Honors & Awards
Duke Medical Imaging Training Grant, Duke University, NIH (2011-2013)
Editor’s Award, International Journal of Hyperthermia (2014)
Cancer Translational Nanotechnology Training Grant, Stanford University (01/01/2016 - present)
Doctor of Philosophy, Duke University (2015)
Master of Science, Duke University (2009)
Bachelor of Science, Johns Hopkins University (2007)
Multi-spin echo spatial encoding provides three-fold improvement of temperature precision during intermolecular zero quantum thermometry.
Magnetic resonance in medicine
Intermolecular multiple quantum coherences (iMQCs) are a source of MR contrast with applications including temperature imaging, anisotropy mapping, and brown fat imaging. Because all applications are limited by signal-to-noise ratio (SNR), we developed a pulse sequence that detects intermolecular zero quantum coherences with improved SNR.A previously developed pulse sequence that detects iMQCs, HOMOGENIZED with off resonance transfer (HOT), was modified with a multi-spin echo spatial encoding scheme (MSE-HOT). MSE-HOT uses a series of refocusing pulses to generate a stack of images that are averaged in postprocessing for higher SNR. MSE-HOT performance was quantified by measuring its temperature accuracy and precision during hyperthermia of ex vivo red bone marrow samples.MSE-HOT yielded a three-fold improvement in temperature precision relative to previous pulse sequences. Sources of improved precision were 1) echo averaging and 2) suppression of J-coupling in the methylene protons of fat. MSE-HOT measured temperature change with an accuracy of 0.6°C.MSE-HOT improved the temperature accuracy and precision of HOT to a level that is sufficient for hyperthermia of bone marrow. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/mrm.25789
View details for PubMedID 26077531
Intermolecular zero quantum coherences enable accurate temperature imaging in red bone marrow.
Magnetic resonance in medicine
Red bone marrow metastases are common in breast and prostate cancer patients, but those metastases are currently incurable. Recent developments show that hyperthermia could be a successful treatment for bone metastasis, but thermometry remains difficult or inaccurate in red marrow.The technique evaluated in this study measures the evolution frequency of intermolecular zero quantum coherences (iZQCs) between fat and water. The iZQC evolution frequency was mapped linearly to temperature. The temperature accuracy and coherence lifetime of the iZQC method were evaluated against other thermometry methods that are based on localized spectroscopy and multiple gradient echo imaging.The temperature coefficient (α) was 9.8 ± 0.7 ppb/°C with the iZQC method and 2 ± 7 ppb/°C with traditional localized spectroscopy.Because the accuracy of thermometry is limited by the reproducibility of α between samples, iZQCs provide nearly a 10-fold accuracy improvement in red marrow (0.7 ppb/°C for iZQCs versus 7 ppb/°C for localized spectroscopy.) The iZQC technique in this study will for the first time allow accurate and quantitative thermal imaging of red marrow. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.
View details for DOI 10.1002/mrm.25372
View details for PubMedID 25043195
A method to convert MRI images of temperature change into images of absolute temperature in solid tumours
INTERNATIONAL JOURNAL OF HYPERTHERMIA
2013; 29 (6): 569-581
During hyperthermia (HT), the therapeutic response of tumours varies substantially within the target temperature range (39-43 °C). Current thermometry methods are either invasive or measure only temperature change, which limits the ability to study tissue responses to HT. This study combines manganese-containing low temperature sensitive liposomes (Mn-LTSL) with proton resonance frequency shift (PRFS) thermometry to measure absolute temperature in tumours with high spatial and temporal resolution using MRI.Liposomes were loaded with 300 mM MnSO(4). The phase transition temperature (T(m)) of Mn-LTSL samples was measured by differential scanning calorimetry (DSC). The release of manganese from Mn-LTSL in saline was characterised with inductively coupled plasma atomic emission spectroscopy. A 2T GE small animal scanner was used to acquire dynamic T1-weighted images and temperature change images of Mn-LTSL in saline phantoms and fibrosarcoma-bearing Fisher-344 rats receiving hyperthermia after Mn-LTSL injection.The T(m) of Mn-LTSL in rat blood was 42.9 ± 0.2 °C (DSC). For Mn-LTSL samples (0.06 mM-0.5 mM Mn(2+) in saline) heated monotonically from 30 °C to 50 °C, a peak in the rate of MRI signal enhancement occurred at 43.1° ± 0.3 °C. The same peak in signal enhancement rate was observed during heating of fibrosarcoma tumours (N = 3) after injection of Mn-LTSL, and the peak was used to convert temperature change images into absolute temperature. Accuracies of calibrated temperature measurements were in the range 0.9-1.8 °C.The release of Mn(2+) from Mn-LTSL affects the rate of MR signal enhancement which enables conversion of MRI-based temperature change images to absolute temperature.
