[Show abstract][Hide abstract] ABSTRACT: PurposeTo improve 19F flip angle calibration and compensate for B1 inhomogeneities in quantitative 19F MRI of sparse molecular epitopes with perfluorocarbon (PFC) nanoparticle (NP) emulsion contrast agents.Materials and Methods
Flip angle sweep experiments on PFC-NP point source phantoms with three custom-designed 19F/1H dual-tuned coils revealed a difference in required power settings for 19F and 1H nuclei, which was used to calculate a calibration ratio specific for each coil. An image-based correction technique was developed using B1-field mapping on 1H to correct for 19F and 1H images in two phantom experiments.ResultsOptimized 19F peak power differed significantly from that of 1H power for each coil (P < 0.05). A ratio of 19F/1H power settings yielded a coil-specific and spatially independent calibration value (surface: 1.48 ± 0.06; semicylindrical: 1.71 ± 0.02, single-turn-solenoid: 1.92 ± 0.03). 1H-image-based B1 correction equalized the signal intensity of 19F images for two identical 19F PFC-NP samples placed in different parts of the field, which were offset significantly by ∼66% (P < 0.001), before correction.Conclusion19F flip angle calibration and B1-mapping compensations to the 19F images employing the more abundant 1H signal as a basis for correction resulted in a significant change in the quantification of sparse 19F MR signals from targeted PFC NP emulsions. J. Magn. Reson. Imaging 2014.
Journal of Magnetic Resonance Imaging 11/2014; · 2.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Restoring an antithrombotic surface to suppress ongoing thrombosis is an appealing strategy for treatment of acute cardiovascular disorders such as erosion of atherosclerotic plaque. An antithrombotic surface would present an alternative to systemic anticoagulation with attendant risks of bleeding. We have designed thrombin-targeted nanoparticles (NPs) that bind to sites of active clotting to extinguish local thrombin activity and inhibit platelet deposition while exhibiting only transient systemic anticoagulant effects. Perfluorocarbon nanoparticles (PFC NP) were functionalized with thrombin inhibitors (either D-phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone or bivalirudin) by covalent attachment of more than 15 000 inhibitors to each PFC NP. Fibrinopeptide A (FPA) ELISA demonstrated that thrombin-inhibiting NPs prevented cleavage of fibrinogen by both free and clot-bound thrombin. Magnetic resonance imaging (MRI) confirmed that a layer of thrombin-inhibiting NPs prevented growth of clots in vitro. Thrombin-inhibiting NPs were administered in vivo to C57BL6 mice subjected to laser injury of the carotid artery. NPs significantly delayed thrombotic occlusion of the artery, whereas an equivalent bolus of free inhibitor was ineffective. For thrombin-inhibiting NPs, only a short-lived (~10 min) systemic effect on bleeding time was observed, despite prolonged clot inhibition. Imaging and quantification of in vivo antithrombotic NP layers was demonstrated by MRI of the PFC NP. 19F MRI confirmed colocalization of particles with arterial thrombi, and quantitative 19F spectroscopy demonstrated specific binding and retention of thrombin-inhibiting NPs in injured arteries. The ability to rapidly form and image a new antithrombotic surface in acute vascular syndromes while minimizing risks of bleeding would permit a safer method of passivating active lesions than current systemic anticoagulant regimes.
[Show abstract][Hide abstract] ABSTRACT: Expanded and aberrant bronchial vascularity, a prominent feature of the chronic asthmatic airway, might explain persistent airway wall edema and sustained leukocyte recruitment. Since it is well established that there are causal relationships between exposure to house dust mite (HDM) and the development of asthma, determining the effects of HDM in rats, mammals with a bronchial vasculature similar to humans, provides an opportunity to study the effects of bronchial angiogenesis on airway function directly. We studied rats exposed bi-weekly to HDM (Der p 1; 50 μg/challenge by intranasal aspiration, 1, 2, 3 weeks) and measured the time course of appearance of increased blood vessels within the airway wall. Results demonstrated that within 3 weeks of HDM exposure, the number of vessels counted within airway walls of bronchial airways (0.5-3 mm perimeter) increased significantly. These vascular changes were accompanied by increased airway responsiveness to methacholine. A shorter exposure regimen (2 weeks of bi-weekly exposure) was insufficient to cause a significant increase in functional vessels or reactivity. Yet, (19)F/(1)H MR imaging at 3T following αvβ3-targeted perfluorocarbon nanoparticle infusion revealed a significant increase in (19)F signal in rat airways after 2 weeks of bi-weekly HDM, suggesting earlier activation of the process of neovascularization. Although many antigen-induced mouse models exist, mice lack a bronchial vasculature and consequently lack the requisite human parallels to study bronchial edema. Overall, our results provide an important new model to study the impact of bronchial angiogenesis on chronic inflammation and airways hyperreactivity.
