Abstract 13358: Monocyte and Macrophage-Directed Peptide Amphiphile Micelles Modulate Cytoskeletal Organization and Target Atherosclerosis
Background: Atherosclerosis is a multifactorial disease with a well-established inflammatory component. Diagnostic imaging technologies have made great strides to define the degree of atherosclerotic burden. However, there may be additional benefit to detecting vulnerable, more inflammatory plaques. Such an approach could have diagnostic and prognostic value, and by targeting pathological cells of an atheroma, may also provide opportunities to deliver disease-modifying therapy.
Results: To this end, we characterized monocyte-targeting, peptide amphiphile micelles (PAMs) that use the chemokine receptor CCR2-binding motif of monocyte chemoattractant protein-1 (MCP-1). These MCP-1 PAMs bind to monocytes and macrophages in vitro and exhibit some biofunctional properties of the MCP-1 native protein. Compared to PAMs containing scrambled peptides, MCP-1 PAMs induced increased F-actin polymerization in a murine macrophage cell line derived from WEHI-274.1 cells (0.99 ± 0.02 vs. 1.24 ± 0.03 units, n=50, p < 5 x 10-3), and in primary bone marrow derived macrophages (1.05 ± 0.07 vs. 1.92 ± 0.07 units, n=40, p < 1 x 10-13). In addition to increased actin polymerization, MCP-1 PAMS induce WEHI-274.1 monocyte cell line adhesion and spreading (196 ± 7 μm2 vs. 132 ± 7 μm2 for scrambled PAMs, n=40, p < 1 x 10-8). Using confocal microscopy, the increased actin polymerization is observed as curvilinear ruffles at the leading edges, and this actin can be observed locally at sites of integrin ligation in response to MCP-1 PAMs. Moreover, macrophages treated with MCP-1 PAMs upregulate integrin activity, quantified through binding of αV integrin-targeting microbeads (46 ± 5 beads per 100 cells vs. 16 ± 2 beads per 100 cells for scrambled PAMs, p < 1 x 10-4). In vivo, MCP-1 PAMs label atherosclerotic aortas in mice in proportion to the severity of the lesions and CCR2 expression, and the PAMs demonstrate physiologic clearance without any obvious adverse side effects.
Conclusion: MCP-1 PAMs are promising protein mimetic nanoparticles that can target monocytes and macrophages, modify their cytoskeleton, and label sites of advancing atherosclerosis. Harnessing their targetable bioactivity in macrophages for therapeutic benefit is an ongoing focus.
Author Disclosures: D. Hyatt: None. E. Chung: None. M. Tirrell: None. F.J. Alenghat: None.
- © 2014 by American Heart Association, Inc.