiphile Supramolecular Nanofibers Designed to Target Abdominal Aortic Aneurysms

Autor: Benjamin T. Ledford, Adam W. Akerman, Kui Sun, David C. Gillis, Jenna M. Weiss, Johnny Vang, Smaranda Willcox, Tristan D. Clemons, Hiroaki Sai, Ruomeng Qiu, Mark R. Karver, Jack D. Griffith, Nick D. Tsihlis, Samuel I. Stupp, John S. Ikonomidis, Melina R. Kibbe
Rok vydání: 2022
Předmět:
Zdroj: ACS Nano
ISSN: 1936-086X
1936-0851
DOI: 10.1021/acsnano.1c06258
Popis: 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 co-assembling 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.
Databáze: OpenAIRE
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