Nanotechnology for molecular imaging and targeted therapy.
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Cardiovascular Diseases↗
Biomedical subjects
Samuel A Wickline
Publications and source records attributed to Samuel A Wickline.
Improved molecular imaging contrast agent for detection of human thrombus.
Molecular imaging of microthrombus within fissures of unstable atherosclerotic plaques requires sensitive detection with a thrombus-specific agent. Effective molecular imaging has been previously demonstrated with fibrin-targeted Gd-DTPA-bis-oleate (BOA) nanoparticles. In this study, the relaxivity of an improved fibrin-targeted paramagnetic formulation, Gd-DTPA-phosphatidylethanolamine (PE), was compared with Gd-DTPA-BOA at 0.05-4.7 T. Ion- and particle-based r(1) relaxivities (1.5 T) for Gd-DTPA-PE (33.7 (s*mM)(-1) and 2.48 x 10(6) (s*mM)(-1), respectively) were about twofold higher than for Gd-DTPA-BOA, perhaps due to faster water exchange with surface gadolinium. Gd-DTPA-PE nanoparticles bound to thrombus surfaces via anti-fibrin antibodies (1H10) induced 72% +/- 5% higher change in R(1) values at 1.5 T (deltaR(1) = 0.77 +/- 0.02 1/s) relative to Gd-DTPA-BOA (deltaR(1) = 0.45 +/- 0.02 1/s). These studies demonstrate marked improvement in a fibrin-specific molecular imaging agent that might allow sensitive, early detection of vascular microthrombi, the antecedent to stroke and heart attack.
Contrast Media↗
Targeted ultrasonic contrast agents for molecular imaging and therapy.
Targeted contrast agents are expanding the detectability and diagnosis of pathology from a strict anatomic to biochemical basis. Moreover, these new agents, in their various forms, offer the potential for site-specific drug and gene delivery, i.e., the "magic bullet" first postulated by Paul Erhlich 100 years ago. The ability to direct drugs to the molecular signatures of disease, to confirm noninvasively their presence at the site-of-interest, and to quantify the adequacy of local drug concentration at the time of treatment, ie, rational targeted drug delivery, offers exciting new clinical paradigms in the near future.
Antibodies, Monoclonal↗
Chronological age modifies the microscopic remodeling process in viable cardiac tissue after infarction.
To define the impact of age on microscopic structural remodeling after myocardial infarction, the physical properties of infarct scar tissue and viable remote zone tissues in young (3 months) and older adult (18 months) Fischer rats were quantified with the use of high-frequency (50 MHz) high-resolution acoustic microscopy 3 months after coronary artery occlusion. We observed that integrated backscatter increased by 100% in the viable zones of old animals after infarction, but remained relatively unaffected in the same regions of younger animals. Mathematical models of myocardial scattering behavior indicated that a 25% increase in stiffness of the extracellular matrix materials in viable zones likely occurred in the older animals. Alterations in gross tissue collagen content were not responsible for this increased stiffness. These observations are compatible with the hypothesis that progressive age-related changes in the quality of the collagen (e.g., excessive age-related crosslinking) rather than its amount per se may have altered the stiffness of the extracellular matrix of remodeled viable tissue in older animals.
Aging↗
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. 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.
Animals↗
Molecular imaging, targeted therapeutics, and nanoscience.
The recent emergence of "molecular imaging" as an academic discipline has set the stage for an evolutionary leap in diagnostic imaging. Recent advances in nuclear, ultrasound, optical, and magnetic resonance imaging have generated interest in molecular imaging across all modalities and across various academic, industrial, and governmental agencies. In this perspective, examples of the progress and the prospects for the future of molecular imaging and linked targeted therapeutics are reviewed.
Animals↗
Blood contrast enhancement with a novel, non-gaseous nanoparticle contrast agent.
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Animals↗
Molecular imaging and targeted drug delivery with a novel, ligand-directed paramagnetic nanoparticle technology.
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Animals↗
Report from the First International Conjoint Conference on Cardiovascular Magnetic Resonance and Echocardiography.
The opinions formulated in this conference represent expressions of promise and enthusiasm about charting the course for the future of cardiovascular imaging and the role that might be played by CMR and echocardiography. All attendees agreed that this conference provided a novel venue for friendly debate and discussion in an open forum that could facilitate research and clinical service planning, and that other similar conferences should be held to focus on additional methodologies and topics. Indeed, planning is already underway for a Second Conference with comparative CMR and nuclear imaging as a focus.
Cardiovascular Diseases↗
Improvements in the ultrasonic contrast of targeted perfluorocarbon nanoparticles using an acoustic transmission line model.
