[show abstract][hide abstract] ABSTRACT: Successful translation of nonviral gene delivery to therapeutic applications requires detailed understanding of in vivo trafficking of the vehicles. This report compares the pharmacokinetic and biodistribution profiles of polyethylene glycol-b-polyphosphoramidate (PEG-b-PPA)/DNA micellar nanoparticles after administration through intravenous infusion, intrabiliary infusion, and hydrodynamic injection using single photon emission computed tomography/computed tomography (SPECT/CT) imaging. Nanoparticles were labeled with (111)In using an optimized protocol to retain their favorable physicochemical properties. Quantitative imaging analysis revealed different in vivo trafficking kinetics for PEG-b-PPA/DNA nanoparticles after different routes of administration. The intrabiliary infusion resulted in the highest liver uptake of micelles compared with the other two routes. Analysis of intrabiliary infusion by the two-compartment pharmacokinetic modeling revealed efficient retention of micelles in the liver and minimal micelle leakage from the liver to the blood stream. This study demonstrates the utility of SPECT/CT as an effective noninvasive imaging modality for the characterization of nanoparticle trafficking in vivo and confirms that intrabiliary infusion is an effective route for liver-targeted delivery of DNA-containing nanoparticles.
[show abstract][hide abstract] ABSTRACT: Therapeutic cell retention and engraftment are critical for myocardial regeneration. Underlying mechanisms, including the role of tissue perfusion, are not well understood. In Wistar Kyoto rats, syngeneic cardiosphere-derived cells (CDCs) were injected intramyocardially, after experimental myocardial infarction. CDCs were labeled with [(18)F]-FDG (n = 7), for quantification of 1-h retention, or with sodium-iodide-symporter gene (NIS; n = 8), for detection of 24-h engraftment by reporter imaging. Perfusion was imaged simultaneously. Infarct size was 37 ± 9 and 38 ± 9% of LV in FDG and NIS groups. Cell signal was located in the infarct border zone in all animals. No significant relationship was observed between infarct size and 1-h CDC retention (r = -0.65; P = 0.11). However, infarct size correlated significantly with 24-h engraftment (r = 0.75; P = 0.03). Residual perfusion at the injection site was not related to cell retention/engraftment. Larger infarcts are associated with improved CDC engraftment. This observation encourages further investigation of microenvironmental conditions after ischemic damage and their role in therapeutic cell survival.
Archiv für Kreislaufforschung 06/2011; 106(6):1379-86. · 7.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: In this paper, we discuss the design of a compact gamma camera for high-resolution prostate cancer imaging using Cadmium Zinc Telluride (CdZnTe or CZT) radiation detectors. Prostate cancer is a common disease in men. Nowadays, a blood test measuring the level of prostate specific antigen (PSA) is widely used for screening for the disease in males over 50, followed by (ultrasound) imaging-guided biopsy. However, PSA tests have a high falsepositive rate and ultrasound-guided biopsy has a high likelihood of missing small cancerous tissues. Commercial methods of nuclear medical imaging, e.g. PET and SPECT, can functionally image the organs, and potentially find cancer tissues at early stages, but their applications in diagnosing prostate cancer has been limited by the smallness of the prostate gland and the long working distance between the organ and the detectors comprising these imaging systems. CZT is a semiconductor material with wide band-gap and relatively high electron mobility, and thus can operate at room temperature without additional cooling. CZT detectors are photon-electron direct-conversion devices, thus offering high energy-resolution in detecting gamma rays, enabling energy-resolved imaging, and reducing the background of Compton-scattering events. In addition, CZT material has high stopping power for gamma rays; for medical imaging, a few-mm-thick CZT material provides adequate detection efficiency for many SPECT radiotracers. Because of these advantages, CZT detectors are becoming popular for several SPECT medical-imaging applications. Most recently, we designed a compact gamma camera using CZT detectors coupled to an application-specific-integratedcircuit (ASIC). This camera functions as a trans-rectal probe to image the prostate gland from a distance of only 1-5 cm, thus offering higher detection efficiency and higher spatial resolution. Hence, it potentially can detect prostate cancers at their early stages. The performance tests of this camera have been completed. The results show better than 6-mm resolution at a distance of 1 cm. Details of the test results are discussed in this paper.
