Abstract 13425: Nanoparticle-Mediated Monocyte-Selective Delivery of Pitavastatin Inhibits Monocyte Activation and Attenuates Plaque Destabilization and Rupture in ApoE-Deficient Mice
Background: Prevention of plaque destabilization and rupture is the most effective therapeutic strategy for acute coronary syndrome (ACS). Monocyte activation is suggested to play a critical role in the pathogenesis of ACS. However, there is no direct evidence for the cause-effect relation between monocyte activation and ACS. We tested the hypothesis that nanoparticle (NP)-mediated monocyte-selective delivery of pitavastatin (Pitava) inhibits monocyte activation, plaque destabilization, and rupture.
Methods and Results: We used a murine model of plaque destabilization and rupture in the brachiocephalic arteries of ApoE-deficient mice fed with high-fat diet and infused with angiotensin II. Adoptive transfer of thioglycollate-induced activated monocytes/macrophages increased serum markers of monocyte activation (MCP-1, M-CSF, and MMP-9), and enhanced plaque destabilization (fibrous cap thinning, macrophage infiltration) and rupture (Figure A). We then prepared bioabsorbable FITC-incorporated NPs, which were uptaken by CD11b+ monocytes and then delivered selectively into the target lesions (brachiocephalic arteries; arrows in Figure B) after intravenous injection. Treatment with Pitava-NP (weekly intravenous injection of 0.4 mg/kg pitavastatin for 4 weeks), but not that with FITC-NP or Pitava alone, reduced monocyte activation markers and inhibited plaque destabilization and rupture (Figure C). In contrast, oral daily administration of Pitava at 1 mg/kg per day for 4 weeks (total dose: 28 mg/kg) showed equivalent therapeutic effects as seen with Pitava-NP treatment (1.6 mg/kg).
Conclusion: This NP-mediated delivery of Pitava into atherosclerotic plaques was more effective in inhibiting monocyte activation and attenuating plaque destabilization and rupture compared with intravenous Pitava alone or systemic administration of Pitava in this model. This nanotechnology platform may be a new therapeutic strategy for ACS in future.
- © 2010 by American Heart Association, Inc.