[Show abstract][Hide abstract] ABSTRACT: The Doppler echocardiographic E-wave is generated when the left ventricle's suction pump attribute initiates transmitral flow. In some subjects E-waves are accompanied by L-waves whose occurrence has been correlated with diastolic dysfunction. The mechanisms for L-wave generation have not been fully elucidated. We propose that the recirculating diastolic intraventricular vortex ring generates L-waves and based on this mechanism, we predict the presence of L-waves in the right ventricle (RV). We imaged intraventricular flow using Doppler echocardiography and phase-contrast magnetic resonance imaging (PC-MRI) in ten healthy volunteers. L-waves were recorded in all subjects with highest velocities measured typically 2 cm below the annulus. Fifty-five percent of cardiac cycles (189 of 345) had L-waves. Color M-mode images eliminated mid-diastolic transmitral flow as the cause of the observed L-waves. 3-D intraventricular flow patterns were imaged via PC-MRI and independently validated our hypothesis. Additionally as predicted, L-waves were observed in the RV, by both echocardiography and PC-MRI. The re-entry of the E-wave generated vortex ring flow through a suitably located echo sample volume can be imaged as the L-wave. These waves are a general feature and a direct consequence of LV and RV diastolic fluid mechanics.
Journal of Applied Physiology 06/2014; · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Due to their small size, lower cost, short reproduction cycle, and genetic manipulation, rodents have been widely used to test the safety and efficacy for pharmaceutical development in human disease. In this report, MRI cholangiography demonstrated an unexpected rapid (<5min) biliary elimination of gadolinium-perfluorocarbon nanoparticles (approximately 250nm diameter) into the common bile duct and small intestine of rats, which is notably different from nanoparticle clearance patterns in larger animals and humans. Unawareness of this dissimilarity in nanoparticle clearance mechanisms between small animals and humans may lead to fundamental errors in predicting nanoparticle efficacy, pharmacokinetics, biodistribution, bioelimination, and toxicity.
Nanomedicine: nanotechnology, biology, and medicine 05/2014; · 6.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In nanomedicine, the hydrophobic nature of paclitaxel has favored its incorporation into many nanoparticle formulations for anti-cancer chemotherapy. At lower doses taxanes are reported to elicit anti-angiogenic responses. In the present study, the facile synthesis, development and characterization of a new lipase-labile docetaxel prodrug is reported and shown to be an effective anti-angiogenic agent in vitro and in vivo. The Sn 2 phosphatidylcholine prodrug was stably incorporated into the lipid membrane of αvβ3-integrin targeted perfluorocarbon (PFC) nanoparticles (αvβ3-Dxtl-PD NP) and did not appreciably release during dissolution against PBS buffer or plasma over three days. Overnight exposure of αvβ3-Dxtl-PD NP to plasma spiked with phospholipase enzyme failed to liberate the taxane from the membrane until the nanoparticle integrity was compromised with alcohol. The bioactivity and efficacy of αvβ3-Dxtl-PD NP in endothelial cell culture was as effective as Taxol(®) or free docetaxel in methanol at equimolar doses over 96 hours. The anti-angiogenesis effectiveness of αvβ3-Dxtl-PD NP was demonstrated in the Vx2 rabbit model using MR imaging of angiogenesis with the same αvβ3-PFC nanoparticle platform. Nontargeted Dxtl-PD NP had a similar MR anti-angiogenesis response as the integrin-targeted agent, but microscopically measured decreases in tumor cell proliferation and increased apoptosis were detected only for the targeted drug. Equivalent dosages of Abraxane(®) given over the same treatment schedule had no effect on angiogenesis when compared to control rabbits receiving saline only. These data demonstrate that αvβ3-Dxtl-PD NP can reduce MR detectable angiogenesis and slow tumor progression in the Vx2 model, whereas equivalent systemic treatment with free taxane had no benefit.