[show abstract][hide abstract] ABSTRACT: Quantification of acute myocardial retention and lung bio-distribution of cardiosphere-derived cells (CDCs) following transplantation is important to improve engraftment.
We studied acute(1 hour) cardiac/lung retention in 4 groups (n = 25) of rats (normal--NL, acute ischemia-reperfusion--AI-RM, acute permanent ligation-PL, and chronic infarct by ischemia-reperfusion--CI-R) using intra-myocardial delivery, 1 group using intracoronary delivery (acute ischemia-reperfusion, AI-RC, n = 5) and 1 group using intravenous delivery (acute ischemia-reperfusion, AI-RV, n = 5) of CDCs by PET. Cardiac retention was similar in the NL, AI-RM, CI-R, and A-IRC groups (13.6% ± 2.3% vs. 12.0% ± 3.9% vs. 9.9 ± 2.8 vs. 15.4% ± 5.5%; P = NS), but higher in PL animals (22.9% ± 5.2%; P < .05). Low cardiac retention was associated with significantly higher lung activity in NL and AI-RM groups (43.3% ± 5.6% and 39.9% ± 9.3%), compared to PL (28.5% ± 5.9%), CI-R (20.2% ± 9.3%), and A-IRC (19.9% ± 5.6%) animals (P < .05 vs. AI-RM and NL). Lung activity was highest following intravenous CDC delivery (55.1% ± 9.3%, P < .001) and was associated with very low cardiac retention (0.8% ± 1.06%). Two-photon microscopy indicated that CDCs escaped to the lungs via the coronary veins following intra-myocardial injection.
Acute cardiac retention and lung bio-distribution vary with the myocardial substrate and injection route. Intra-myocardially injected CDCs escape into the lungs via coronary veins, an effect that is more pronounced in perfused myocardium.
Journal of Nuclear Cardiology 03/2011; 18(3):443-50. · 2.85 Impact Factor
[show abstract][hide abstract] ABSTRACT: Our goal was to evaluate a multi-pinhole (MPH) collimator which allows changing configurations for mouse imaging and rat imaging.
The collimator length can be adjusted from 5 cm for rat imaging to a maximum of 8 cm for mouse imaging. Projections of mouse- and rat-size phantoms were simulated with collimator length of 8 cm, and the rat-size phantom was additionally simulated with collimator length of 5 cm. Bias and noise were assessed in the reconstructed images. Three physical phantoms were used to evaluate the axial sampling and resolutions for one-, four-, and five-pinhole single photon emission computed tomography (SPECT). Images of three different-sized rodents were also acquired.
Simulations showed that for rat imaging, shorter collimator length provided an improved bias-noise trade-off compared to that of longer collimator length. Axial distortions were significantly reduced for MPH compared to single pinhole imaging. The smallest rods visible for mouse imaging and rat imaging were 1 and 1.6 mm, respectively, and their corresponding absolute sensitivities were 3.47% and 2.02% at the center field-of-view for 5-pinhole imaging. The count ratios were 1:3.78:4.42, respectively, for one-, four-, and five-pinhole for same acquisition time. Good image quality was observed in real animal studies.
This collimator allows flexible single pinhole and MPH SPECT imaging for rodents, achieving high resolution and detection efficiency with minimal image artifacts.
Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 02/2011; 14(1):60-9. · 2.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: We investigated whether small-animal positron emission tomography (PET) could be used in combination with computed tomography (CT) imaging techniques for longitudinal monitoring of the injured spinal cord. In adult female Sprague-Dawley rats (n = 6), the ninth thoracic (T9) spinal cord segment was exposed by laminectomy and subsequently contused using the Infinite Horizon impactor (Precision System and Instrumentation, Lexington, KY) at 225 kDyn. In control rats (n = 4), the T9 spinal cord was exposed by laminectomy but not contused. At 0.5 hours and 3, 7, and 21 days postinjury, 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) was given intravenously followed 1 hour later by sequential PET and CT. Regions of interest (ROIs) at T9 (contused) and T6 (uninjured) spinal cord segments were manually defined on CT images and aided by fiduciary markers superimposed onto the coregistered PET images. Monte Carlo simulation revealed that about 33% of the activity in the ROIs was due to spillover from adjacent hot areas. A simulation-based partial-volume compensation (PVC) method was developed and used to correct for this spillover effect. With PET-CT, combined with PVC, we were able to serially measure standardized uptake values of the T9 and T6 spinal cord segments and reveal small, but significant, differences. This approach may become a tool to assess the efficacy of spinal cord repair strategies.
[show abstract][hide abstract] ABSTRACT: The goal of the study was to investigate data acquisition strategies and image reconstruction methods for a stationary SPECT insert that can operate inside an MRI scanner with a 12 cm bore diameter for simultaneous SPECT/MRI imaging of small animals. The SPECT insert consists of 3 octagonal rings of 8 MR-compatible CZT detectors per ring surrounding a multi-pinhole (MPH) collimator sleeve. Each pinhole is constructed to project the field-of-view (FOV) to one CZT detector. All 24 pinholes are focused to a cylindrical FOV of 25 mm in diameter and 34 mm in length. The data acquisition strategies we evaluated were optional collimator rotations to improve tomographic sampling; and the image reconstruction methods were iterative ML-EM with and without compensation for the geometric response function (GRF) of the MPH collimator. For this purpose, we developed an analytic simulator that calculates the system matrix with the GRF models of the MPH collimator. The simulator was used to generate projection data of a digital rod phantom with pinhole aperture sizes of 1 mm and 2 mm and with different collimator rotation patterns. Iterative ML-EM reconstruction with and without GRF compensation were used to reconstruct the projection data from the central ring of 8 detectors only, and from all 24 detectors. Our results indicated that without GRF compensation and at the default design of 24 projection views, the reconstructed images had significant artifacts. Accurate GRF compensation substantially improved the reconstructed image resolution and reduced image artifacts. With accurate GRF compensation, useful reconstructed images can be obtained using 24 projection views only. This last finding potentially enables dynamic SPECT (and/or MRI) studies in small animals, one of many possible application areas of the SPECT/MRI system. Further research efforts are warranted including experimentally measuring the system matrix for improved geometrical accuracy, incorporating the co-registered MRI image in SPECT reconstruction, and exploring potential applications of the simultaneous SPECT/MRI SA system including dynamic SPECT studies.
[show abstract][hide abstract] ABSTRACT: We aim to establish an evaluation platform for the GE eXplore VISTA small animal positron emission tomography (PET) scanner, a dual layer phoswich system, by using Monte Carlo simulation.
We developed a detection model based on the Geant4 Application for Tomographic Emission to realistically reproduce the physics of PET, the scanner configuration, and the data collecting system of an eXplore VISTA system. For verification purpose, several different physical phantoms were simulated to perform evaluation tests, including sensitivity, spatial resolution, scatter fraction, and count rate performance, which were compared with an actual scanner. After the experimental validation, our detection model was applied to assess the quantification loss in the reconstructed images associated with photon attenuation, photon scatter, and random coincidences.
A simulated sensitivity profile as a function of 18F point source axial position was fitted to the measured results. In terms of spatial resolution, agreement was within 10-18% for the point source at various locations. The simulated and measured scatter fractions differed by less than 4.3 and 5.2% for the physical mouse and rat phantoms, respectively. The count rate performance of our model was matched by the measured results, up to the peak activity concentration of 455 kBq/ml for the mouse-sized phantom and 141 kBq/ml for the rat-sized phantom. Finally, we found that photon attenuation is the dominant physical degrading factor in quantitative analysis (> 13.4%).
