Atheroma Niche‐Responsive Nanocarriers for Immunotherapeutic Delivery

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.

[1]  P. K. Sharma.  Atherosclerosis. , 2020, The Journal of the Association of Physicians of India.

[2]  S. Stupp,et al.  Covalent-supramolecular hybrid polymers as muscle-inspired anisotropic actuators , 2018, Nature Communications.

[3]  A. Lavasanifar,et al.  Nanomedicine for immunosuppressive therapy: achievements in pre-clinical and clinical research , 2018, Expert opinion on drug delivery.

[4]  Xing Li,et al.  Ac2-26 Induces IKKβ Degradation Through Chaperone-Mediated Autophagy Via HSPB1 in NCM-Treated Microglia , 2018, Front. Mol. Neurosci..

[5]  M. Kibbe,et al.  Peptide Amphiphile Nanostructures for Targeting of Atherosclerotic Plaque and Drug Delivery , 2018, Advanced biosystems.

[6]  R. Bitton,et al.  Using small-angle X-ray scattering (SAXS) to study the structure of self-assembling biomaterials , 2018 .

[7]  Shreya Kar,et al.  Annexin-A1 enhances breast cancer growth and migration by promoting alternative macrophage polarization in the tumour microenvironment , 2017, Scientific Reports.

[8]  Ruibing Wang,et al.  Non-proinflammatory and responsive nanoplatforms for targeted treatment of atherosclerosis. , 2017, Biomaterials.

[9]  G. Leoni,et al.  The advantageous role of annexin A1 in cardiovascular disease , 2017, Cell adhesion & migration.

[10]  M. Fornage,et al.  Heart Disease and Stroke Statistics—2017 Update: A Report From the American Heart Association , 2017, Circulation.

[11]  M. Mattson,et al.  Impact of lysosome status on extracellular vesicle content and release , 2016, Ageing Research Reviews.

[12]  M. Kibbe,et al.  Targeted Nanotherapies for the Treatment of Surgical Diseases , 2016, Annals of surgery.

[13]  G. Truskey,et al.  Poly(Ethylene Glycol) Hydrogel Scaffolds Containing Cell-Adhesive and Protease-Sensitive Peptides Support Microvessel Formation by Endothelial Progenitor Cells , 2015, Cellular and Molecular Bioengineering.

[14]  G. Schatz,et al.  Energy landscapes and function of supramolecular systems , 2015, Nature materials.

[15]  Samuel I Stupp,et al.  Shape-Dependent Targeting of Injured Blood Vessels by Peptide Amphiphile Supramolecular Nanostructures. , 2015, Small.

[16]  Ira Tabas,et al.  Recent insights into the cellular biology of atherosclerosis , 2015, The Journal of cell biology.

[17]  O. Farokhzad,et al.  Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice , 2015, Science Translational Medicine.

[18]  E. W. Meijer,et al.  Pathway selection in peptide amphiphile assembly. , 2014, Journal of the American Chemical Society.

[19]  S. Stupp,et al.  Supramolecular Nanofibers of Peptide Amphiphiles for Medicine. , 2013, Israel journal of chemistry.

[20]  J. Frostegård.  Immunity, atherosclerosis and cardiovascular disease , 2013, BMC Medicine.

[21]  S. Stupp,et al.  Tuning nanostructure dimensions with supramolecular twisting. , 2013, The journal of physical chemistry. B.

[22]  R. Bitton,et al.  Nanostructure-templated control of drug release from peptide amphiphile nanofiber gels. , 2012, Soft matter.

[23]  Lucas H. Hofmeister,et al.  Physiologically relevant oxidative degradation of oligo(proline) cross-linked polymeric scaffolds. , 2011, Biomacromolecules.

[24]  J. Ji,et al.  Photo-responsive, biocompatible polymeric micelles self-assembled from hyperbranched polyphosphate-based polymers , 2011 .

[25]  Kenneth W Dunn,et al.  A practical guide to evaluating colocalization in biological microscopy. , 2011, American journal of physiology. Cell physiology.

[26]  M. Perretti,et al.  FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin‐derived peptide‐stimulated phagocytosis , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  J. Hubbell,et al.  Enhanced proteolytic degradation of molecularly engineered PEG hydrogels in response to MMP-1 and MMP-2. , 2010, Biomaterials.

[28]  I. Tabas.  Macrophage death and defective inflammation resolution in atherosclerosis , 2010, Nature Reviews Immunology.

[29]  B. Grant,et al.  Pathways and mechanisms of endocytic recycling , 2009, Nature Reviews Molecular Cell Biology.

[30]  Xia Zhang,et al.  Activation of Murine Macrophages , 2008, Current protocols in immunology.

[31]  Wim Jiskoot,et al.  Extrinsic Fluorescent Dyes as Tools for Protein Characterization , 2008, Pharmaceutical Research.

[32]  Nick D. Tsihlis,et al.  The role of nitric oxide in the pathophysiology of intimal hyperplasia. , 2007, Journal of vascular surgery.

[33]  J. Heinecke,et al.  Role of amphipathic α-helical structural elements in removing cellular cholesterol and protecting against cardiovascular disease , 2007 .

[34]  J. Sluijter,et al.  Matrix Metalloproteinase 2 Is Associated With Stable and Matrix Metalloproteinases 8 and 9 With Vulnerable Carotid Atherosclerotic Lesions: A Study in Human Endarterectomy Specimen Pointing to a Role for Different Extracellular Matrix Metalloproteinase Inducer Glycosylation Forms , 2006, Stroke.

[35]  F. Cunha,et al.  TNF‐α  mediates the induction of nitric oxide synthase in macrophages but not in neutrophils in experimental cutaneous leishmaniasis , 2003, European journal of immunology.

[36]  E. Stadtman,et al.  Free radical-mediated oxidation of free amino acids and amino acid residues in proteins , 2003, Amino Acids.

[37]  Aldons J. Lusis,et al.  Atherosclerosis : Vascular biology , 2000 .

[38]  J. Joseph,et al.  The peroxynitrite generator, SIN-1, becomes a nitric oxide donor in the presence of electron acceptors. , 1999, Archives of biochemistry and biophysics.

[39]  R. Ross,et al.  Atherosclerosis is an inflammatory disease. , 1998, American heart journal.

[40]  H. Birkedal‐Hansen,et al.  APMA (4-aminophenylmercuric acetate) activation of stromelysin-1 involves protein interactions in addition to those with cysteine-75 in the propeptide. , 1996, Biochemistry.

[41]  J. Aten,et al.  Measurement of co‐localization of objects in dual‐colour confocal images , 1993, Journal of microscopy.

[42]  E. Stadtman,et al.  Conversion of amino acid residues in proteins and amino acid homopolymers to carbonyl derivatives by metal-catalyzed oxidation reactions. , 1989, The Journal of biological chemistry.

[43]  K. Schilling,et al.  Oxygen effect in the radiolysis of proteins. Part 2. Bovine serum albumin. , 1984, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[44]  T. Springer,et al.  Mac-1 antigen: quantitative expression in macrophage populations and tissues, and immunofluorescent localization in spleen. , 1982, Journal of immunology.