Abstract
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.
Highlights
Cardiovascular disease is the leading cause of morbidity and mortality in industrialized nations and the largest cause of disability-adjusted life years globally [1]
To determine whether fractalkine was present in areas of arterial injury, rat carotid arteries harvested 24 h after balloon injury were stained for the fractalkine ligand CX3CL1 (Figure 1A)
Targeted and Non-Targeted peptide amphiphiles (PAs) Form Nanofibers To identify a unique targeting epitope that is present in both the atherosclerotic niche and neointimal hyperplaTsioa,iwdeenrteifvyieawuednitqhueelittearragteutirneganedpiftooupnedtahaptepistipdreesseeqnut einnceboththattmheimaitchsearofrsaclgemroetnict onficChXe3aCnRd1, the fnreaoctinaltkiminael rheycpepertporla[s2ia1,].wWeercehvioesweeodnethferalcittaerlkatiunree-taarngdetfeodunsedqauepnecpeti(dSeFPsEeqLuDeLnEceNtFhEaYt DmDimSiAcsEAa ) to sfyrnagthmeesnizteofinCtoX3aCRp1e,ptthideefraamctpalhkiipnhe ilreec(ePpAto)r C[2116]-.VWVAe AchKo[sTeAoMnRe Afr]aScFtaPlEkiLnDe-LtaErNgeFteEdYDseDquSAenEcAe, where C16 a fatty acid palmitoyl group attached to the N-terminus of the peptide sequence
Summary
Cardiovascular disease is the leading cause of morbidity and mortality in industrialized nations and the largest cause of disability-adjusted life years globally [1]. Neointimal hyperplasia is mediated by a series of complex interactions of sustained autocrine and paracrine growth factor and cytokine expression on cells in the vascular wall, including VSMC and adventitial fibroblasts [7,8,9,10,11] This cascade of events after arterial injury leads to narrowing of the arterial lumen and introduces further difficulty in re-intervention. Development of a therapy that effectively prevents atherosclerosis and inhibits the development of neointimal hyperplasia if vascular intervention is required is a significant unmet clinical need in cardiovascular medicine. Fractalkine is one such target involved in both disease processes
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