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Biomedical subjects

Samuel A Wickline

Publications and source records attributed to Samuel A Wickline.

At least 19 recordsLinked to original sources
PubMed2006

Endothelial alpha(v)beta3 integrin-targeted fumagillin nanoparticles inhibit angiogenesis in atherosclerosis.

OBJECTIVE: Angiogenic expansion of the vasa vasorum is a well-known feature of progressive atherosclerosis, suggesting that antiangiogenic therapies may stabilize or regress plaques. Alpha(v)beta3 integrin-targeted paramagnetic nanoparticles were prepared for noninvasive assessment of angiogenesis in early atherosclerosis, for site-specific delivery of antiangiogenic drug, and for quantitative follow-up of response. METHODS AND RESULTS: Expression of alpha(v)beta3 integrin by vasa vasorum was imaged at 1.5 T in cholesterol-fed rabbit aortas using integrin-targeted paramagnetic nanoparticles that incorporated fumagillin at 0 microg/kg or 30 microg/kg. Both formulations produced similar MRI signal enhancement (16.7%+/-1.1%) when integrated across all aortic slices from the renal arteries to the diaphragm. Seven days after this single treatment, integrin-targeted paramagnetic nanoparticles were readministered and showed decreased MRI enhancement among fumagillin-treated rabbits (2.9%+/-1.6%) but not in untreated rabbits (18.1%+/-2.1%). In a third group of rabbits, nontargeted fumagillin nanoparticles did not alter vascular alpha(v)beta3-integrin expression (12.4%+/-0.9%; P>0.05) versus the no-drug control. In a second study focused on microscopic changes, fewer microvessels in the fumagillin-treated rabbit aorta were counted compared with control rabbits. CONCLUSIONS: This study illustrates the potential of combined molecular imaging and drug delivery with targeted nanoparticles to noninvasively define atherosclerotic burden, to deliver effective targeted drug at a fraction of previous levels, and to quantify local response to treatment.

Angiogenesis Inhibitors↗
PubMed2006

MR tagging demonstrates quantitative differences in regional ventricular wall motion in mice, rats, and men.

Rats and genetically manipulated mouse models have played an important role in the exploration of molecular causes of cardiovascular diseases. However, it has not been fully investigated whether mice or rats and humans manifest similar patterns of ventricular wall motion. Although similarities in anatomy and myofiber architecture suggest that fundamental patterns of ventricular wall motion may be similar, the considerable differences in heart size, heart rate, and sarcomeric protein isoforms may yield quantitative differences in ventricular wall mechanics. To further our understanding of the basic mechanisms of myofiber contractile performance, we quantified regional and global indexes of ventricular wall motion in mice, rats, and men using magnetic resonance (MR) imaging. Both regular cine and tagged MR images at apical, midventricular, and basal levels were acquired from six male volunteers, six Fischer 344 rats, and seven C57BL/6 mice. Morphological parameters and ejection fraction were computed directly from cine images. Myocardial twist (rotation angle), torsion (net twist per unit length), circumferential strain, and normalized radial shortening were calculated by homogeneous strain analysis from tagged images. Our data show that ventricular twist was conserved among the three species, leading to a significantly smaller torsion, measured as net twist per unit length, in men. However, both circumferential strain and normalized radial shortening were the largest in male subjects. Although other parameters, such as circumferential-longitudinal shear strain, need to be evaluated, and the causes of these differences in contractile mechanics remain to be elucidated, the preservation of twist appears fundamental to cardiac function and should be considered in studies that extrapolate data from animals to humans.

Adolescent↗
PubMed2006

Targeted PARACEST nanoparticle contrast agent for the detection of fibrin.

A lipid-encapsulated perfluorocarbon nanoparticle molecular imaging contrast agent that utilizes a paramagnetic chemical exchange saturation transfer (PARACEST) chelate is presented. PARACEST agents are ideally suited for molecular imaging applications because one can switch the contrast on and off at will simply by adjusting the pulse sequence parameters. This obviates the need for pre- and postinjection images to define contrast agent binding. Spectroscopy (4.7T) of PARACEST nanoparticles revealed a bound water peak at 52 ppm, in agreement with results from the water-soluble chelate. Imaging of control nanoparticles showed no appreciable contrast, while PARACEST nanoparticles produced >10% signal enhancement. PARACEST nanoparticles were targeted to clots via antifibrin antibodies and produced a contrast-to-noise ratio (CNR) of 10 at the clot surface.

