Journal
JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY
Volume 6, Issue 9-10, Pages 3226-3234Publisher
AMER SCIENTIFIC PUBLISHERS
DOI: 10.1166/jnn.2006.428
Keywords
angioplasty; macrophages; bisphosphonates; restenosis; nanoparticles
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The present study explored a novel strategy for attenuation of restenosis after arterial injury by a bisphosphonate encapsulated in polymeric nanoparticles (NP) for transient selective depletion of macrophages. A bisphosphonate (BP), 2-(2-Aminopyrimidino) ethyldiene-1,1-bisphosphonic acid betaine (ISA), was successfully formulated in 400 nm sized polylactide/glycolide-based NP with high yield (69%) and entrapment efficiency (60% w/w). ISA NP, but not blank NP or free I SA, exhibited specific and significant cytotoxic effect on macrophages-like RAW 264 cells, in a dose-dependent manner, with no inhibitory effect on the growth of smooth muscle cells (SMCs). Fluorescent pyrene-labeled NP were shown to be taken up by RAW 264 cells, but not by SMCs. Intravenously (IV) administered ISA NP (15 mg/kg, single dose on day-1) resulted in a significant attenuation of neointima to media area ratio (N/M) by 40% and stenosis by 45% 14 days after rat carotid injury, in comparison to animals treated with free ISA, buffer or blank NR However, the effect was not preserved 30 days post injury, and an insignificant reduction of neointimal formation was observed. Neointimal hyperplasia was also significantly suppressed after subcutaneous (SC) injection of ISA NP (15 mg/kg, single dose on day-1), reducing both N/M and stenosis. Intraperitoneal (IP) injection of silica, a known selective toxin for macrophages, (1000 mg/kg), also resulted in a significant inhibition of N/M and stenosis, which further reinforces the cause-effect relationship of macrophage-inactivation and the prevention of neointima formation. Biocompatible and biodegradable NP loaded with ISA characterized by high colloidal stability, reproducible activity, and high drug entrapment warrant further consideration for restenosis therapy, and may be useful in other disease processes involving monocytes/macrophages.
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