Super-paramagnetic iron oxide nanoparticles for use in extrapulmonary tuberculosis diagnosis.

The limited sensitivity of serological tests for mycobacterial antigens has encouraged the development of a nanoparticle probe specific for the extrapulmonary form of Mycobacterium tuberculosis (Mtb). We developed an innovative probe comprised of super-paramagnetic iron oxide (SPIO) nanoparticles conjugated with Mtb surface antibody (MtbsAb-nanoparticles) to provide ultrasensitive imaging of biomarkers involved in extrapulmonary Mtb infection. MtbsAb-nanoparticles were significantly conjugated with Mtb bacilli. The extent of contrast enhancement reduction on magnetic resonance imaging (MRI) for Mtb and human monocytic THP1 cells was proportional to the concentration of MtbsAb-nanoparticles. When MtbsAb-nanoparticles were intravenously injected into mice bearing Mtb granulomas, the granulomatous site showed a 14-fold greater reduction in signal intensity enhancement on T(2) -weighted MR images compared with an opposing site that received PBS injection. Mtb sAb-nanoparticles represent a new non-invasive technology for the diagnosis of extrapulmonary Mtb.

T1 efficacy of EVP-ABD: a potential manganese-based MR contrast agent for hepatic vascular and tissue phase imaging.

PURPOSE: To evaluate the T1 efficacy of EVP-ABD, a new manganese (Mn)-based contrast agent, for vascular and liver tissue enhancement in comparison with currently approved agents. MATERIALS AND METHODS: Ten Yorkshire pigs (body weight, 26 -46 kg) were used for the efficacy evaluation, nine for kinetic T1 evaluation (three each agent) and one for post EVP-ABD imaging. With a fast imaging scheme to monitor T1 values of blood and liver, 10 micromol/kg EVP-ABD was injected intravenously and compared with gadopentetate dimeglumine (Magnevist, GdDTPA) and mangafodipir trisodium (Teslascan, mangafodipir trisodium) at routine clinical dosages. All were imaged with 3D T1 Gradient Recalled Echo (GRE) sequence (TR/TE/alpha = 3.8/1.6/25 degrees ) prior to and 10 minutes post injection using a 1.5-T whole-body scanner. Additional high-resolution 2D liver images (TR/TE/alpha = 50/4.6/40 degrees ) and arterial phase images of the upper aorta were acquired from the pig for post EVP-ABD imaging. RESULTS: At 10 micromol/kg, EVP-ABD provided a dramatic decline in blood T1, comparable to 0.1 mmol/kg GdDTPA, followed by a rapid return to blood baseline T1 values. In addition to the blood enhancement phase, EVP-ABD achieved a 70% reduction in liver T1 within 2 minutes postadministration, with an imaging window of at least 2 hours. A substantially improved signal-to-noise ratio (SNR) was observed in both the 2D and 3D liver images postcontrast. CONCLUSION: EVP-ABD demonstrated peak vascular enhancement similar to GdDTPA and prolonged specific liver enhancement exceeding mangafodipir trisodium. EVP-ABD has favorable T1 enhancing characteristics with the potential to allow for a comprehensive liver evaluation.

TmDOTA-: a sensitive probe for MR thermometry in vivo.

The lanthanide complex, thulium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (TmDOTA-), has been investigated as an agent for MR thermometry in vivo. The chemical shifts of the TmDOTA- protons were highly sensitive to temperature at a clinically relevant field strength, yet insensitive to pH and the presence of Ca2+. Given the excellent stability of lanthanide-DOTA complexes and high thermal sensitivity, TmDOTA- is expected to be a good candidate for MR thermometry in vivo.

Simultaneous measurements of temperature and pH in vivo using NMR in conjunction with TmDOTP5-.

NMR techniques for temperature and pH measurements have attracted increasing interest in recent years, motivated in part by the growing importance of medical hyperthermia for the treatment of cancer. The chemical shifts of thulium 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetrakis(methylene phosphonate) (TmDOTP5-) have been studied as a function of temperature and pH. The results demonstrate that TmDOTP5- resonance shifts are highly sensitive to temperature (approximately 1.0 ppm/degrees C) and pH (approximately 3.2 ppm/pH unit) at clinically relevant field strengths. A new method is presented which utilizes two magnetically non-equivalent protons in TmDOTP5- for simultaneous NMR measurements of both temperature and pH. The difference in the chemical shift values of pairs of 1H resonances provides a temperature sensitivity of about 1.6 ppm/ degrees C. The technique is demonstrated in live rats undergoing ultrasound-induced hyperthermia therapy.

Proton nuclear magnetic resonance measurement of p-boronophenylalanine (BPA): a therapeutic agent for boron neutron capture therapy.

