Atheroma Niche-Responsive Nanocarriers for Immunotherapeutic Delivery

Adv Healthc Mater. 2019 Feb;8(3):e1801545. doi: 10.1002/adhm.201801545. Epub 2019 Jan 8.

Abstract

Nanomedicine is a promising, noninvasive approach to reduce atherosclerotic plaque burden. However, drug delivery is limited without the ability of nanocarriers to sense and respond to the diseased microenvironment. In this study, nanomaterials are developed from peptide amphiphiles (PAs) that respond to the increased levels of matrix metalloproteinases 2 and 9 (MMP2/9) or reactive oxygen species (ROS) found within the atherosclerotic niche. A pro-resolving therapeutic, Ac2-26, derived from annexin-A1 protein, is tethered to PAs using peptide linkages that cleave in response to MMP2/9 or ROS. By adjusting the molar ratios and processing conditions, the Ac2-26 PA can be co-assembled with a PA containing an apolipoprotein A1-mimetic peptide to create a targeted, therapeutic nanofiber (ApoA1-Ac226 PA). The ApoA1-Ac2-26 PAs demonstrate release of Ac2-26 within 24 h after treatment with MMP2 or ROS. The niche-responsive ApoA1-Ac2-26 PAs are cytocompatible and reduce macrophage activation from interferon gamma and lipopolysaccharide treatment, evidenced by decreased nitric oxide production. Interestingly, the linkage chemistry of ApoA1-Ac2-26 PAs significantly affects macrophage uptake and retention. Taken together, these findings demonstrate the potential of PAs to serve as an atheroma niche-responsive nanocarrier system to modulate the inflammatory microenvironment, with implications for atherosclerosis treatment.

Keywords: Ac2-26; atherosclerosis; drug delivery; immunotherapy; nanomedicine; peptide amphiphile.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Annexin A1* / chemistry
  • Annexin A1* / pharmacology
  • Apolipoprotein A-I* / chemistry
  • Apolipoprotein A-I* / pharmacology
  • Atherosclerosis* / immunology
  • Atherosclerosis* / pathology
  • Atherosclerosis* / therapy
  • Cell Line
  • Drug Carriers* / chemistry
  • Drug Carriers* / pharmacology
  • Immunotherapy*
  • Matrix Metalloproteinase 2 / chemistry
  • Matrix Metalloproteinase 2 / pharmacology
  • Matrix Metalloproteinase 9 / chemistry
  • Matrix Metalloproteinase 9 / pharmacology
  • Mice
  • Nanofibers* / chemistry
  • Nanofibers* / therapeutic use
  • Peptides* / chemistry
  • Peptides* / pharmacology
  • Plaque, Atherosclerotic* / immunology
  • Plaque, Atherosclerotic* / pathology
  • Plaque, Atherosclerotic* / therapy

Substances

  • Annexin A1
  • Apolipoprotein A-I
  • Drug Carriers
  • Peptides
  • annexin A1 peptide (2-26)
  • Matrix Metalloproteinase 2
  • Mmp2 protein, mouse
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse