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

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. In this study, we present the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands were 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 were systematically optimized. In vitro studies indicated that the GW-encapsulated NPs upregulated the LXR target genes and downregulated pro-inflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV-GW-NPs) successfully reached atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (~30%) compared to the PBS group, which was with greater efficacy vs. non-targeting NPs encapsulating GW (GW-NPs) (~18%). In addition, mice administered the Col IV-GW-NPs did 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.