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

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

Advanced healthcare materials (2020-04-25)
Naomi Benne, Renata Martins Cardoso, Aimee L Boyle, Alexander Kros, Wim Jiskoot, Johan Kuiper, Joke Bouwstra, Miranda Van Eck, Bram Slütter
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.

MATERIALS
Product Number
Brand
Product Description

Avanti
DSPE-PEG(2000) Carboxylic Acid, Avanti Research - A Croda Brand 880135P, powder
Sigma-Aldrich
1,2-Dioleoyl-sn-glycero-3-phosphocholine, lyophilized powder
Avanti
18:1 Cy5 PC, Avanti Research - A Croda Brand
Avanti
18:0 PEG2000 PE, Avanti Research - A Croda Brand
Avanti
18:1 (Δ9-Cis) PC (DOPC), Avanti Research - A Croda Brand
Avanti
18:0 PEG2000 PE, Avanti Research - A Croda Brand 880120C
Avanti
18:1 (Δ9-Cis) PC (DOPC), Avanti Research - A Croda Brand
Avanti
18:1 PS (DOPS), Avanti Research - A Croda Brand
Avanti
18:1 PS (DOPS), Avanti Research - A Croda Brand