Development and analysis of radiolabeled magnetic nanoparticles for positron emission tomography and magnetic resonance imaging

Nanoparticles possess unique characteristics that make them well suited for molecular imaging. Particles can be synthesized in a systematic fashion with tight control over diameter and surface chemistry. Contrary to existing gadolinium-based MRI contrast agents, nanoparticle MRI contrast agents circulate in the blood for long periods of time, offer higher sensitivity, and exhibit little known toxicity. The qualities of nanoparticles are also well suited to the design of PET probes. Because of their large surface area nanoparticles can be radiolabeled at high specific activity, increasing the sensitivity of detection as well as the payload of therapeutic isotopes. The work presented here focuses on the development and biological application of novel radiolabeled magnetic nanoparticles for multimodal PET/MRI imaging. The nanoparticle probes contained crystalline iron oxide cores capable of producing strong MRI contrast. Cores were coated with either a micelle composed of functionalized PEGylated lipids, or a cross-linked dextran shell modified with heterobifuntional PEG polymers. For PET imaging, magnetic nanoparticles were labeled with the radionuclide 64Cu. Copper‐64 is a cyclotron produced positron emitter used for PET imaging. With a 12.7 hour half-life, 64Cu can be used to image particles in vivo for up to 48 hr and can be used to evaluate ex vivo biodistribution for 72 hours. 64Cu nuclides also undergo β‐ decay, making it a useful isotope for radiotherapy. Nanoparticles were labeled with 64Cu and PET and MRI contrast and evaluated using phantoms. Pharmacokinetic information was measured using in vivo small animal PET/CT and ex vivo biodistribution at multiple time points. Particles were targeted to the angiogenesis marker αvβ3 integrin using a cyclized arginine-glycine-aspartic acid (RGD) peptide with high affinity for αvβ3 and tested in two tumor models. A unilateral tumor model was constructed using the αvβ3-positive U87MG glioblastoma line, and a bilateral model was constructed using the M21 (αvβ3 positive) and M21L (αvβ3 negative) melanoma lines. In vivo PET/CT and MRI showed that targeted nanoparticles produced both PET and MRI contrast in tumors. In conclusion, we report the development of magnetic nanoparticles for dual‐PET/MR imaging. These findings provide insight into the design and development of future multimodality PET/MRI probes.Ph.D.Committee Chair: Gang Bao; Committee Member: Kurt D. Pennell; Committee Member: Mark M. Goodman; Committee Member: Xiaoping P. Hu; Committee Member: Yadong Wan

Comparison of the diagnostic value of a small, single channel, electrocardiogram monitoring patch with a standard 3-lead Holter system over 24 hours in dogs

Introduction/Objectives: The aim of this study was to compare a novel small event recorder device, the Carnation Ambulatory Monitor (CAM), with a standard Holter. Animals: Nineteen adult dogs. Material and methods: Comparative and explorative study. The two devices were simultaneously applied for approximately 24 h. Results: Analysis time (P=0.013) and percentage of artefacts (P<0.001) were greater for the CAM (110 min [40–264]; and 9% [0–34], respectively) compared to a standard Holter (30 min [18–270]; and 0.3% [0–9], respectively). The total number of beats (P=0.017) and maximum (P=0.02) and mean (P=0.037) heart rates were lower for the CAM (113,806 ± 23,619 beats; 227 ± 35 bpm; and 88 ± 22 bpm, respectively) compared to the standard Holter (131,640 ± 40,037 beats; 260 ± 64 bpm; and 92 ± 26 bpm, respectively). The minimal heart rate (P=0.725), number of pauses (P=0.078), duration of the longest pause (P=0.087), number of ventricular ectopic complexes (P=0.55), ventricular couplets (P=0.186), ventricular triplets (P=0.203), ventricular tachycardia (P=0.05), Lown grade (P=0.233), presence or absence of ventricular bigeminy, trigeminy, supraventricular tachycardia, and atrial fibrillation (P=0.98) did not differ. The CAM missed some relevant events, like complex ventricular arrhythmias, and the Lown grade did not match in 5/19 dogs when comparing the devices. Conclusions: Cardiac Ambulatory Monitor can be used to record ECG traces in dogs over a prolonged period, allowing to detect arrhythmias. Due to some clinically relevant limitations, including a higher percentage of artefacts, a longer reading time (which precludes quantitative counts of >300ventricular premature complexes), and underestimation of complex ventricular arrhythmias, the CAM appears not suitable for quantitative arrhythmia analysis in dogs

Transfer-matrix scaling from disorder-averaged correlation lengths for diluted Ising systems

A transfer matrix scaling technique is developed for randomly diluted systems, and applied to the site-diluted Ising model on a square lattice in two dimensions. For each allowed disorder configuration between two adjacent columns, the contribution of the respective transfer matrix to the decay of correlations is considered only as far as the ratio of its two largest eigenvalues, allowing an economical calculation of a configuration-averaged correlation length. Standard phenomenological-renormalisation procedures are then used to analyse aspects of the phase boundary which are difficult to assess accurately by alternative methods. For magnetic site concentration $p$ close to $p_c$, the extent of exponential behaviour of the $T_c \times p$ curve is clearly seen for over two decades of variation of $p - p_c$. Close to the pure-system limit, the exactly-known reduced slope is reproduced to a very good approximation, though with non-monotonic convergence. The averaged correlation lengths are inserted into the exponent-amplitude relationship predicted by conformal invariance to hold at criticality. The resulting exponent $\eta$ remains near the pure value (1/4) for all intermediate concentrations until it crosses over to the percolation value at the threshold.Comment: RevTeX 3, 11 pages +5 figures, uuencoded, to appear in Phys. Rev. B (1994), PUC/RJ preprin