Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr−/− Mice

Mikyung Yu, Jaume Amengual, Arjun Menon, Nazila Kamaly, Felix Zhou, Xiaoding Xu, Phei Er Saw, Seung Joo Lee, Kevin Si, Carleena Angelica Ortega, Won Il Choi, In Hyun Lee, Yazan Bdour, Jinjun Shi, Morteza Mahmoudi, Sangyong Jon, Edward A. Fisher, Omid C. Farokhzad

Research output: Contribution to journalArticlepeer-review

Abstract

The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV–GW–NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (≈30%) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW–NPs) (≈18%). In addition, mice administered the Col IV–GW–NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.

Original languageEnglish (US)
Article number1700313
JournalAdvanced Healthcare Materials
Volume6
Issue number20
DOIs
StatePublished - Oct 25 2017
Externally publishedYes

Keywords

  • GW3965
  • atherosclerosis
  • liver X receptor (LXR)
  • nanoparticles
  • targeted drug delivery

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering
  • Pharmaceutical Science

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