E-selectin-targeted copolymer reduces atherosclerotic lesions, adverse cardiac remodeling, and dysfunction

Olga Tsoref, Dalia Tyomkin, Uri Amit, Natalie Landa, Osnat Cohen-Rosenboim, David Kain, Moran Golan, Nili Naftali-Shani, Ayelet David, Jonathan Leor

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Endothelial activation with up-regulation of E-selectin adhesion molecules mediates leukocyte rolling along the vascular wall and controls inflammation in many diseases including atherosclerosis and heart failure. Therefore, we aimed to test the hypothesis that inhibition of E-selectin-mediated interactions by a new E-selectin-targeted copolymer could inhibit the progression of atherosclerosis. To target E-selectin on activated endothelium, we developed a new N-(2-hydroxypropyl)methacrylamide (HPMA)-based E-selectin binding copolymer with or without dexamethasone (Dex) (designated P-(Esbp)-Dex and P-Esbp, respectively). To determine the effect of P-(Esbp)-Dex and P-Esbp on atherosclerosis, we allocated ApoE (−/−) mice on a high fat diet, to weekly intra-peritoneal injections of either 1) P-Esbp; 2) P-(Esbp)-Dex; 3) free Dex (1 mg/kg) or 4) saline, for four weeks. Aortic atherosclerosis and left ventricular (LV) remodeling and function were assessed by serial ultrasound studies and histology. Monocytes and macrophages were characterized by flow cytometry. After four weeks of treatment, P-Esbp effectively targeted aortic atherosclerotic lesions. Both P-Esbp and P-(Esbp)-Dex reduced wall thickening of the ascending aortas. However, only the drug-free copolymer (P-Esbp) significantly decreased the areas of necrotic core in the plaques and switched spleen macrophages toward an anti-inflammatory (M2) phenotype. Furthermore, P-Esbp attenuated adverse LV remodeling and dysfunction in ApoE (−/−) mice. In summary, P-Esbp copolymer targets activated endothelial cells, regresses and stabilizes atherosclerotic plaques, and prevents adverse LV remodeling and dysfunction in ApoE (−/−) mice. Our results suggest a new, drug-free macromolecular therapy to treat vascular inflammation.

Original languageEnglish
Pages (from-to)136-147
Number of pages12
JournalJournal of Controlled Release
Volume288
DOIs
StatePublished - 28 Oct 2018

Keywords

  • Adhesion molecules
  • Atherosclerosis
  • E-selectin
  • Inflammation
  • Nano-medicine

ASJC Scopus subject areas

  • Pharmaceutical Science

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