Contrast Media↗
PubMed2006

Molecular imaging by MRI.

The goal of molecular imaging is to detect pathologic biomarkers, which can lead to early recognition of diseases, better therapeutic management, and improved monitoring for recurrence. MRI is a particularly attractive method for molecular imaging applications, due to its noninvasive nature, outstanding signal to noise ratio, high spatial resolution, exceptional tissue contrast, and short imaging times. Site-specific MRI contrast agents have been developed to target biologic processes that occur early in the development of atherosclerotic plaques, including angiogenesis and lipid accumulation, or biosignatures that appear later, such as fibrin and tissue factor resulting from plaque rupture. Moreover, targeted contrast agents can also serve as drug delivery vehicles, combining diagnosis and therapy. If ultimately successful, these emerging molecular imaging agents and techniques will allow early disease recognition and quantification prompting therapeutic intervention before serious sequelae ensue.

Antibiotics, Antineoplastic↗
PubMed2006

MR three-dimensional molecular imaging of intramural biomarkers with targeted nanoparticles.

In this study, porcine carotid arteries were subjected to balloon overstretch injury followed by local delivery of paramagnetic nanoparticles targeted to alphavbeta3-integrin expressed by smooth muscle cells or collagen III within the extracellular matrix. Carotid T1-weighted angiography and vascular imaging was performed at 1.5T. While MR angiograms were indistinguishable between control and targeted vessel segments, alphavbeta3-integrin-and collagen Ill-targeted nanoparticles spatially delineated patterns and volumes of stretch injury. In conclusion, MR molecular imaging with alphavbeta3-integrin or collagen Ill-targeted nanoparticles enables the non-invasive, three-dimensional characterization of arterial pathology unanticipated from routine angiography.

Animals↗
PubMed2006

In vitro demonstration using 19F magnetic resonance to augment molecular imaging with paramagnetic perfluorocarbon nanoparticles at 1.5 Tesla.

OBJECTIVES: This study explored the use of F spectroscopy and imaging with targeted perfluorocarbon nanoparticles for the simultaneous identification of multiple bio-signatures at 1.5 T. MATERIALS AND METHODS: Two nanoparticle emulsions with perfluoro-15-crown-5-ether (CE) or perfluorooctylbromide (PFOB) cores were targeted in vitro to fibrin clot phantoms (n=12) in 4 progressive ratios using biotin-avidin interactions. The CE nanoparticles incorporated gadolinium. Fluorine images were acquired using steady-state gradient-echo techniques; spectra using volume-selective and nonselective sampling. RESULTS: On conventional T1-weighted imaging, clots with CE nanoparticles enhanced as expected, with intensity decreasing monotonically with CE concentration. All clots were visualized using wide bandwidth fluorine imaging, while restricted bandwidth excitation permitted independent imaging of CE or PFOB nanoparticles. Furthermore, F imaging and spectroscopy allowed visual and quantitative confirmation of relative perfluorocarbon nanoparticle distributions. CONCLUSIONS: F MRI/S molecular imaging of perfluorocarbon nanoparticles in vitro suggests that noninvasive phenotypic characterization of pathologic bio-signatures is feasible at clinical field strengths.

Animals↗
PubMed2006

Acoustic activation of targeted liquid perfluorocarbon nanoparticles does not compromise endothelial integrity.

