Abstract 10285: A Nanomedicine Approach to Restenosis promoting endothelial healing with Targeted Delivery of a New Lipase-labile, Myc-Max Antagonist Prodrug
C-Myc, a transcription factor, is increased in vascular smooth muscle cells following vascular injury. Anti-sense oligonucleotides (AS-ODN) have been shown to inhibit c-Myc and reduce stenosis in animal models, but the local delivery of AS-ODN was ineffective in humans. In the present study, we hypothesized that a nanomedicine approach incorporating a cryptic c-Myc-inhibitor prodrug could be delivered and enzymatically released to effectively inhibit VSMC proliferation with minimal impact on endothelial proliferation. A sn-2 lipase labile Myc-inhibitor prodrug (Myc-PD) was synthesized and confirmed by mass-spectroscopy. The Myc-PD was included at 2mole% into the surfactant of a previously described αvβ3-perfluorocarbon nanoparticle (PFC-NP, ~250nm). Human coronary VSMC and HUVEC cells were plated on coverslips (2500 cells/well), incubated 1 hour with αvβ3-Myc-PD PFC-NP, αvβ3-No-Drug-PFC-NP, DMSO, free myc-inhibitor (Myc-I) in DMSO, or media (6 reps/group). Vascular smooth muscle cell proliferation was measured using alamar blue staining at 24 and 48 hours. αvβ3-Myc-PD-PFC-NP decreased (p<0.05) VSMC proliferation at 24 and 48 hours (fig) whereas free Myc-I, αvβ3-No drug PFC-NP, media, and DMSO controls had no effect. No differences (p>0.05) were found for HUVEC given αvβ3-Myc-PD PFC-NP or αvβ3-No-Drug-PFC-NP with or without angiotensin II stimulation. Fluorescence microscopy confirmed selective binding of targeted nanoparticles versus the non-targeted agent to both cell types. These data demonstrate for the first time, the effective synthesis of a lipase-labile Myc-PD and its potential use as a targeted nanomedicine approach to prevent restenosis. We suggest that intramural delivery of αvβ3-Myc-PD NP, alone or with stents, offers an attractive new approach to restenosis.
- © 2011 by American Heart Association, Inc.