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 T 1 -weighted MRI at 4.7T. MRI 19 F 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.

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We have used the fluorescence probe Prodan to characterize the structure of reverse micelles formed in the ternary system of surfactant Aerosol OT, sodium bis(2-ethylhexyl) sulfosuccinate (AOT)/heptane/water. Our results demonstrate that Prodan is a novel and powerful probe of the features of reverse micellar systems as a consequence of its solubility and measurable fluorescence intensity in a wide range of solvents of varying polarity. These characteristics govern the distribution of the probe into the microregions of the reverse micelle and yield fluorescence properties simultaneously indicative of multiple locations. We observe four principal microenvironments for Prodan, including an inner “free” water pool, a bound water region, the AOT interface, and the surrounding hydrocarbon solvent phase. As the parameters of surfactant concentration and the molar ratio of water to surfactant are varied, we attribute the observed emission characteristics of Prodan to specific micellar structural features including heterogeneity of the water pool, the variable polarities of the bound and free water regions, the hydrophobicity and permeability of the surfactant interface, and the hydration of Na+ counterions in the bound water region.

Our investigations seek to illustrate the use of fluorescence spectral deconvolution to characterize multiple partitioning sites for aromatic chromophores within aqueous and reverse micelles. The spatial distribution of solutes within micellar systems is dictated by a variety of noncovalent interactions. To probe for multiple partitioning microenvironments, we use the aromatic fluorophore Prodan with its extensive solubility in a range of media and its appreciable spectral sensitivity to the polarity of its surroundings. We conduct a systematic study of the partitioning of Prodan in aqueous micellar systems with anionic, cationic, zwitterionic, and nonionic surfactant headgroups and in reverse micellar systems with both anionic and cationic surfactant headgroups. By deconvoluting the overall Prodan fluorescence emission spectrum into a sum of overlapping Gaussian functions, the principal microenvironments of the Prodan molecules may be ascertained. Fluorescence data are consistent with the location of Prodan in a variety of sites, including partitionings that may be influenced by electrostatic, hydrophobic, dipolar, and cation−π interactions in both aqueous and reverse micelles.

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