Perfluorocarbon nanoparticles consisting essentially of liquid perfluoro-octyl bromide (PFOB) core surrounded by a lipid monolayer can serve as highly specific site-targeted contrast and therapeutic agents after binding to cellular biomarkers. Based on previous findings that ultrasound applied at 2 MHz and 1.9 mechanical index (MI) for a 5-min duration dramatically enhances the cellular interaction of targeted PFOB nanoparticles with melanoma cells in vitro without inducing apoptosis or other harmful effects to cells that are targeted, we sought to define mechanisms of interaction and the safety profile of ultrasound used in conjunction with liquid perfluorocarbon nanoparticles for targeted drug delivery, as compared with conventional microbubble ultrasound contrast agents under identical insonification conditions. Cell-culture inserts were used to grow a confluent monolayer of human umbilical vein endothelial cells. Definity in conjunction with continuous wave ultrasound (2.25 MHz for 1 and 5 min) increased the permeability of monolayer by four to six times above the normal, decreased transendothelial electrical resistance (a sign of reduced membrane integrity), and decreased cell viability by approximately 50%. Histological evaluation demonstrated extensive disruptions of cell monolayers. Nanoparticles (both nontargeted and targeted) elicited no changes in these different measures under similar insonification conditions and did not disrupt cell monolayers. We hypothesize that ultrasound facilitates drug transport from the perfluorocarbon nanoparticles not by cavitation-induced effects on cell membrane but rather by direct interaction with the nanoparticles that stimulate lipid exchange and drug delivery.

Acoustics↗
PubMed2006

Characterization of digital waveforms using thermodynamic analogs: detection of contrast-targeted tissue in vivo.

We describe characterization of backscatter from tumor tissue targeted with a nanoparticle-based ultrasound contrast agent in vivo using analogs of thermodynamic quantities. We apply these waveform characteristics to detection of tumor neovasculature in tumors implanted in athymic nude mice, which were imaged using a research ultrasound scanner over a 2-hour period after injection of alpha upsilon beta3-targeted perfluorocarbon nanoparticles. Images were constructed from backscattered ultrasound using two different approaches: fundamental B-mode imaging and a signal receiver based on a thermodynamic analog (H(C)). The study shows that the thermodynamic analog is capable of detecting differences in backscattered signals that are not apparent with the B-mode approach.

Algorithms↗
PubMed2006

Targeted magnetic resonance imaging contrast agents.

The era of personalized medicine is emerging as physicians attempt to diagnose disease in asymptomatic individuals and treat pathology early in its natural history. A novel tool in an emerging armamentarium, molecular imaging will allow noninvasive characterization and segmentation of patients for delivering custom-tailored therapy. Nanoparticulate agents, such as superparamagnetic agents, liposomes, perfluorocarbon nanoparticle emulsions, and dendrimers, are being intensively researched as formulation platforms for various targeted clinical applications. As exemplified by perfluorocarbon nanoparticles, these new agents, in combination with the rapid innovations in imaging hardware and software, will allow the emergence of new medical diagnostic and therapeutic paradigms.

Contrast Media↗
PubMed2005

Applications of nanotechnology to atherosclerosis, thrombosis, and vascular biology.

The role of nanotechnology in cardiovascular diagnosis is expanding rapidly. The goal of this brief review is to illustrate selected examples of nanosystems that have been applied to the arenas of atherosclerosis, thrombosis, and vascular biology. The technologies for producing targeted nanosystems are multifarious and reflect end uses in many cases. The results to date indicate rapid growth of interest and capability in the field. The future of cardiovascular diagnosis already is being impacted by nanosystems that can both diagnose pathology and treat it with targeted delivery systems.

Animals↗
PubMed2005

Paradoxical increase in ventricular torsion and systolic torsion rate in type I diabetic patients under tight glycemic control.

OBJECTIVES: This study sought to characterize the early features of diabetic cardiomyopathy by magnetic resonance imaging (MRI) tagging. BACKGROUND: The earliest manifestations of diabetic cardiomyopathy have not been well established, especially under tight glycemic management. We hypothesized that torsion measurements would identify subclinical contractile alterations in type I diabetics with normal left ventricular ejection fraction, mass, blood pressure, and aggressive glycemic control. We also sought to characterize the influence of elevated resting heart rates (HRs) of diabetics on torsion. METHODS: Sixteen patients with type I diabetes and 10 control patients underwent cine and tagged MRI with a 1.5-T scanner. Torsion, strain, and their rates were measured. To quantify the influence of chronotropic and inotropic stimulation on torsion, nine healthy volunteers underwent MRI tagging at rest, after atropine injection, and after exercise. RESULTS: Diabetic patients (hemoglobin A1c, 6.8 +/- 0.4%) had a higher resting HR (77.0 +/- 12.4 beats/min vs. 59.0 +/- 5.6 beats/min; p < 0.01), higher maximal torsion by 23% (3.5 +/- 0.9 degrees/cm vs. 2.7 +/- 0.4 degrees/cm; p < 0.01) and higher maximal systolic torsion rate (TR-s) by 25% (0.013 +/- 0.003 degrees/cm/s vs. 0.010 +/- 0.002 degrees/cm/s, p = 0.01). Torsion did not significantly change with chronotropic stimulation (p = 0.30). CONCLUSIONS: In diabetics under tight glycemic control, we observed a surprising increase in torsion and TR-s unrelated to chronotropic influences of HR. We propose that increased torsion and TR-s could represent early predictive markers of the propensity to cardiac dysfunction in asymptomatic type I diabetics. Furthermore, these findings seem fundamental to the diabetic state itself and unaccounted for by other comorbidities.

