Complement Receptor Targeted Liposomes Encapsulating the Liver X Receptor Agonist GW3965 Accumulate in and Stabilize Atherosclerotic Plaques

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.

Polymer‐Functionalized Mitochondrial Transplantation to Plaque Macrophages as a Therapeutic Strategy Targeting Atherosclerosis

“…[45] A similar biodistribution and macrophage association was observed in a study by Benne and coworkers, who showed increased retention of cyclic peptide Lyp-1 liposomes in atherosclerotic plaque macrophages. [51] Taken together, our results corroborate the accumulation of IV-administered constructs in atherosclerotic plaques, specifically in macrophages, and highlight the potential of Dextran-TPP mitochondria for treatment in other diseases characterized by both metabolic dysregulation and enhanced vascular permeability/preferential site-specific localization.…”

Advances in imaging and treatment of atherosclerosis based on organic nanoparticles

“… 104,105 In recent years, delivery of anti-atherosclerosis drugs using liposomes has also attracted widespread attention. 16,106–108 Considering that curcumin can reduce the side effects of statins, Li et al designed liposomes loaded with atorvastatin and curcumin (AC-Lipo) for combination therapy of atherosclerosis. They found that, compared to liposomes loaded with only atorvastatin, AC-Lipo significantly reduced the expression of ICAM-1 and E-selectin on plaque endothelial cells, leading to decreased atherosclerotic plaque content, showing AC-Lipo could synergistically reduce plaque lipid content and inflammatory cytokine expression.…”

“…In general, NPs applied for anti-atherosclerosis purposes may be divided primarily into inorganic NPs and organic NPs. Compared to inorganic NPs, organic NPs, such as polymeric NPs, 14 liposomes, 15 micelles, 16 and high-density lipoprotein NPs, 17 have the advantages of high drug-loading capacity, good biocompatibility, long circulation time, and rapid elimination from the body. Organic NPs are modified to optimize their target specificity, tissue-penetration depth, duration, and so on, providing the possibility for early diagnosis and effective treatment of atherosclerosis.…”

Recent advance in treatment of atherosclerosis: Key targets and plaque-positioned delivery strategies

“… 253 LyP-1 liposomes loaded by GW3965 also locate to atherosclerotic plaques and cut down the number of macrophages. 254 …”