Search

Purpose: The purpose of this study was to demonstrate the feasibility of using a custom gradient sequence on an unmodified 3T magnetic resonance imaging (MRI) scanner to perform magnetic resonance navigation (MRN) by investigating the blood flow control method in vivo, reproducing the obtained rheology in a phantom mimicking porcine hepatic arterial anatomy, injecting magnetized microbead aggregates through an implantable catheter, and steering the aggregates across arterial bifurcations for selective tumor embolization. Materials and Methods: In the first phase, arterial hepatic velocity was measured using cine phase‐contrast imaging in seven pigs under free‐flow conditions and controlled‐flow conditions, whereby a balloon catheter is used to occlude arterial flow and saline is injected at different rates. Three of the seven pigs previously underwent selective lobe embolization to simulate a chemoembolization procedure. In the second phase, the measured in vivo controlled‐flow velocities were approximately reproduced in a Y‐shaped vascular bifurcation phantom by injecting saline at an average rate of 0.6 mL/s with a pulsatile component. Aggregates of 200‐μm magnetized particles were steered toward the right or left hepatic branch using a 20‐mT/m MRN gradient. The phantom was oriented at 0°, 45°, and 90° with respect to the B0 magnetic field. The steering differences between left–right gradient and baseline were calculated using Fisher's exact test. A theoretical model of the trajectory of the aggregate within the main phantom branch taking into account gravity, magnetic force, and hydrodynamic drag was also designed, solved, and validated against the experimental results to characterize the physical limitations of the method. Results: At an injection rate of 0.5 mL/s, the average flow velocity decreased from 20 ± 15 to 8.4 ± 5.0 cm/s after occlusion in nonembolized pigs and from 13.6 ± 2.0 to 5.4 ± 3.0 cm/s in previously embolized pigs. The pulsatility index measured to be 1.7 ± 1.8 and 1.1 ± 0.1 for nonembolized and embolized pigs, respectively, decreased to 0.6 ± 0.4 and 0.7 ± 0.3 after occlusion. For MRN performed at each orientation, the left–right distribution of aggregates was 55%, 25%, and 75% on baseline and 100%, 100%, and 100% (P < 0.001, P = 0.003, P = 0.003) after the application of MRN, respectively. According to the theoretical model, the aggregate reaches a stable transverse position located toward the direction of the gradient at a distance equal to 5.8% of the radius away from the centerline within 0.11 s, at which point the aggregate will have transited through a longitudinal distance of 1.0 mm from its release position. Conclusion: In this study, we showed that the use of a balloon catheter reduces arterial hepatic flow magnitude and variation with the aim to reduce steering failures caused by fast blood flow rates and low magnetic steering forces. A mathematical model confirmed that the reduced flow rate is low enough to maximize steering ratio. After reproducing the flow rate in a vascular bifurcation phantom, we demonstrated the feasibility of MRN after injection of microparticle aggregates through a dedicated injector. This work is an important step leading to MRN‐based selective embolization techniques in humans. [ABSTRACT FROM AUTHOR]

Zirconium-89 (89Zr) is an ideal radiometal isotope for antibody-based positron emission tomography (immunoPET) as its physical half-life (3.27 days) is a good match with the biological half-life of larger molecular weight targeting molecules, such as antibodies (3–4 days), and its positron emission (BR = 100% EC/β+, Eβ+,avg = 395.5 keV) is suited for high resolution PET imaging. Concerns over the in vivo stability of the most commonly used 89Zr-chelator, desferrioxamine B (DFO), have spurred efforts into the development of alternative 89Zr-chelators that withstand the release of osteophilic 89Zr4+. Herein we report the new chelator 1,3-propanediamine-N,N,N′,N′-tetrakis[(2-(aminomethyl)-3-hydroxy-1,6-dimethyl-4(1H)-pyridinone)acetamide] (THPN) based on four 3-hydroxy-4-pyridinone (3,4-HOPO) coordinating groups, as a potentially superior chelator over DFO. THPN has been demonstrated to quantitatively form a monometallic complex with Zr4+ within 10 min at ambient temperature at as low as 10−6 M concentrations of the chelator. The resulting complexes were studied in vitro and in vivo. The 89Zr-THPN complex was stable in serum and outperformed the 89Zr-DFO complex in a direct transchelation challenge. Healthy mice excreted 89Zr-THPN rapidly without signs of demetalation or residual organ uptake. This renders THPN as a promising alternative to DFO and introduces the first octadentate 3,4-HOPO chelator to the field. [ABSTRACT FROM AUTHOR]