Adult↗
PubMed2005

Molecular MR imaging of melanoma angiogenesis with alphanubeta3-targeted paramagnetic nanoparticles.

Neovascularization is a critical component in the progression of malignant melanoma. The objective of this study was to determine whether alpha(nu)beta(3)-targeted paramagnetic nanoparticles can detect and characterize sparse alpha(nu)beta integrin expression on neovasculature induced by nascent melanoma xenografts ( approximately 30 mm(3)) at 1.5T. Athymic nude mice bearing human melanoma tumors were intravenously injected with alpha(v)beta(3)-integrin-targeted paramagnetic nanoparticles, nontargeted paramagnetic nanoparticles, or alpha(v)beta(3)-targeted-nonparamagnetic nanoparticles 2 hr before they were injected with alpha(v)beta(3)-integrin-targeted paramagnetic nanoparticles (i.e., in vivo competitive blockade) and imaged with MRI. Contrast enhancement of neovascularity in animals that received alpha(nu)beta(3)-targeted paramagnetic nanoparticles increased 173% by 120 min. Signal contrast with nontargeted paramagnetic nanoparticles was approximately 50% less than that in the targeted group (P < 0.05). Molecular MRI results were corroborated by histology. In a competitive cell adhesion assay, incubation of alpha(nu)beta(3)-expressing cells with targeted nanoparticles significantly inhibited binding to a vitronectin-coated surface, confirming the bioactivity of the targeted nanoparticles. The present study lowers the limit previously reported for detecting sparse biomarkers with molecular MRI in vivo. This technique may be employed to noninvasively detect very small regions of angiogenesis associated with nascent melanoma tumors, and to phenotype and stage early melanoma in a clinical setting.

Analysis of Variance↗
PubMed2005

Correlation analysis of stenotic aortic valve flow patterns using phase contrast MRI.

Phase contrast MRI is an emerging tool for evaluating valvular pathology. However, the effects of variable image position and valvular pathology on velocity measurements have not been explored. We compare velocity maps with correlation methods, used in image processing to align images and quantify their similarity, to define these effects on calculations of valve orifice area. Quantitative flow images were acquired in four parallel planes (2 in aortic root, 2 in outflow tract), in patients (n = 22) with aortic stenosis. Velocity-time integrals (VTIs) were computed and cross-correlations were performed to quantitatively compare the shapes and relative positions of three-dimensional flow profiles between scans at various positions. Supravalvular VTIs correlated well with one another (R = 0.96), with comparable values. The two subvalvular VTIs exhibited a linear relationship (R = 0.93) but with a 23% difference in mean values. Cross-correlations between supravalvular levels were maximized at (0, 0) offset (indicating concentrically aligned jets) for 19/23 patients, with an average maximum value of 0.957 +/- 0.028; the average for the remainder was 0.800 +/- 0.037. For subvalvular levels, all cross-correlations were maximized at (0, 0) with average maximum 0.968 +/- 0.160. The aortic VTI measurements were comparable, indicating relative insensitivity to the position of the imaging plane; in the LVOT, measurements were only somewhat position-dependent. We conclude that phase contrast MRI is a robust tool for the evaluation of aortic stenosis.

Adult↗
PubMed2005

Targeted contrast agents for magnetic resonance imaging and ultrasound.