Targeted acoustic contrast agents offer the potential for sensitive ultrasonic detection of pathologic tissues. We have previously reported the development of a ligand-targeted, lipid-encapsulated, liquid perfluorodichlorooctane ultrasonic contrast system with a small nominal particle size (approximately 250-nm diameter). Perfluorocarbon nanoparticles substantially increase reflectivity when bound to targeted surfaces, and we propose that this system can be approximated physically as a simple, thin layer, acoustic transmission line. In this study, we evaluate this model and compare the ultrasonic reflectivity of different perfluorocarbon formulations with widely varying acoustic impedances targeted to either nitrocellulose membranes or plasma thrombi in vitro. Five perfluorocarbons were investigated: perfluorohexane (PFH), perfluorooctane (PFO), perfluorooctyl bromide (PFOB), perfluorodichlorooctane (PFDCO), and perfluorodecalin (PFD). Ultrasonic reflection was measured by acoustic microscopy (17 to 35 MHz). Acoustic reflectivity was increased (P < 0.05) by all targeted perfluorocarbon formulations, and the magnitude of the contrast effect was inversely correlated with the perfluorocarbon acoustic impedance. PFH nanoparticles exhibited the greatest enhancement, and PFD nanoparticles showed the least. The acoustic transmission line model predicted well the relative differences in acoustic reflectivity and frequency dependence among the perfluorocarbon formulations. For future clinical applications, PFO nanoparticles may provide the best combination of acoustic enhancement, in vivo physical stability, and safety.
Acoustics↗
Characterization of aortic microstructure with ultrasound: implications for mechanisms of aortic function and dissection.
Specific ultrasonic tissue characterization parameters were correlated with the three-dimensional architecture and material properties (density, compressibility, size, and orientation) of aortic elastic elements at the microscopic level. The medial layer of 10 samples of normal canine aorta were insonified in vitro utilizing acoustic microscopy from 30 to 44 MHz. The following quantitative indexes exhibited substantial anisotropic elastic behavior in radial (R), circumferential (C), and longitudinal (L) directions: backscatter coefficient (R:0.9 +/- 0.2; C:0.008 +/- 0.0008; LL:0.0077 +/- 0.0008 sr(-1) cm(-1)); frequency dependence of backscatter (R:3.3; C:1.4; L:1.5); attenuation coefficients 1(R:105 +/- 22; L:135 +/- 13; C:131 +/- 14 dB/cm). Thus, the ultrasonic indexes are anisotropic: equivalent in the C and L directions, but markedly different in the R direction. These data are indicative of an aortic microstructure that interacts with ultrasonic waves as thin sheet-like elastic layers instead of independent elastin fibers. This specific sheet-like organization of elastin microfibers may function to limit shear injury to concentric aortic lamellae and prevent aortic dissection. The marked anisotropic behavior of normal aortas suggests that ultrasound may be useful for nondestructive characterization of vascular integrity.
Aortic Dissection↗
Temperature dependence of acoustic impedance for specific fluorocarbon liquids.
Recent studies by our group have demonstrated the efficacy of perfluorocarbon liquid nanoparticles for enhancing the reflectivity of tissuelike surfaces to which they are bound. The magnitude of this enhancement depends in large part on the difference in impedances of the perfluorocarbon, the bound substrate, and the propagating medium. The impedance varies directly with temperature because both the speed of sound and the mass density of perfluorocarbon liquids are highly temperature dependent. However, there are relatively little data in the literature pertaining to the temperature dependence of the acoustic impedance of these compounds. In this study, the speed of sound and density of seven different fluorocarbon liquids were measured at specific temperatures between 20 degrees C and 45 degrees C. All of the samples demonstrated negative, linear dependencies on temperature for both speed of sound and density and, consequently, for the acoustic impedance. The slope of sound speed was greatest for perfluorohexane (-278 +/- 1.5 cm/s-degrees C) and lowest for perfluorodichlorooctane (-222 +/- 0.9 cm/s-degrees C). Of the compounds measured, perfluorohexane exhibited the lowest acoustic impedance at all temperatures, and perfluorodecalin the highest at all temperatures. Computations from a simple transmission-line model used to predict reflectivity enhancement from surface-bound nanoparticles are discussed in light of these results.
Contrast Media↗
Magnetic resonance molecular imaging with nanoparticles.
Molecular imaging agents are extending the potential of noninvasive medical diagnosis from basic gross anatomic descriptions to complicated phenotypic characterizations based on the recognition of unique cell surface biochemical signatures. Although originally the purview of nuclear medicine, molecular imaging is now a prominent feature of most clinically relevant imaging modalities, in particular magnetic resonance (MR) imaging. MR nanoparticulate agents afford the opportunity not only for targeted diagnostic studies but also for image-monitored site-specific therapeutic delivery, much like the "magic bullet" envisioned by Paul Erhlich 100 years ago. Combining high-resolution MR molecular imaging with drug delivery will facilitate verification and quantification of treatment (ie, rational targeted therapy) and will offer new clinical approaches to many diseases.
Cell Movement↗