[Show abstract][Hide abstract] ABSTRACT: MR cholangiography shows unexpected, rapid excretion of 250 nm-sized paramagnetic perfluorocarbon nanoparticles into the rat bile duct and small intestine in less than 5 minutes.
Nanomedicine: Nanotechnology, Biology and Medicine. 01/2014;
[Show abstract][Hide abstract] ABSTRACT: Angiogenesis is an important constituent of many inflammatory pulmonary diseases, which has been unappreciated until recently. Early neovascular expansion in the lungs in preclinical models and patients is very difficult to assess noninvasively, particularly quantitatively. The present study demonstrated that (19)F/(1)H MR molecular imaging with αvβ3-targeted perfluorocarbon nanoparticles can be used to directly measure neovascularity in a rat left pulmonary artery ligation (LPAL) model, which was employed to create pulmonary ischemia and induce angiogenesis. In rats 3 days after LPAL, simultaneous (19)F/(1)H MR imaging at 3T revealed a marked (19)F signal in animals 2 h following αvβ3-targeted perfluorocarbon nanoparticles [(19)F signal (normalized to background) = 0.80 ± 0.2] that was greater (p = 0.007) than the non-targeted (0.30 ± 0.04) and the sham-operated (0.07 ± 0.09) control groups. Almost no (19)F signal was found in control right lung with any treatment. Competitive blockade of the integrin-targeted particles greatly decreased the (19)F signal (p = 0.002) and was equivalent to the non-targeted control group. Fluorescent and light microscopy illustrated heavy decorating of vessel walls in and around large bronchi and large pulmonary vessels. Focal segmental regions of neovessel expansion were also noted in the lung periphery. Our results demonstrate that (19)F/(1)H MR molecular imaging with αvβ3-targeted perfluorocarbon nanoparticles provides a means to assess the extent of systemic neovascularization in the lung.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: To evaluate the feasibility of prospectively guiding 4-dimensional (4D) magnetic resonance imaging (MRI) image acquisition using triggers at preselected respiratory amplitudes to achieve T(2) weighting for abdominal motion tracking. METHODS AND MATERIALS: A respiratory amplitude-based triggering system was developed and integrated into a commercial turbo spin echo MRI sequence. Initial feasibility tests were performed on healthy human study participants. Four respiratory states, the middle and the end of inhalation and exhalation, were used to trigger 4D MRI image acquisition of the liver. To achieve T(2) weighting, the echo time and repetition time were set to 75 milliseconds and 4108 milliseconds, respectively. Single-shot acquisition, together with parallel imaging and partial k-space imaging techniques, was used to improve image acquisition efficiency. 4D MRI image sets composed of axial or sagittal slices were acquired. RESULTS: Respiratory data measured and logged by the MRI scanner showed that the triggers occurred at the appropriate respiratory levels. Liver motion could be easily observed on both 4D MRI image datasets by sensing either the change of liver in size and shape (axial) or diaphragm motion (sagittal). Both 4D MRI image datasets were T(2)-weighted as expected. CONCLUSIONS: This study demonstrated the feasibility of achieving T(2)-weighted 4D MRI images using amplitude-based respiratory triggers. With the aid of the respiratory amplitude-based triggering system, the proposed method is compatible with most MRI sequences and therefore has the potential to improve tumor-tissue contrast in abdominal tumor motion imaging.
International journal of radiation oncology, biology, physics 02/2013; · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rationale: Cardiomyocyte organization is a critical determinant of coordinated cardiac contractile function. Because of the acute opening of the pulmonary circulation, the relative workload of the left ventricle (LV) and right ventricle (RV) changes substantially immediately after birth. We hypothesized that three dimensional cardiomyocyte architecture might be required to adapt rapidly to accommodate programmed perinatal changes of cardiac function. Materials and Methods: Isolated fixed hearts from pig fetuses or pigs at mid-gestation, pre-born, postnatal day 1 (P1), P5, P14, and adulthood were acquired for diffusion-weighted magnetic resonance imaging (DTMRI). Cardiomyocyte architecture was visualized by 3D fiber tracking and was quantitatively evaluated by the measured helix angle (α(h)). Upon the completion of MRI, hearts were sectioned and stained with hematoxylin/eosin to evaluate cardiomyocyte alignment; with picrosirius red to evaluate collagen content; and with anti-Ki67 to evaluate postnatal cell proliferation. Results: The helical architecture of cardiomyocyte was observed as early as the mid-gestational period. Post-natal changes of cardiomyocyte architecture were observed from P1 to P14, which primary occurred in the septum and RV free wall (RVFW). In the septum, the volume ratio of LV- vs. RV-associated cardiomyocytes rapidly changed from RV-LV balanced pattern at birth to LV dominant pattern by P14. In the RVFW, subendocardial α(h) decreased by approximately 30° from P1 to P14. Conclusions: The helical architecture of cardiomyocyte is developed as early as the mid-gestation period. Substantial and rapid adaptive changes in cardiac microarchitecture suggested considerable developmental plasticity of cardiomyocyte form and function in the postnatal period.