View details for DOI 10.3109/02656736.2013.790091
View details for Web of Science ID 000323484600009
View details for PubMedID 23957326
The relationship between tissue oxygenation and redox status using magnetic resonance imaging
INTERNATIONAL JOURNAL OF ONCOLOGY
2012; 41 (6): 2103-2108
The recent development of a bi-modality magnetic resonance imaging/electron paramagnetic resonance imaging (MRI/EPRI) platform has enabled longitudinal monitoring of both tumor oxygenation and redox status in murine cancer models. The current study used this imaging platform to test the hypothesis that a more reducing tumor microenvironment accompanies the development of tumor hypoxia. To test this, the redox status of the tumor was measured using Tempol as a redox‑sensitive MRI contrast agent, and tumor hypoxia was measured with Oxo63, which is an oxygen-sensitive EPRI spin probe. Images were acquired every 1-2 days in mice bearing SCCVII tumors. The median pO(2) decreased from 14 mmHg at 7 days after tumor implantation to 7 mmHg at 15 days after implantation. Additionally, the hypoxic fraction, defined as the percentage of the tumor that exhibited a pO(2)<10 mmHg, increased with tumor size (from 10% at 500 mm(3) to 60% at 3,500 mm(3)). The rate of Tempol reduction increased as a function of tumor volume (0.4 min(-1) at 500 mm(3) to 1.7 min(-1) at 3,500 mm(3)), suggesting that the tumor microenvironment became more reduced as the tumor grew. The results show that rapid Tempol reduction correlates with decreased tumor oxygenation, and that the Tempol decay rate constant may be a surrogate marker for tumor hypoxia.
View details for DOI 10.3892/ijo.2012.1638
View details for Web of Science ID 000311587900024
View details for PubMedID 23007796
- Accessing long-lived nuclear singlet states between chemically equivalent spins without breaking symmetry NATURE PHYSICS 2012; 8 (11): 831-837
A novel nitroxide is an effective brain redox imaging contrast agent and in vivo radioprotector
FREE RADICAL BIOLOGY AND MEDICINE
2011; 51 (3): 780-790
Individuals are exposed to ionizing radiation during medical procedures and nuclear disasters, and this exposure can be carcinogenic, toxic, and sometimes fatal. Drugs that protect individuals from the adverse effects of radiation may therefore be valuable countermeasures against the health risks of exposure. In the current study, the LD(50/30) (the dose resulting in 50% of exposed mice surviving 30 days after exposure) was determined in control C3H mice and mice treated with the nitroxide radioprotectors Tempol, 3-CP, 16c, 22c, and 23c. The pharmacokinetics of 22c and 23c were measured with magnetic resonance imaging (MRI) in the brain, blood, submandibular salivary gland, liver, muscle, tongue, and myocardium. It was found that 23c was the most effective radioprotector of the five studied: 23c increased the LD(50/30) in mice from 7.9±0.15Gy (treated with saline) to 11.47±0.13Gy (an increase of 45%). Additionally, MRI-based pharmacokinetic studies revealed that 23c is an effective redox imaging agent in the mouse brain, and that 23c may allow functional imaging of the myocardium. The data in this report suggest that 23c is currently the most potent known nitroxide radioprotector, and that it may also be useful as a contrast agent for functional imaging.
View details for DOI 10.1016/j.freeradbiomed.2011.05.019
View details for Web of Science ID 000292856900022
View details for PubMedID 21664459
Nitroxides as Cancer Imaging Agents
ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY
2011; 11 (4): 347-358
Nitroxides are low molecular weight (150-400 Da) superoxide dismutase mimics that exhibit antioxidant, radical scavenging, and radioprotective activity. Additionally, the paramagnetic nature of nitroxides makes them viable as both spin probes for electron paramagnetic resonance imaging as well as contrast agents for magnetic resonance imaging. These imaging techniques enable in vivo monitoring of nitroxide metabolism. In biological systems, nitroxide metabolism occurs predominantly via reduction of the nitroxide to a hydroxylamine. The rate of nitroxide reduction can increase or decrease due to either oxidative stress, suggesting that nitroxides can provide an imaging-based assay of tissue redox status. The current review briefly summarizes the potential clinical applications of nitroxides, and focuses on the biochemical and tumor microenvironmental factors that affect the rate of nitroxide reduction. The potential therapeutic applications and bio-reduction mechanisms are discussed in the context of their relevance to oncology.
View details for Web of Science ID 000290614400004
View details for PubMedID 21434855
Magnetic resonance imaging of organic contrast agents in mice: capturing the whole-body redox landscape
FREE RADICAL BIOLOGY AND MEDICINE
2011; 50 (3): 459-468
Nitroxides are a class of stable free radicals that have several biomedical applications including radioprotection and noninvasive assessment of tissue redox status. For both of these applications, it is necessary to understand the in vivo biodistribution and reduction of nitroxides. In this study, magnetic resonance imaging was used to compare tissue accumulation (concentration) and reduction of two commonly studied nitroxides: the piperidine nitroxide Tempol and the pyrrolidine nitroxide 3-CP. It was found that 3-CP was reduced 3 to 11 times slower (depending on the tissue) than Tempol in vivo and that maximum tissue concentration varies substantially between tissues (0.6-7.2mM). For a given tissue, the maximum concentration usually did not vary between the two nitroxides. Furthermore, using electron paramagnetic resonance spectroscopy, we showed that the nitroxide reduction rate depends only weakly on cellular pO(2) in the oxygen range expected in vivo. These observations, taken with the marked variation in nitroxide reduction rates observed between tissues, suggest that tissue pO(2) is not a major determinant of the nitroxide reduction rate in vivo. For the purpose of redox imaging, 3-CP was shown to be an optimal choice based on the achievable concentrations and bioreduction observed in vivo.
View details for DOI 10.1016/j.freeradbiomed.2010.11.028
View details for Web of Science ID 000287429600006
View details for PubMedID 21130158