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Open AccessArticle

Development of Fractalkine-Targeted Nanofibers that Localize to Sites of Arterial Injury

1
Department of Surgery, Center for Nanotechnology in Drug Delivery, University of North Carolina, Chapel Hill, NC 27599, USA
2
Simpson Querrey Institute, Northwestern University, Chicago, IL 60611, USA
3
Department of Chemistry, Northwestern University, Evanston, IL 60208, USA
4
Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, USA
5
Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
6
Department of Medicine, Northwestern University, Chicago, IL 60611, USA
7
Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599, USA
*
Author to whom correspondence should be addressed.
Nanomaterials 2020, 10(3), 420; https://doi.org/10.3390/nano10030420
Received: 30 December 2019 / Revised: 25 February 2020 / Accepted: 26 February 2020 / Published: 28 February 2020
Atherosclerosis is the leading cause of death and disability around the world, with current treatments limited by neointimal hyperplasia. Our goal was to synthesize, characterize, and evaluate an injectable, targeted nanomaterial that will specifically bind to the site of arterial injury. Our target protein is fractalkine, a chemokine involved in both neointimal hyperplasia and atherosclerosis. We showed increased fractalkine staining in rat carotid arteries 24 h following arterial injury and in the aorta of low-density lipoprotein receptor knockout (LDLR-/-) mice fed a high-fat diet for 16 weeks. Three peptide amphiphiles (PAs) were synthesized: fractalkine-targeted, scrambled, and a backbone PA. PAs were ≥90% pure on liquid chromatography/mass spectrometry (LCMS) and showed nanofiber formation on transmission electron microscopy (TEM). Rats systemically injected with fractalkine-targeted nanofibers 24 h after carotid artery balloon injury exhibited a 4.2-fold increase in fluorescence in the injured artery compared to the scrambled nanofiber (p < 0.001). No localization was observed in the non-injured artery or with the backbone nanofiber. Fluorescence of the fractalkine-targeted nanofiber increased in a dose dependent manner and was observed for up to 48 h. These data demonstrate the presence of fractalkine after arterial injury and the localization of our fractalkine-targeted nanofiber to the site of injury and serve as the foundation to develop this technology further. View Full-Text
Keywords: neointimal hyperplasia; arterial injury; cardiovascular disease prevention; fractalkine; nanofibers; targeted therapeutic; targeted delivery vehicle neointimal hyperplasia; arterial injury; cardiovascular disease prevention; fractalkine; nanofibers; targeted therapeutic; targeted delivery vehicle
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Graphical abstract

  • Supplementary File 1:

    PDF-Document (PDF, 532 KB)

  • Externally hosted supplementary file 1
    Doi: 10.5281/zenodo.3595384
    Description: Supplemental Figure 1. (A) Schematic of fractalkine (CX3CL1) and its associated receptor (CX3CR1) on monocytes. Monocytes attracted to the area by soluble CX3CL1 (sCX3CL1), attach to activated endothelial cells through fractalkine, and undergo diapedesis to enter the subendothelial space. (B) Positive staining for fractalkine in atherosclerotic artery with no staining seen in control non-atherosclerotic artery. Fluorescent microscopy of atherosclerotic artery in mice fed high-fat diet for 22 weeks, artery stained for CX3CL1. Green = autofluorescence of arterial lamina, blue = DAPI nuclear stain, and red = Alexa546/CX3CL1 antibody. 20X magnification, n=3/treatment group.
  • Externally hosted supplementary file 2
    Doi: 10.5281/zenodo.3595384
    Description: Supplemental Figure 2. LCMS characterization of the fractalkine-targeted PA nanofiber. (A) HPLC trace of the fractalkine-targeted PA shows 90% purity. (B) Deconvoluted electrospray ionization (ESI) mass spectrometry (MS) of targeted nanofiber shows peaks at the expected mass (3209 and 3226 (NH3 adduct) m/z) for fractalkine-targeted PA.
  • Externally hosted supplementary file 3
    Doi: 10.5281/zenodo.3595384
    Description: Supplemental Figure 3. Characterization of the scrambled PA nanofiber. (A) Conventional transmission electron microscopy (TEM) images of scrambled nanofibers. (B) HPLC trace of the scrambled PA shows 92% purity. (C) Deconvoluted electrospray ionization (ESI) mass spectrometry (MS) of scrambled nanofiber shows peaks at the expected mass (3226.58) for the scrambled PA.
  • Externally hosted supplementary file 4
    Doi: 10.5281/zenodo.3595384
    Description: Supplemental Figure 4. LCMS characterization of the backbone PA nanofiber. (A) HPLC trace of the backbone PA shows greater than 92% purity. (B) Deconvoluted electrospray ionization (ESI) mass spectrometry (MS) of backbone nanofiber shows peaks at the expected mass (1393 m/z) for the backbone PA.
  • Externally hosted supplementary file 5
    Doi: 10.5281/zenodo.3595384
    Description: Supplemental Figure 5. Circular dichroism spectroscopy demonstrates that the backbone PA nanofiber exhibits beta-sheet formation, the fractalkine targeting PA nanofiber exhibits α-helical characteristics, and the scrambled PA nanofiber exhibits random coils.
MDPI and ACS Style

Kassam, H.A.; Gillis, D.C.; Dandurand, B.R.; Karver, M.R.; Tsihlis, N.D.; Stupp, S.I.; Kibbe, M.R. Development of Fractalkine-Targeted Nanofibers that Localize to Sites of Arterial Injury. Nanomaterials 2020, 10, 420.

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