EBioMedicine. 2021 Dec 05;74:103725. doi: 10.1016/j.ebiom.2021.103725. Epub 2021 Dec 05.
Phospholipid nanoparticles: Therapeutic potentials against atherosclerosis via reducing cholesterol crystals and inhibiting inflammation.
EBioMedicine
Yonghong Luo, Yanhong Guo, Huilun Wang, Minzhi Yu, Kristen Hong, Dan Li, Ruiting Li, Bo Wen, Die Hu, Lin Chang, Jifeng Zhang, Bo Yang, Duxin Sun, Anna S Schwendeman, Y Eugene Chen
Affiliations
Affiliations
- Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Second Xiangya Hospital, Central South University, Hunan Province, China.
- Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: [email protected].
- Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
- Second Xiangya Hospital, Central South University, Hunan Province, China.
- Department of Cardiac Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].
- Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Cardiac Surgery, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: [email protected].
PMID: 34879325
PMCID: PMC8654800 DOI: 10.1016/j.ebiom.2021.103725
Abstract
BACKGROUND: Atherosclerosis-related cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Cholesterol crystals (CCs) induce inflammation in atherosclerosis and are associated with unstable plaques and poor prognosis, but no drug can remove CCs in the clinic currently.
METHODS: We generated a phospholipid-based and high-density lipoprotein (HDL)-like nanoparticle, miNano, and determined CC-dissolving capacity, cholesterol efflux property, and anti-inflammation effects of miNano in vitro. Both normal C57BL/6J and Apoe-deficient mice were used to explore the accumulation of miNano in atherosclerotic plaques. The efficacy and safety of miNano administration to treat atherosclerosis were evaluated in the Ldlr-deficient atherosclerosis model. The CC-dissolving capacity of miNano was also detected using human atherosclerotic plaques ex vivo.
FINDINGS: We found that miNano bound to and dissolved CCs efficiently in vitro, and miNano accumulated in atherosclerotic plaques, co-localized with CCs and macrophages in vivo. Administration of miNano inhibited atherosclerosis and improved plaque stability by reducing CCs and macrophages in Ldlr-deficient mice with favorable safety profiles. In macrophages, miNano prevented foam cell formation by enhancing cholesterol efflux and suppressed inflammatory responses via inhibiting TLR4-NF-κB pathway. Finally, in an ex vivo experiment, miNano effectively dissolved CCs in human aortic atherosclerotic plaques.
INTERPRETATION: Together, our work finds that phospholipid-based and HDL-like nanoparticle, miNano, has the potential to treat atherosclerosis by targeting CCs and stabilizing plaques.
FUNDING: This work was supported by the National Institutes of Health HL134569, HL109916, HL136231, and HL137214 to Y.E.C, HL138139 to J.Z., R21NS111191 to A.S., by the American Heart Association 15SDG24470155, Grant Awards (U068144 from Bio-interfaces and G024404 from M-BRISC) at the University of Michigan to Y.G., by the American Heart Association 19PRE34400017 and Rackham Helen Wu award to M.Y., NIH T32 GM07767 to K. H., Barbour Fellowship to D.L.
Copyright © 2021. Published by Elsevier B.V.
Keywords: Atherosclerosis; Cholesterol crystal; HDL; Inflammation; Nanoparticle
Conflict of interest statement
Declaration of Competing Interest The authors have declared that no conflict of interest exists.
