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Biomedical subjects

Gregory M Lanza

Publications and source records attributed to Gregory M Lanza.

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

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

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

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↗
PubMed2005

Acoustic characterization in whole blood and plasma of site-targeted nanoparticle ultrasound contrast agent for molecular imaging.

The ability to enhance specific molecular markers of pathology with ultrasound has been previously demonstrated by our group employing a nanoparticle contrast agent [Lanza et al., Invest. Radiol. 35, 227-234 (2000); Ultrasound Med. Biol. 23, 863-870 (1997)]. One of the advantages of this agent is very low echogenicity in the blood pool that allows increased contrast between the blood pool and the bound, site-targeted agent. We measured acoustic backscatter and attenuation coefficient as a function of the contrast agent concentration, ambient pressure, peak acoustic pressure, and as an effect of duty cycle and wave form shape. Measurements were performed while the nanoparticles were suspended in either whole porcine blood or plasma. The nanoparticles were only detectable when insonified within plasma devoid of red blood cells and were shown to exhibit backscatter levels more than 30 dB below the backscatter from whole blood. Attenuation of nanoparticles in whole porcine blood was not measurably different from that of whole blood alone over a range of concentrations up to eight times the maximum in vivo dose. The resulting data provide upper bounds on blood pool attenuation coefficient and backscatter and will be needed to more precisely define levels of molecular contrast enhancement that may be obtained in vivo.

Animals↗
PubMed2005

Magnetic resonance nanoparticles for cardiovascular molecular imaging and therapy.

Molecular vascular imaging represents a novel tool that promises to change the current medical paradigm of 'see and treat' to a 'detect and prevent' strategy. Nanoparticle agents, such as superparamagnetic nanoparticles and perfluorocarbon nanoparticle emulsions, have been developed for noninvasive imaging, particularly for magnetic resonance imaging. Designed to target specific epitopes in tissues, these agents are beginning to enter clinical trials for cardiovascular applications. The delivery of local therapy with these nanoparticles, using mechanisms such as contact-facilitated drug delivery, is in the advanced stages of preclinical research. Ultimately, combined diagnostic and therapeutic nanoparticle formulations may allow patients to be characterized noninvasively and segmented to receive custom-tailored therapy. This review focuses on recent developments of nanoparticle technologies with an emphasis on cardiovascular applications of magnetic resonance imaging.

Animals↗
PubMed2004

Quantification of stenotic mitral valve area with magnetic resonance imaging and comparison with Doppler ultrasound.

OBJECTIVES: The purpose of this study was to evaluate the reliability of the pressure half-time (PHT) method for estimating mitral valve areas (MVAs) by velocity-encoded cardiovascular magnetic resonance (VE-CMR) and to compare the method with paired Doppler ultrasound. BACKGROUND: The pressure half-time Doppler echocardiography method is a practical technique for clinical evaluation of mitral stenosis. As CMR continues evolving as a routine clinical tool, its use for estimating MVA requires thorough evaluation. METHODS: Seventeen patients with mitral stenosis underwent echocardiography and CMR. Using VE-CMR, MVA was estimated by PHT method. Additionally, peak E and peak A velocities were defined. Interobserver repeatability of VE-CMR was evaluated. RESULTS: By Doppler, MVAs ranged from 0.87 to 4.49 cm2; by CMR, 0.91 to 2.70 cm2, correlating well between modalities (r = 0.86). The correlation coefficient for peak E and peak A between modalities was 0.81 and 0.89, respectively. Velocity-encoded CMR data analysis provided robust, repeatable estimates of peak E, peak A, and MVA (r = 0.99, 0.99, and 0.96, respectively). CONCLUSIONS: Velocity-encoded cardiovascular magnetic resonance can be used routinely as a robust tool to quantify MVA via mitral flow velocity analysis with PHT method.

Aged↗
PubMed2004

Targeted nanoparticles for quantitative imaging of sparse molecular epitopes with MRI.

Before molecular imaging with MRI can be applied clinically, certain problems, such as the potential sparseness of molecular epitopes on targeted cell surfaces, and the relative weakness of conventional targeted MR contrast agents, must be overcome. Accordingly, the conditions for diagnostic conspicuity that apply to any paramagnetic MRI contrast agent with known intrinsic relaxivity were examined in this study. A highly potent paramagnetic liquid perfluorocarbon nanoparticle contrast agent ( approximately 250 nm diameter, >90,000 Gd3+/particle) was imaged at 1.5 T and used to successfully predict a range of sparse concentrations in experimental phantoms with the use of standard MR signal models. Additionally, we cultured and targeted the smooth muscle cell (SMC) monolayers that express "tissue factor," a glycoprotein of crucial significance to hemostasis and response to vascular injury, by conjugating an anti-tissue factor antibody fragment to the nanoparticles to effect specific binding. Quantification of the signal from cell monolayers imaged at 1.5 T demonstrated, as predicted via modeling, that only picomolar concentrations of paramagnetic perfluorocarbon nanoparticles were required for the detection and quantification of tissue factor at clinical field strengths. Thus, for targeted paramagnetic agents carrying high payloads of gadolinium, it is possible to quantify molecular epitopes present in picomolar concentrations in single cells with routine MRI.

Analysis of Variance↗
PubMed2004

Quantitative "magnetic resonance immunohistochemistry" with ligand-targeted (19)F nanoparticles.

Unstable atherosclerotic plaques exhibit microdeposits of fibrin that may indicate the potential for a future rupture. However, current methods for evaluating the stage of an atherosclerotic lesion only involve characterizing the level of vessel stenosis, without delineating which lesions are beginning to rupture. Previous work has shown that fibrin-targeted, liquid perfluorocarbon nanoparticles, which carry a high payload of gadolinium, have a high sensitivity and specificity for detecting fibrin with clinical (1)H MRI. In this work, the perfluorocarbon content of the targeted nanoparticles is exploited for the purposes of (19)F imaging and spectroscopy to demonstrate a method for quantifiable molecular imaging of fibrin in vitro at 4.7 T. Additionally, the quantity of bound nanoparticles formulated with different perfluorocarbon species was calculated using spectroscopy. Results indicate that the high degree of nanoparticle binding to fibrin clots and the lack of background (19)F signal allow accurate quantification using spectroscopy at 4.7 T, as corroborated with proton relaxation rate measurements at 1.5 T and trace element (gadolinium) analysis. Finally, the extension of these techniques to a clinically relevant application, the evaluation of the fibrin burden within an ex vivo human carotid endarterectomy sample, demonstrates the potential use of these particles for uniquely identifying unstable atherosclerotic lesions in vivo.

Arteriosclerosis↗