Novel E-selectin Binding Polymers Reduce Atherosclerotic Lesions in ApoE^(-/-) mice

Background: Atherosclerosis is characterized by acute and chronic vascular inflammation and leukocyte infiltration that result in plaque formation, instability, and rupture. E-selectin is the adhesion molecule expressed on activated endothelium which recruits leucocytes to the inflammation site, making it a therapeutic target able to interfere with the development and progression of atherosclerosis.

Objectives: We aimed to test the hypothesis that E-selectin-targeted polymers with and without the anti-inflammatory drug would prevent inflammation and plaque progression.

Methods and Results: To target and modulate vascular inflammation we used novel N-(2-hydroxypropyl)-meth-acrylamide (HPMA) polymers conjugated with peptides that bind E-selectin with high affinity, with and without dexamethasone 1mg/kg (P-ESBP-Dex, P-ESBP). Five-month-old ApoE^(-/-) mice were fed western diet (WD) for 8 weeks. To assess the plaques, vascular ultrasound (US) was performed 4 weeks after onset of WD. We used a novel Vevo Vasc software application designed to measure in-vivo vessel wall anatomy and motion in small-animal models. Following the US mice were randomly divided into 4 treatment groups: P-ESBP-Dex, P-ESBP, free dexamethasone and saline, and received 4 weekly intraperitoneal injections. One week after the final injection we performed a second US and aortas were harvested for histological analysis. Our data showed that both P-ESBP and P-ESBP-Dex selectively targeted atherosclerotic lesions and reduced ascending aorta wall thickness. Furthermore, the addition of dexamethasone to the ESBP-polymers did not increase their therapeutic effect.

Conclusion: Our findings suggest that ESBP-polymers reduce atherosclerotic lesions by preventing leukocyte recruitment to the vessel wall and propose a novel nanomedicine-based strategy to treat atherosclerosis and stabilize vulnerable plaque.