Nanoparticles Containing a Liver X Receptor Agonist Inhibit Inflammation and Atherosclerosis

Overview

Journal Adv Healthc Mater

Specialties Biomedical Engineering
Biotechnology

Date 2014 Aug 27

PMID 25156796

Citations 39

Authors

Xue-Qing Zhang

Orli Even-Or

Xiaoyang Xu

Mariska van Rosmalen

Lucas Lim

Suresh Gadde

Omid C Farokhzad

Edward A Fisher

Affiliations

Soon will be listed here.

Abstract

Liver X receptor (LXR) signaling pathways regulate lipid metabolism and inflammation, which has generated widespread interest in developing synthetic LXR agonists as potential therapeutics for the management of atherosclerosis. In this study, it is demonstrated that nanoparticles (NPs) containing the synthetic LXR agonist GW3965 (NP-LXR) exert anti-inflammatory effects and inhibit the development of atherosclerosis without causing hepatic steatosis. These NPs are engineered through self-assembly of a biodegradable diblock poly(lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-b-PEG) copolymer. NP-LXR is significantly more effective than free GW3965 at inducing LXR-target gene expression and suppressing inflammatory factors in macrophages in vitro and in vivo. Additionally, the NPs elicit negligible lipogenic gene stimulation in the liver. Using the Ldlr (-/-) mouse model of atherosclerosis, abundant colocalization of fluorescently labeled NPs within plaque macrophages following systemic administration is seen. Notably, six intravenous injections of NP-LXR over 2 weeks markedly reduce the CD68-positive cell (macrophage) content of plaques (by 50%) without increasing total cholesterol or triglycerides in the liver and plasma. Together, these findings identify GW3965-encapsulated PLGA-b-PEG NPs as a promising nanotherapeutic approach to combat atherosclerosis, providing the benefits of LXR agonists without their adverse effects on hepatic and plasma lipid metabolism.

Citing Articles

The Liver X Receptor Promotes Immune Homeostasis via Controlled Activation of the Innate Immune System in the Liver.

Nakashima H, Kearney B, Kinoshita M Biomolecules. 2025; 15(1).

PMID: 39858420 PMC: 11764419. DOI: 10.3390/biom15010025.

Advances in drug delivery to atherosclerosis: Investigating the efficiency of different nanomaterials employed for different type of drugs.

Perera B, Wu Y, Nguyen N, Ta H Mater Today Bio. 2023; 22:100767.

PMID: 37600355 PMC: 10433009. DOI: 10.1016/j.mtbio.2023.100767.

Targeting macrophages in atherosclerosis using nanocarriers loaded with liver X receptor agonists: A narrow review.

Yang T, Miao M, Yu W, Wang X, Xia F, Li Y Front Mol Biosci. 2023; 10:1147699.

PMID: 36936982 PMC: 10018149. DOI: 10.3389/fmolb.2023.1147699.

Nanomaterials-Based Novel Immune Strategies in Clinical Translation for Cancer Therapy.

Wahab S, Ghazwani M, Hani U, Hakami A, Almehizia A, Ahmad W Molecules. 2023; 28(3).

PMID: 36770883 PMC: 9920693. DOI: 10.3390/molecules28031216.

Advances in imaging and treatment of atherosclerosis based on organic nanoparticles.

Tu S, He W, Han J, Wu A, Ren W APL Bioeng. 2022; 6(4):041501.

PMID: 36483980 PMC: 9726224. DOI: 10.1063/5.0127835.

References

Farokhzad O . Nanotechnology for drug delivery: the perfect partnership. Expert Opin Drug Deliv. 2008; 5(9):927-9. DOI: 10.1517/17425247.5.9.927. View

Joseph S, McKilligin E, Pei L, Watson M, Collins A, Laffitte B . Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci U S A. 2002; 99(11):7604-9. PMC: 124297. DOI: 10.1073/pnas.112059299. View

Harel-Adar T, Ben Mordechai T, Amsalem Y, Feinberg M, Leor J, Cohen S . Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair. Proc Natl Acad Sci U S A. 2011; 108(5):1827-32. PMC: 3033268. DOI: 10.1073/pnas.1015623108. View