References
- Hear Res. 2020 Oct;396:108073 - PubMed
- Front Cell Neurosci. 2017 Nov 08;11:355 - PubMed
- Atherosclerosis. 2016 Apr;247:111-7 - PubMed
- J Am Coll Cardiol. 2013 Jan 29;61(4):404-410 - PubMed
- Eur Heart J. 2020 Jun 21;41(24):2313-2330 - PubMed
- EBioMedicine. 2018 Feb;28:225-233 - PubMed
- Arterioscler Thromb Vasc Biol. 2011 Sep;31(9):2007-14 - PubMed
- J Am Coll Cardiol. 2017 Jul 4;70(1):1-25 - PubMed
- Atherosclerosis. 2019 Aug;287:100-111 - PubMed
- Biomolecules. 2019 Sep 20;9(10): - PubMed
- Pharmacol Ther. 2020 Oct;214:107620 - PubMed
- Atherosclerosis. 2019 Apr;283:79-84 - PubMed
- N Engl J Med. 2019 Dec 26;381(26):2497-2505 - PubMed
- Atherosclerosis. 2016 Aug;251:197-205 - PubMed
- EBioMedicine. 2020 Oct;60:102985 - PubMed
- Sci Rep. 2016 Aug 30;6:31750 - PubMed
- Lancet Diabetes Endocrinol. 2020 Jan;8(1):36-49 - PubMed
- Eur Heart J. 2020 Jun 21;41(24):2236-2239 - PubMed
- Circ Res. 2013 Jul 19;113(3):252-65 - PubMed
- Immunobiology. 2014 Oct;219(10):786-92 - PubMed
- J Clin Invest. 1993 Aug;92(2):883-93 - PubMed
- Trends Biochem Sci. 2005 Jan;30(1):43-52 - PubMed
- JAMA. 2007 Apr 18;297(15):1675-82 - PubMed
- J Pharmacol Exp Ther. 2020 Feb;372(2):193-204 - PubMed
- J Lipid Res. 2017 Jan;58(1):124-136 - PubMed
- J Clin Lipidol. 2010 May-Jun;4(3):156-64 - PubMed
- J Control Release. 2020 Dec 10;328:792-804 - PubMed
- Cardiovasc Res. 2021 Feb 04;: - PubMed
- Biomedicines. 2020 Sep 23;8(10): - PubMed
- Front Immunol. 2018 May 29;9:1163 - PubMed
- J Clin Invest. 2015 Oct 1;125(10):3819-30 - PubMed
- PLoS One. 2012;7(12):e53280 - PubMed
- J Control Release. 2021 Jan 10;329:361-371 - PubMed
- Eur Heart J. 2014 Dec 7;35(46):3277-86 - PubMed
- N Engl J Med. 2020 Nov 5;383(19):1838-1847 - PubMed
- N Engl J Med. 2017 May 4;376(18):1713-1722 - PubMed
- J Lipid Res. 2015 Sep;56(9):1727-37 - PubMed
- Pharmacol Ther. 2016 Jan;157:28-42 - PubMed
- Nature. 2010 Apr 29;464(7293):1357-61 - PubMed
- J Cardiol. 2017 Jan;69(1):253-259 - PubMed
- J Cell Sci. 2019 Dec 2;132(23): - PubMed
- J Am Heart Assoc. 2020 Aug 4;9(15):e016506 - PubMed
- J Mater Chem B. 2020 Feb 19;8(7):1496-1506 - PubMed
- N Engl J Med. 2017 Sep 21;377(12):1119-1131 - PubMed
- Am J Cardiol. 2017 Nov 15;120(10):1699-1707 - PubMed
- Int J Mol Sci. 2020 Jan 22;21(3): - PubMed
- J Am Coll Cardiol. 2015 Feb 17;65(6):630-2 - PubMed
- Behav Res Methods. 2007 May;39(2):175-91 - PubMed
- J Clin Invest. 1997 Feb 15;99(4):773-80 - PubMed
- Eur Heart J. 2020 Nov 7;41(42):4092-4099 - PubMed
- Nat Immunol. 2013 Aug;14(8):812-20 - PubMed
- Curr Opin Lipidol. 2013 Oct;24(5):419-25 - PubMed
- Arch Otolaryngol. 1978 Dec;104(12):726-9 - PubMed
- JAMA Cardiol. 2018 Sep 1;3(9):815-822 - PubMed
- JAMA. 2003 Nov 5;290(17):2292-300 - PubMed
- PLoS One. 2017 Jun 30;12(6):e0180303 - PubMed
- Science. 2015 Jul 17;349(6245):316-20 - PubMed
- Circulation. 2002 Apr 30;105(17):2064-70 - PubMed
- J Am Coll Cardiol. 2017 Oct 31;70(18):2278-2289 - PubMed
- Ochsner J. 2014 Winter;14(4):669-72 - PubMed
- Nat Rev Drug Discov. 2003 Mar;2(3):214-21 - PubMed
- Biochim Biophys Acta. 2007 Jun;1768(6):1311-24 - PubMed
- Sci Transl Med. 2016 Apr 6;8(333):333ra50 - PubMed
- Eur Heart J. 2012 Mar;33(5):657-65 - PubMed
- Am J Pathol. 2018 Feb;188(2):525-538 - PubMed
- Immunology. 2016 Nov;149(3):306-319 - PubMed
- Atherosclerosis. 1978 Dec;31(4):473-80 - PubMed
- Int J Pharm. 2020 Jun 30;584:119440 - PubMed
- Eur Heart J. 2016 Jul 01;37(25):1959-67 - PubMed
- Circulation. 2001 Dec 18;104(25):3103-8 - PubMed
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