Macromolecular gadolinium (Gd)-based contrast agents are in development as blood pool markers for MRI. HPG-GdF is a 583 kDa hyperbranched polyglycerol doubly tagged with Gd and Alexa 647 nm dye, making it both MR and histologically visible. In this study we examined the location of HPG-GdF in whole-tumor xenograft sections matched to in vivo DCE-MR images of both HPG-GdF and Gadovist. Despite its large size, we have shown that HPG-GdF extravasates from some tumor vessels and accumulates over time, but does not distribute beyond a few cell diameters from vessels. Fractional plasma volume (fPV) and apparent permeability-surface area product (aPS) parameters were derived from the MR concentration-time curves of HPG-GdF. Non-viable necrotic tumor tissue was excluded from the analysis by applying a novel bolus arrival time (BAT) algorithm to all voxels. aPS derived from HPG-GdF was the only MR parameter to identify a difference in vascular function between HCT116 and HT29 colorectal tumors. This study is the first to relate low and high molecular weight contrast agents with matched whole-tumor histological sections. These detailed comparisons identified tumor regions that appear distinct from each other using the HPG-GdF biomarkers related to perfusion and vessel leakiness, while Gadovist-imaged parameter measures in the same regions were unable to detect variation in vascular function. We have established HPG-GdF as a biocompatible multi-modal high molecular weight contrast agent with application for examining vascular function in both MR and histological modalities. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Mesothelin is expressed in many cancers, especially in mesothelioma and lung, pancreatic and ovarian cancers. In the present study, we evaluate 111In labeled antimesothelin antibodies as an imaging bioprobe for the SPECT imaging of mesothelin-expressing tumors. Methods: We radiolabeled the antimesothelin antibodies mAbMB and mAbK1 with 111In using the p-SCN-bn-DTPA chelator. The immunoreactivity, affinity (K d ) and internalization properties of the resulting two 111In labeled antibodies were evaluated in vitro using mesothelin-expressing A431K5 cells. The biodistribution and microSPECT/CT imaging studies with 111In labeled antibodies were performed in mice bearing both mesothelin positive (A431K5) and mesothelin negative (A431) tumors. Results: In vitro studies demonstrated that 111In-mAbMB bound with a higher affinity (K d =3.6±1.7 nM) to the mesothelin-expressing A431K5 cells than did the 111In-mAbK1 (K d =29.3±2.3 nM). 111In-mAbMB was also internalized at a greater rate and extent into the A431K5 cells than was the 111In-mAbK1. Biodistribution studies showed that 111In-mAbMB was preferentially localized in A431K5 tumors when compared to A431 tumors. At the low dose, the peak A431K5 tumor uptake of 9.65±2.65% ID/g (injected dose per gram) occurred at 48 h, while at high dose tumor uptake peaked with 14.29±6.18% ID/g at 72 h. Non-specific localization of 111In-mAbMB was mainly observed in spleen.111In-mAbK1 also showed superior localization in A431K5 tumors than in A431 tumors, but the peak uptake was only 3.04±0.68% ID/g at 24 h. MicroSPECT/CT studies confirmed better visualization of A431K5 tumors with 111In-mAbMB, than with 111In-mAbK1. Conclusion: SPECT imaging of mesothelin expressing tumors was demonstrated successfully. Our findings indicate that the antimesothelin antibody mAbMB has the potential to be developed into a diagnostic agent for imaging mesothelin-expressing cancers. [Copyright &y& Elsevier]

Syntheses of vanadium complexes using the naturally occurring ligands isomaltol (Hima) and allomaltol (Hama), as well as a newly synthesized, potentially tetradentate diaminodipyrone [H2 (en(ama)2], are reported. Complete characterization of the resulting compounds [trans-VO(ima)2(H2O), VO(ama)2, V(ima)3, V(ama)3 and VO(en(ama)2)&rcub;, including X-ray crystallography analyses for trans-VO(ima)2 (H2O) and V(ima)3, are presented herein. Potentiometric titrations (25°C, / = 0.16 M NaCI) were used to measure stability constants in the V(lV)-Hima system; these data were compared to previous data collected on the V(lV)—L (L = Hma, Hama) systems. The in vivo efficacy of these compounds to lower the blood glucose levels of STZ-diabetic rats was tested; all but VO(en(ama)2) produced significant decreases in plasma glucose levels. The results were compared to those of the benchmark compound BMOV [VO(ma)2, bis(maltolato)oxovanadium(IV)], a known insulin-enhancing agent. [ABSTRACT FROM AUTHOR]