Abstract
Atherosclerosis is characterized by the retention of lipids in foam cells in the arterial intima. The liver X receptor (LXR) agonist GW3965 is a promising therapeutic compound, since it induces reverse cholesterol transport in foam cells. However, hepatic LXR activation increases plasma and liver lipid levels, inhibiting its clinical development. Herein, a formulation that specifically enhances GW3965 deposition in the atherosclerotic lesion is aimed to be developed. GW3965 is encapsulated in liposomes functionalized with the cyclic peptide Lyp-1 (CGNKRTRGC), which binds the p32 receptor expressed on foam cells. These liposomes show preferential uptake by foam cells in vitro and higher accumulation in atherosclerotic plaques in mice compared to non-targeted liposomes as determined by in vivo imaging. Flow cytometry analysis of plaques reveals increased retention of Lyp-1 liposomes in atherosclerotic plaque macrophages compared to controls (p < 0.05). Long term treatment of established plaques in LDLR -/- mice with GW3965-containing Lyp-1 liposomes significantly reduces plaque macrophage content by 50% (p < 0.01). Importantly, GW3965-containing Lyp-1 liposomes do not increase plasma or hepatic lipid content. Thus, GW3965-containing Lyp-1 liposomes successfully target the atherosclerotic macrophages allowing plaque stabilization without commonly observed side effects of LXR agonists.
Highlights
Introduction arterial intimaThe liver X receptor (LXR) agonist GW3965 is a promisingAtherosclerosis is the predominant undertherapeutic compound, since it induces reverse cholesterol transport in foam cells
We found that the percentage of collagen in the plaques was significantly increased in mice treated with GW3965-loaded Lyp-1 liposomes as compared to all other groups (Figure 4C,F)
We showed that loading of an LXR agonist, GW3965, in Lyp-1-bearing liposomes induces a highly relevant stabilization of pre-established atherosclerotic lesions, in contrast to free GW3965 or GW3965 encapsulated in non-targeted liposomes
Summary
Introduction arterial intimaThe liver X receptor (LXR) agonist GW3965 is a promisingAtherosclerosis is the predominant undertherapeutic compound, since it induces reverse cholesterol transport in foam cells. Hepatic LXR activation increases plasma and liver lipid levels, inhibiting its clinical development. GW3965 is encapsulated in liposomes functionalized with the cyclic peptide Lyp-1 (CGNKRTRGC), which binds the p32 receptor expressed on foam cells. These liposomes show preferential uptake by foam cells in vitro and higher accumulation in atherosclerotic plaques in mice compared to non-targeted liposomes as determined by in vivo imaging. GW3965-containing Lyp-1 liposomes successfully target the atherosclerotic macrophages allowing site of inflammation and the formation of atherosclerotic plaques.[4]
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