The development of contrast agents that can be localized to a particular tissue or cellular epitope will potentially allow the noninvasive visualization and characterization of a variety of disease states. Recent advances have been made in the field of molecular imaging with magnetic resonance imaging and ultrasound and varied approaches have been devised to overcome the high background tissue signal. The types of agents and applications developed include gadolinium-conjugated targeting molecules for imaging of fibrin, superparamagnetic iron oxide particles for stem-cell tracking, multimodal perfluorocarbon nanoparticles for visualization of angiogenesis, liposomes for targeting atheroma components, and microbubbles for imaging transplant rejection.

Animals↗
PubMed2005

Sonic activation of molecularly-targeted nanoparticles accelerates transmembrane lipid delivery to cancer cells through contact-mediated mechanisms: implications for enhanced local drug delivery.

Liquid perfluorocarbon nanoparticles serve as sensitive and specific targeted contrast and drug delivery vehicles by binding to specific cell surface markers. We hypothesized that application of acoustic energy at diagnostic power levels could promote nanoparticle-associated drug delivery by stimulating increased interaction between the nanoparticle's lipid layer and the targeted cell's plasma membrane. Ultrasound (mechanical index = 1.9) applied with a conventional ultrasound imaging system to nanoparticles targeted to alpha(v)beta3-integrins on C32 melanoma cancer cells in vitro produced no untoward effects. Within 5 min, lipid delivery from nanoparticles into cell cytoplasm was dramatically augmented. We also demonstrate the operation of a potential physical mechanism for this effect, the acoustic radiation force on the nanoparticles, which may contribute to the enhanced lipid delivery. Accordingly, we propose that local delivery of lipophilic substances (e.g., drugs) from targeted nanoparticles directly into cell cytoplasm can be augmented rapidly and safely with conventional ultrasound imaging devices through nondestructive mechanisms.

Cell Line, Tumor↗
PubMed2005

1H/19F magnetic resonance molecular imaging with perfluorocarbon nanoparticles.

Developments in genomics, proteomics, and cell biology are leading a trend toward individualized segmentation and treatment of patients based on early, noninvasive recognition of unique biosignatures. Although developments in molecular imaging have been dominated by nuclear medicine agents in the past, the advent of nanotechnology in the 1990s has led to magnetic resonance (MR) molecular agents that allow detection of sparse biomarkers with a high-resolution imaging modality that can provide both physiological and functional agents. A wide variety of nanoparticulate MR contrast agents have emerged, most of which are superparamagnetic iron oxide-based constructs. However, this chapter focuses on a diagnostic and therapeutic perfluorocarbon (PFC) nanoparticulate platform that is not only effective as a T1-weighted agent, but also supports (19)F MR spectroscopy and imaging. The unique capability of (19)F permits confirmation and segmentation of MR contrast images as well as direct quantification of nanoparticle concentrations within a voxel. PFC nanoparticles have the capability to effectively deliver therapeutic agents to target sites by a novel mechanism termed "contact-facilitated drug delivery." Combined with MR spectroscopy, the concentration of drug delivered to the target site can be determined and the expected response predicted. Moreover, mixtures of nanoparticles with different perfluorocarbon cores can provide a quantitative, multispectral signal, which can be used to simultaneously distinguish the relative concentrations of several important epitopes within a region of interest. In conjunction with rapid improvements in MR imaging, the prospects for personalized medicine and early recognition and treatment of disease have never been better.

Animals↗
PubMed2005

Characterization of digital waveforms using thermodynamic analogs: applications to detection of materials defects.

We describe characterization of digital signals using analogs of thermodynamic quantities: the topological entropy, Shannon entropy, thermodynamic energy, partition function, specific heat at constant volume, and an idealized version of Shannon entropy in the limit of digitizing with infinite dynamic range and sampling rate. We show that analysis based on these quantities is capable of detecting differences between digital signals that are undetectable by conventional methods of characterization based on peak-to-peak amplitude or signal energy. We report the results of applying thermodynamic quantities to a problem from nondestructive materials evaluation: detection of foreign objects (FO) embedded near the surface of thin graphite/epoxy laminates using backscattered waveforms obtained by C-scanning the laminate. The characterization problem was to distinguish waveforms acquired from the region containing the FO from those acquired outside. In all cases the thermodynamic analogs exhibit significant increases (up to 20-fold) in contrast and for certain types of FO materials permit detection when energy or amplitude methods fail altogether.

Journal Article↗