Published Online
on November 11, 2002

A more recent version of this article appeared on November 26, 2002

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Submitted on May 1, 2002
Revised on August 22, 2002
Accepted on August 24, 2002

Targeted Antiproliferative Drug Delivery to Vascular Smooth Muscle Cells With a Magnetic Resonance Imaging Nanoparticle Contrast Agent. Implications for Rational Therapy of Restenosis

Gregory M. Lanza MD, PhD^*, Xin Yu ScD, Patrick M. Winter PhD, Dana R. Abendschein PhD, Kerry K. Karukstis PhD, Michael J. Scott BS, Lori K. Chinen MS, Ralph W. Fuhrhop , David E. Scherrer MS, and Samuel A. Wickline MD

From the Department of Medicine, Division of Cardiology, Washington University Medical School, St Louis, Mo (G.M.L., X.Y., P.M.W., D.R.A., M.J.S., L.K.C., R.W.F., D.E.S., S.A.W.), and the Department of Chemistry, Harvey Mudd College, Claremont, Calif (K.K.K.).

^* To whom correspondence should be addressed. E-mail: greg{at}soundlab.wustl.edu.

Background—Restenosis is a serious complication of coronary angioplasty that involves the proliferation and migration of vascular smooth muscle cells (VSMCs) from the media to the intima, synthesis of extracellular matrix, and remodeling. We have previously demonstrated that tissue factor-targeted nanoparticles can penetrate and bind stretch-activated vascular smooth muscles in the media after balloon injury. In the present study, the concept of VSMC-targeted nanoparticles as a drug-delivery platform for the prevention of restenosis after angioplasty is studied.

Methods and Results—Tissue factor-targeted nanoparticles containing doxorubicin or paclitaxel at 0, 0.2, or 2.0 mole% of the outer lipid layer were targeted for 30 minutes to VSMCs and significantly inhibited their proliferation in culture over the next 3 days. Targeting of the nanoparticles to VSMC surface epitopes significantly increased nanoparticle antiproliferative effectiveness, particularly for paclitaxel. In vitro dissolution studies revealed that nanoparticle drug release persisted over one week. Targeted antiproliferative results were dependent on the hydrophobic nature of the drug and noncovalent interactions with other surfactant components. Molecular imaging of nanoparticles adherent to the VSMC was demonstrated with high-resolution T₁-weighted MRI at 4.7T. MRI ¹⁹F spectroscopy of the nanoparticle core provided a quantifiable approach for noninvasive dosimetry of targeted drug payloads.

Conclusions—These data suggest that targeted paramagnetic nanoparticles may provide a novel, MRI-visualizable, and quantifiable drug delivery system for the prevention of restenosis after angioplasty.

Key words: restenosis • drugs • magnetic resonance imaging

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