ABSTRACT
Figure 16.1 Cardiac magnetic resonance signal enhancement up to eight weeks after treatment with targeted fumagillin nanoparticles +/– oral atorvastatin. Reprinted from Winter et al. (2008), Copyright 2008, with permission from Elsevier.
Short interfering RNA (siRNA) modulation of monocytedependent inflammatory responses represents another promising avenue for the treatment of atherosclerotic plaque. Inflammatory monocytes (Ly-6Chigh) depend on monocyte chemokine protein 1 (MCP1) binding to the chemokine receptor CCR2 to traffic to sites of injury, while noninflammatory monocytes (Ly-6Clo) respond through fractalkine (in humans) protein and the chemokine receptor CX3CR1 (Leuschner et al., 2011). Increased invasion of Ly-6Chigh monocytes promotes atherosclerosis, making the monocytes an attractive target for reducing atherosclerotic burden. Treating apoE−/− mice with established atherosclerosis for three weeks with lipid NPs carrying siCCR2 reduced monocyte/macrophage number in atherosclerotic plaques by 82%, including a marked reduction of inflammatory Ly-6Chigh monocytes. Immunohistochemistry showed a 46% reduction in myeloid cells and a 38% reduction of lesion size in the aortic root (Leuschner et al., 2011). Kamaly et al. designed polymeric NPs containing the antiinflammatory peptide Ac2-26, an annexin A1/lipocortin 1-mimetic peptide, for use as therapeutics to dampen chronic inflammation (Kamaly et al., 2013). The NPs were built from biodegradable diblock poly(lactic-co-glycolic acid)-block-polyethyleneglycol (PLGA-b-PEG) and peptide-conjugated PLGA-PEG targeted using a collagen IV-targeted heptapeptide ligand identified by phage display biopanning. The targeting takes advantage of the exposure of collagen IV that occurs at sites of vascular inflammation and injury (Kamaly et al., 2013). In a hind-limb ischemia model, systemic injection of collagen-targeted Ac2-26 NPs reduced polymorphonuclear neutrophil (PMN) infiltration by 30% and decreased tissue damage. The NPs also reduced PMN infiltration and decreased the resolution interval in a zymosan-induced peritonitis model (Kamaly et al., 2013). The ability of the NPs to reduce inflammation in the chronic setting of atherosclerosis will be of great interest. Another area of interest is the prevention of vascular smooth muscle proliferation following vascular injury, which can result, for example, in restenosis of vessels following angioplasty and stent placement. Cahn et al. developed multifunctional NPs, which they termed “nanoburrs,” for controlled spatiotemporal delivery of the antiproliferative agent paclitaxel to injured vasculature (Chan et al., 2010). They designed 60 nm core-shell hybrid NPs composed of a
