Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent: implications for rational therapy of restenosis.
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.


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.
Lanza
Gregory M
GM
Department of Medicine, Division of Cardiology, Washington University Medical School, St Louis, Mo 63110, USA. greg@soundlab.wustl.edu
Yu
Xin
X
Winter
Patrick M
PM
Abendschein
Dana R
DR
Karukstis
Kerry K
KK
Scott
Michael J
MJ
Chinen
Lori K
LK
Fuhrhop
Ralph W
RW
Scherrer
David E
DE
Wickline
Samuel A
SA
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003287:Contrast Media / Q000737:chemistry / Q000494:pharmacology*; D023903:Coronary Restenosis / Q000517:prevention & control*; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D017611:Fluorine Compounds / Q000737:chemistry; D005466:Fluorocarbons / Q000737:chemistry / Q000494:pharmacology; D019786:Gadolinium DTPA / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019301:Oleic Acid / Q000737:chemistry / Q000494:pharmacology*; D009829:Oleic Acids; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology; D010316:Particle Size; D013552:Swine; D013925:Thromboplastin / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D000972:Antineoplastic Agents, Phytogenic; D003287:Contrast Media; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D017611:Fluorine Compounds; D005466:Fluorocarbons; D009829:Oleic Acids; C469626:gadolinium diethylene-triamine-pentaacetic acid-bis-oleate; D019301:Oleic Acid; D004317:Doxorubicin; D013925:Thromboplastin; D019786:Gadolinium DTPA; D017239:Paclitaxel