Noninvasive in vivo quantitation of boron is necessary for obtaining pharmacokinetic data on candidate boronated delivery agents developed for boron neutron capture therapy (BNCT). Such data, in turn, would facilitate the optimization of the temporal sequence of boronated drug infusion and neutron irradiation. Current approaches to obtaining such pharmacokinetic data include: positron emission tomography employing F-18 labeled boronated delivery agents (e.g., p-boronophenylalanine), ex vivo neutron activation analysis of blood (and very occasionally tissue) samples, and nuclear magnetic resonance (NMR) techniques. In general, NMR approaches have been hindered by very poor signal to noise achieved due to the large quadrupole moments of B-10 and B-11 and (in the case of B-10) very low gyromagnetic ratio, combined with low physiological concentrations of these isotopes under clinical conditions. This preliminary study examines the feasibility of proton NMR spectroscopy for such applications. We have utilized proton NMR spectroscopy to investigate the detectability of p-boronophenylalanine fructose (BPA-f) at typical physiological concentrations encountered in BNCT. BPA-f is one of the two boron delivery agents currently undergoing clinical phase-I/II trials in the U.S., Japan, and Europe. This study includes high-resolution 1H spectroscopic characterization of BPA-f to identify useful spectral features for purposes of detection and quantification. The study examines potential interferences, demonstrates a linear NMR signal response with concentration, and presents BPA NMR spectra in ex vivo blood samples and in vivo brain tissues.

NMR temperature measurements using a paramagnetic lanthanide complex.

NMR thermometry has previously suffered from poor thermal resolution owing to the relatively weak dependence of chemical shift on temperature in diamagnetic molecules. In contrast, the shifts of nuclear spins near a paramagnetic center exhibit strong temperature dependencies. The chemical shifts of the thulium 1,4,7, 10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate) complex (TmDOTP5-) have been studied as a function of temperature, pH, and Ca2+ concentration over ranges which may be encountered in vivo. The results demonstrate that the 1H and 31P shifts in TmDOTP5- are highly sensitive to temperature and may be used for NMR thermometry with excellent accuracy and resolution. A new technique is also described which permits simultaneous measurements of temperature and pH changes from the shifts of multiple TmDOTP5- spectral lines.

TmDOTP5-: a substance for NMR temperature measurements in vivo.

The chemical shifts of 31P and 1H in thulium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate) (TmDOTP5-) are approximately two orders of magnitude more sensitive to temperature than are water proton and 19F shifts. In the physiologically relevant pH range, the 31P and 1H chemical shifts of TmDOTP5- are linear functions of temperature between 25 and 47 degrees C. The results indicate that using TmDOTP5- can provide measurements of temperature in vivo that are significantly more accurate than methods based on water and fluorocarbon chemical shifts.

Automatic motion correction for breast MR imaging.

In 29 gadolinium-enhanced breast magnetic resonance (MR) examinations, breast motion prevented accurate and efficient image processing. To compensate for global rotations and translations, an automatic motion correction method with a ratio-variance minimization algorithm was used to align images at multiple time points through an iterative process. This method reduced breast motion and improved the accuracy and efficiency of lesion detection.

Stereoscopically guided characterization of three-dimensional dynamic MR images of the breast.

A workstation was used to postprocess volume-rendered three-dimensional (3D) dynamic contrast material-enhanced magnetic resonance (MR) images of a breast carcinoma and a breast adenoma. Use of a 3D cursor allowed stereoscopic interactive probing of specific voxels to quantify contrast enhancement over time, which was mapped to a gray scale that effectively displayed enhancement as a fourth dimension. This technique is generally applicable to any time-dependent 3D imaging modality.

Microscopic susceptibility variation and transverse relaxation: theory and experiment.

Microscopic susceptibility variations invariably increase apparent transverse relaxation rates. In this paper, we present comparisons between Monte Carlo simulations and experiments with polystyrene microspheres to demonstrate that this enhanced relaxation can be explained quantitatively for both spin echo and gradient echo imaging experiments. The spheres used (1 to 30 microms), and degree of susceptibility variation (caused by 0-12 mM Dy-DTPA) covered a wide range of biologically relevant compartment sizes and contrast agent concentrations. These results show that several regimes of behavior exist, and that contrast dependence is quite different in these regimes. For a given susceptibility, delta chi, a small range of particle sizes show peak transverse relaxation. For the range of susceptibilities found in the first pass of a clinical IV contrast agent bolus, this size range is 5 to 10 microns, or roughly capillary sized compartments. In both our simulations and experiments, smaller spheres showed quadratic relaxation versus concentration curves, and larger particles showed sublinear behavior. For particles corresponding to the peak relaxivity, the relaxation-concentration curves were linear. In addition, we demonstrated that increasing the diffusion coefficient can increase, decrease, or, paradoxically, leave unaffected the apparent relaxation rate. The regime for which the diffusion coefficient is relatively unimportant corresponds to the region of peak relaxivity. By using the Bloch-Torrey equation to produce scaling rules, the specific Monte Carlo simulations were extended to more general cases. We use these scaling rules to demonstrate why we often find that susceptibility-induced relaxation rates vary approximately linearly with concentration of injected agent.