These results suggested that the proposed detection model is able to produce realistic data from the eXplore VISTA system with knowing the ground truth, thus facilitating its evaluation for small animal PET studies.
Nuclear Medicine Communications 01/2010; 31(1):32-8. · 1.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: We describe a single photon emission computed tomograph (SPECT) which can be operated inside state-of-the-art magnetic resonance imaging (MRI) systems. The combined SPECT/MRI system allows one to acquire simultaneously the data from both modalities and co-register the images in space and time. The new SPECT is based on the semiconductor cadmium zinc telluride (CZT) and application specific integrated circuits (ASICs) - two technologies which are MR-compatible and almost insensitive to magnetic fields. The SPECT camera has an energy resolution of 5.4 keV full-width-half-maximum (FWHM) at the 140-keV photo peak from <sup>99m</sup>Tc for either inside or outside of the MRI. We acquired the first SPECT and MR images from resolution phantoms and mice in-vivo. The experiments show that the MRI is minimally affected by the SPECT camera inside the bore. Preliminary results for the SPECT camera show high sensitivity of about 1.6% and a spatial resolution of 4 mm FWHM.
Nuclear Science Symposium Conference Record (NSS/MIC), 2009 IEEE; 12/2009
[show abstract][hide abstract] ABSTRACT: The aim of this study was to quantify acute myocardial retention of cardiac-derived stem cells (CDCs) and evaluate different delivery methods with positron emission tomography (PET).
Success of stem cell transplantation for cardiac regeneration is partially limited by low retention/engraftment of the delivered cells. A clinically applicable method for accurate quantification of cell retention would enable optimization of cell delivery.
The CDCs were derived from syngeneic, male Wistar Kyoto (WK) rats labeled with [(18)F]-fluoro-deoxy-glucose ((18)FDG) and injected intramyocardially into the ischemic region of female WK rats after permanent left coronary artery ligation. The effects of fibrin glue (FG), bradycardia (adenosine), and cardiac arrest were examined. Imaging with (18)FDG PET was performed for quantification of cell retention. Quantitative polymerase chain reaction (PCR) for the male-specific SRY gene was performed to validate the PET results.
Myocardial retention of cells suspended in phosphate-buffered saline 1 h after delivery was 17.6 +/- 11.5% by PCR and 17.8 +/- 7.3% by PET. When CDCs were injected immediately after induction of cardiac arrest, retention was increased to 75.6 +/- 18.6%. Adenosine slowed the ventricular rate and doubled CDC retention (35.4 +/- 5.3%). A similar increase in CDC retention was observed after epicardial application of FG at the injection site (37.5 +/- 8.2%). The PCR revealed a significant increase in 3-week cell engraftment in the FG animals (22.1 +/- 18.6% and 5.3 +/- 3.1%, for FG and phosphate-buffered saline, respectively).
In vivo PET permits accurate measurement of CDC retention early after intramyocardial delivery. Sealing injection sites with FG or lowering ventricular rate by adenosine might be clinically translatable methods for improving stem cell engraftment in a beating heart.
Journal of the American College of Cardiology 10/2009; 54(17):1619-26. · 14.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: The sympathetic nervous system of the heart plays a key role in the pathophysiology of various cardiac diseases. Small-animal models are valuable for obtaining further insight into mechanisms of cardiac disease and therapy. To determine the translational potential of cardiac neuronal imaging from rodents to humans, we characterized the rat sympathetic nervous system using 3 radiotracers that reflect different subcellular mechanisms: (11)C-meta-hydroxyephedrine (HED), a tracer of neuronal transport showing stable uptake and no washout in healthy humans; (11)C-phenylephrine (PHEN), a tracer of vesicular leakage and intraneuronal metabolic degradation with initial uptake and subsequent washout in humans; and (11)C-epinephrine (EPI), a tracer of vesicular storage with stable uptake and no washout in humans.