AJP Heart and Circulatory Physiology 11/2012; · 4.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cardiac dysfunction is a primary cause of patient mortality in Duchenne muscular dystrophy, potentially related to elevated cytosolic calcium. However, the regional versus global functional consequences of cellular calcium mishandling have not been defined in the whole heart. Here we sought for the first time to elucidate potential regional dependencies between calcium mishandling and myocardial fiber/sheet function as a manifestation of dystrophin-deficient (mdx) cardiomyopathy. Isolated-perfused hearts from 16-mo-old mdx (N = 10) and wild-type (WT; N = 10) were arrested sequentially in diastole and systole for diffusion tensor MRI quantification of myocardial sheet architecture and function. When compared with WT hearts, mdx hearts exhibited normal systolic sheet architecture but a lower diastolic sheet angle magnitude (|β|) in the basal region. The regional diastolic sheet dysfunction was normalized by reducing perfusate calcium concentrations. Optical mapping of calcium transients in isolated hearts (3 mdx and 4 WT) revealed a stretch-inducible regional defect of intracellular calcium reuptake, reflected by a 25% increase of decay times (T(50)) and decay constants, at the base of mdx hearts. The basal region of mdx hearts also exhibited greater fibrosis than did the apex, which matched the regional sheet dysfunction. We conclude that myocardial diastolic sheet dysfunction is observed initially in basal segments along with calcium mishandling, ultimately culminating in increased fibrosis. The preservation of relatively normal calcium reuptake and diastolic/systolic sheet mechanics throughout the rest of the heart, together with the rapid reversibility of functional defects by reducing cytosolic calcium, points to the significance of regional mechanical factors in the progression of the disease.
[Show abstract][Hide abstract] ABSTRACT: Purpose: To develop a practical triggering system based on pre-selected respiratory amplitudes to guide prospectively the image acquisition of 4DMRI to track abdominal tumor motion for radiotherapy treatment planning. Methods: The proposed triggering scheme consists of a preparation stage and an acquisition stage. Immediately prior to MRI acquisition, the preparation stage monitors the respiration via an external respiratory belt. Based on the respiratory amplitude and status (i.e., inhalation↑ or exhalation↓), the respiration cycle is equally divided into N respiratory states. For example, in the 4-state case, the 4 respiratory states are 5%↓", 50%↑, 95%↑ and 50%↓. The 5%↓ and 95%↑ are used instead of 0% and 100% to improve the robustness of the triggering system. Each state is associated with a trigger which starts image acquisition for one and only one slice. A complete 4DMRI imageset requires N dynamic scans. In each dynamic scan, all slices are acquired once and each is in a specific respiratory state. In different dynamic scans, each slice is associated with different respiratory states to form a 4D dataset. For proof-of-principle, the triggering system was integrated into a T2-weighted turbo spin echo sequence (TE=100ms, TR=7122ms) on a clinical 1.5T MRI (Philips Achieva) scanner. The 4-state case was tested on a healthy subject. Results: Plots of the physiology data recorded and exported from the scanner clearly verified that triggers occurred at the expected locations. Four T2-weighted images from a representative slice recorded the liver motion corresponding to the 4 respiratory states. Conclusions: Our results confirmed that the newly-developed system could trigger prospectively to guide 4DMRI image acquisition to achieve T2 weighting, which has a better tumor-tissue contrast than those offered by previous 4DMRI techniques with T1 or T2/T1 weighting. This is a first report of a pure T2-weighted 4DMRI to track respiration induced abdominal motion.
Medical Physics 06/2012; 39(6):3971. · 3.01 Impact Factor