​Atherosclerosis is characterized by the deposit of lipid plaques on artery walls, leading to vessel obstruction and atherosclerotic plaque rupture. Current knowledge suggests that nuclear oxysterol receptors (LXRs) play a central role in the regulation of lipid metabolism. Indeed, pharmacological modulation of LXRs by agonists can activate cholesterol efflux and control plaque progression. This makes LXRs a prime target for therapeutic intervention. Synthetic LXR agonists already exist (e.g. GW3965) which, although promising, have not been commercialized due to adverse effects resulting from non-specific biodistribution.

In this study, researchers developed nanometric micelles capable of selectively transporting a GW3965 analog to atherosclerotic lesions while limiting side effects. This analogue is a prodrug synthesized from GW3965, whose chemical structure enables it to be effectively encapsulated in the micelle core, and to release the "true" active ingredient locally under the action of esterases. In a murine model, they show that micelles loaded with the prodrug have favorable pharmacokinetics and biodistribution towards atherosclerotic plaque. They also observed an upregulation of cholesterol efflux promoter expression, without altering lipid metabolism, a side effect classically observed with GW3965.

Contacts : Edmond Gravel (edmond.gravel@cea.fr) ; Éric Doris (eric.doris@cea.fr) ; Laurent Devel (laurent.devel@cea.fr)