We used a small-animal PET system to study healthy male Wistar rats at baseline, after desipramine (DMI) pretreatment (DMI block), and with DMI injection 15 min after tracer delivery (DMI chase). The rats were kept under general isoflurane anesthesia while dynamic emission scans of the heart were recorded for 60 min after radiotracer injection. A myocardial retention index was determined by normalizing uptake at 40 min to the integral under the arterial input curve. Washout rates were determined by monoexponential fitting of myocardial time-activity curves.
At baseline, HED showed high myocardial uptake and sustained retention, EPI showed moderate uptake and significant biphasic washout, and PHEN showed moderate uptake and monoexponential washout. The average (+/- SD) left ventricular retention index for HED, PHEN, and EPI was 7.38% +/- 0.82%/min, 3.43% +/- 0.45%/min, and 4.24% +/- 0.59%/min, respectively; the washout rate for HED, PHEN, and EPI was 0.13% +/- 0.23%/min, 1.13% +/- 0.35%/min, and 0.50% +/- 0.24%/min, respectively. The DMI chase resulted in increased washout only for HED. DMI block decreased myocardial uptake of all tracers by less than 90%.
Kinetic profiles of HED in the rat myocardium were similar to those of HED in humans, suggesting comparable neuronal transport density. Unlike in humans, however, significant washout of EPI and faster washout of PHEN were encountered, consistent with high intraneuronal metabolic activity, high catecholamine turnover, and reduced vesicular storage. This evidence of increased neuronal activity in rodents has implications for translational studies of cardiac neuronal biology in humans.
Journal of Nuclear Medicine 08/2008; 49(7):1189-95. · 5.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: The purpose of this work is to experimentally evaluate the accuracy of the bilinear transformation method for generating attenuation maps, the accuracy of the CT-based attenuation correction (AC) using these maps for small animal PET imaging, and the reliability of this method when an iodinated contrast agent is introduced in CT scans. The attenuation maps of an attenuation calibration phantom (ACP) with known linear attenuation coefficients (LAC) were generated from both Ge-68 transmission scan and bilinear transformation of CT scan. These maps were then used in AC for quantitative analysis of a hot small sphere imbedded in the ACP phantom. We measured LAC of the mouse blood mixed with an iodinated agent (Fenestra VC) using both Ge-68 transmission scan and bilinear approach, and investigated the effect of CT contrast agent on CT images, attenuation maps and attenuation corrected PET images of the mice, respectively. The phantom experiments showed visually well-matched attenuation maps and within 5% bias agreement on LAC of artificial tissues. CT-based and Ge-transmission-based AC restored the quantitative PET results for the hot small sphere in ACP phantom from -27% error (without AC) to 0.9% and -3.4%, respectively. The animal experiments showed that CT-based AC restored respectively 15-25% and 40- 60% PET image intensities for mouse and rat tissues. With the increasing of the ratio of Fenestra to blood, the difference between the CT-based and Ge-transmission-based LAC of the mixture was increased linearly up to 7% at the maximum ratio, which corresponds to the routine limitation on intravenous injection dose for a mouse. The administration of 0.012 ml/gm Fenestra VC increased 2.1plusmn1.2%, 0.6plusmn0.4%, 0.2plusmn0.2%, 0.4plusmn0.3%, and 0.1plusmn0.2% mean image intensities respectively for the heart chamber, liver, brain, cortical muscle and bladder on PET images with CT-based AC. We conclude that the water-bone- based bilinear approach is adequate for generati-
ng attenuation maps for CT-based AC on small animal PET imaging. The administration of Fenestra VC under the routine dosage (<0.016 ml/gm) results in visible (<7%) deviation on LAC of blood, but negligible (<3% and <1%) over-corrections on mouse heart and other tissues in PET imaging using bilinear-approach- based CT-AC.