Grefhorst A, Elzinga B, Voshol P, Plosch T, Kok T, Bloks V . Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J Biol Chem. 2002; 277(37):34182-90. DOI: 10.1074/jbc.M204887200. View

Ma Y, Xu L, Rodriguez-Agudo D, Li X, Heuman D, Hylemon P . 25-Hydroxycholesterol-3-sulfate regulates macrophage lipid metabolism via the LXR/SREBP-1 signaling pathway. Am J Physiol Endocrinol Metab. 2008; 295(6):E1369-79. PMC: 2603552. DOI: 10.1152/ajpendo.90555.2008. View

Levin N, Bischoff E, Daige C, Thomas D, Vu C, Heyman R . Macrophage liver X receptor is required for antiatherogenic activity of LXR agonists. Arterioscler Thromb Vasc Biol. 2004; 25(1):135-42. DOI: 10.1161/01.ATV.0000150044.84012.68. View

Cash J, White G, Greaves D . Chapter 17. Zymosan-induced peritonitis as a simple experimental system for the study of inflammation. Methods Enzymol. 2009; 461:379-96. DOI: 10.1016/S0076-6879(09)05417-2. View

Im S, Osborne T . Liver x receptors in atherosclerosis and inflammation. Circ Res. 2011; 108(8):996-1001. PMC: 3082200. DOI: 10.1161/CIRCRESAHA.110.226878. View

Peer D, Karp J, Hong S, Farokhzad O, Margalit R, Langer R . Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol. 2008; 2(12):751-60. DOI: 10.1038/nnano.2007.387. View

10.

Zhang Z, Feng S . In vitro investigation on poly(lactide)-Tween 80 copolymer nanoparticles fabricated by dialysis method for chemotherapy. Biomacromolecules. 2006; 7(4):1139-46. DOI: 10.1021/bm050953v. View

11.

Lobatto M, Fuster V, Fayad Z, Mulder W . Perspectives and opportunities for nanomedicine in the management of atherosclerosis. Nat Rev Drug Discov. 2011; 10(11):835-52. PMC: 3623275. DOI: 10.1038/nrd3578. View

12.

Piao Z, Kim M, Jeong M, Yun S, Lee S, Sun H . VDUP1 exacerbates bacteremic shock in mice infected with Pseudomonas aeruginosa. Cell Immunol. 2012; 280(1):1-9. DOI: 10.1016/j.cellimm.2012.11.003. View

13.

Trogan E, Feig J, Dogan S, Rothblat G, Angeli V, Tacke F . Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice. Proc Natl Acad Sci U S A. 2006; 103(10):3781-6. PMC: 1450154. DOI: 10.1073/pnas.0511043103. View

14.

Zhang X, Xu X, Bertrand N, Pridgen E, Swami A, Farokhzad O . Interactions of nanomaterials and biological systems: Implications to personalized nanomedicine. Adv Drug Deliv Rev. 2012; 64(13):1363-84. PMC: 3517211. DOI: 10.1016/j.addr.2012.08.005. View

15.

Joseph S, Tontonoz P . LXRs: new therapeutic targets in atherosclerosis?. Curr Opin Pharmacol. 2003; 3(2):192-7. DOI: 10.1016/s1471-4892(03)00009-2. View

16.

Zelcer N, Tontonoz P . Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest. 2006; 116(3):607-14. PMC: 1386115. DOI: 10.1172/JCI27883. View

17.

Gadde S, Even-Or O, Kamaly N, Hasija A, Gagnon P, Adusumilli K . Development of therapeutic polymeric nanoparticles for the resolution of inflammation. Adv Healthc Mater. 2014; 3(9):1448-1456. PMC: 4160375. DOI: 10.1002/adhm.201300688. View

18.

Tabas I . Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol. 2009; 10(1):36-46. PMC: 2854623. DOI: 10.1038/nri2675. View

19.

Fadok V, Voelker D, Campbell P, Cohen J, Bratton D, Henson P . Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol. 1992; 148(7):2207-16. View

20.

Joseph S, Laffitte B, Patel P, Watson M, Matsukuma K, Walczak R . Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem. 2002; 277(13):11019-25. DOI: 10.1074/jbc.M111041200. View