Co-reporter:
Magnetic Resonance in Medicine 2017 Volume 77(Issue 4) pp:1665-1670
Publication Date(Web):2017/04/01
DOI:10.1002/mrm.26250
PurposeThis study investigated a fundamentally new type of responsive MRI contrast agent for molecular imaging that alters T2 exchange (T2ex) properties after interacting with a molecular biomarker.MethodsThe contrast agent Tm-DO3A-oAA was treated with nitric oxide (NO) and O2. The R1 and R2 relaxation rates of the reactant and product were measured with respect to concentration, temperature, and pH. Chemical exchange saturation transfer (CEST) spectra of the reactant and product were acquired using a 7 Tesla (T) MRI scanner and analyzed to estimate the chemical exchange rates and r2ex relaxivities.ResultsThe reaction of Tm-DO3A-oAA with NO and O2 caused a 6.4-fold increase in the r2 relaxivity of the agent, whereas r1 relaxivity remained unchanged, which demonstrated that Tm-DO3A-oAA is a responsive T2ex agent. The effects of pH and temperature on the r2 relaxivities of the reactant and product supported the conclusion that the product's benzimidazole ligand caused the agent to have a fast chemical exchange rate relative to the slow exchange rate of the reactant's ortho-aminoanilide ligand.ConclusionsT2ex MRI contrast agents are a new type of responsive agent that have good detection sensitivity and specificity for detecting a biomarker, which can serve as a new tool for molecular imaging. Magn Reson Med 77:1665–1670, 2017. © 2016 International Society for Magnetic Resonance in Medicine
Co-reporter:Kyle M. Jones;Edward A. Randtke;Eriko S. Yoshimaru
Molecular Imaging and Biology 2017 Volume 19( Issue 4) pp:617-625
Publication Date(Web):28 November 2016
DOI:10.1007/s11307-016-1029-7
We optimized acido-chemical exchange saturation transfer (acidoCEST) magnetic resonance imaging (MRI), a method that measures extracellular pH (pHe), and translated this method to the radiology clinic to evaluate tumor acidosis.A CEST-FISP MRI protocol was used to image a flank SKOV3 tumor model. Bloch fitting modified to include the direct estimation of pH was developed to generate parametric maps of tumor pHe in the SKOV3 tumor model, a patient with high-grade invasive ductal carcinoma, and a patient with metastatic ovarian cancer. The acidoCEST MRI results of the patient with metastatic ovarian cancer were compared with DCE MRI and histopathology.The pHe maps of a flank model showed pHe measurements between 6.4 and 7.4, which matched with the expected tumor pHe range from past acidoCEST MRI studies in flank tumors. In the patient with metastatic ovarian cancer, the average pHe value of three adjacent tumors was 6.58, and the most reliable pHe measurements were obtained from the right posterior tumor, which favorably compared with DCE MRI and histopathological results. The average pHe of the kidney showed an average pHe of 6.73 units. The patient with high-grade invasive ductal carcinoma failed to accumulate sufficient agent to generate pHe measurements.Optimized acidoCEST MRI generated pHe measurements in a flank tumor model and could be translated to the clinic to assess a patient with metastatic ovarian cancer.
Co-reporter:Gabriela Fernández-Cuervo, Kirsten A. Tucker, Scott W. Malm, Kyle M. Jones, and Mark D. Pagel
Bioconjugate Chemistry 2016 Volume 27(Issue 10) pp:2549
Publication Date(Web):September 22, 2016
DOI:10.1021/acs.bioconjchem.6b00482
Imaging agents for the noninvasive in vivo detection of enzyme activity in preclinical and clinical settings could have fundamental implications in the field of drug discovery. Furthermore, a new class of targeted prodrug treatments takes advantage of high enzyme activity to tailor therapy and improve treatment outcomes. Herein, we report the design and synthesis of new magnetic resonance imaging (MRI) agents that quantitatively detect β-galactosidase and β-glucuronidase activities by measuring changes in chemical exchange saturation transfer (CEST). Based on a modular approach, we incorporated the enzymes’ respective substrates to a salicylate moiety with a chromogenic spacer via a carbamate linkage. This furnished highly selective diamagnetic CEST agents that detected and quantified enzyme activities of glycoside hydrolase enzymes. Michaelis–Menten enzyme kinetics studies were performed by monitoring catalyCEST MRI signals, which were validated with UV–vis assays.
Co-reporter:Gabriela Fernández-Cuervo;Sanhita Sinharay; Mark D. Pagel
ChemBioChem 2016 Volume 17( Issue 5) pp:
Publication Date(Web):
DOI:10.1002/cbic.201600080
Co-reporter:Sanhita Sinharay;Gabriela Fernández-Cuervo;Jasmine P. Acfalle;Mark D. Pagel
Chemistry - A European Journal 2016 Volume 22( Issue 19) pp:6491-6495
Publication Date(Web):
DOI:10.1002/chem.201600685
Abstract
A chemical exchange saturation transfer (CEST) MRI contrast agent has been developed that detects sulfatase enzyme activity. The agent produces a CEST signal at δ=5.0 ppm before enzyme activity, and a second CEST signal appears at δ=9.0 ppm after the enzyme cleaves a sulfate group from the agent. The comparison of the two signals improved detection of sulfatase activity.
Co-reporter:Iman Daryaei, Mahsa Mohammadebrahim Ghaffari, Kyle M. Jones, and Mark D. Pagel
ACS Sensors 2016 Volume 1(Issue 7) pp:857
Publication Date(Web):June 21, 2016
DOI:10.1021/acssensors.6b00203
Responsive CEST MRI biosensors offer good sensitivity and excellent specificity for detection of biomarkers with great potential for clinical translation. We report the application of fosfosal, a phosphorylated form of salicylic acid, for the detection of alkaline phosphatase (AP) enzyme. We detected conversion of fosfosal to salicylic acid in the presence of the enzyme by CEST MRI. Importantly the technique was able to detect AP enzyme expressed in cells in the presence of other cell components, which improves specificity. Various isoforms of the enzyme showed different Michaelis–Menten kinetics and yet these kinetics studies indicated very efficient catalytic rates. Our results with the fosfosal biosensor encourage further in vivo studies.Keywords: alkaline phosphatase; CATALYCEST; CEST MRI; Michaelis−Menten kinetics; molecular imaging
Co-reporter:Gabriela Fernández-Cuervo;Sanhita Sinharay; Mark D. Pagel
ChemBioChem 2016 Volume 17( Issue 5) pp:383-387
Publication Date(Web):
DOI:10.1002/cbic.201500586
Abstract
The simultaneous detection of multiple enzyme activities can improve the specificity of disease diagnoses. We therefore synthesized and characterized a diamagnetic chemical exchange saturation transfer (CEST) MRI contrast agent that can simultaneously detect two enzyme activities. Sulfatase and esterase enzymes cleave the ligands of the CEST agent, releasing salicylic acid that can be detected with CEST MRI. Importantly, both enzymes are required to activate the agent to produce a CEST MRI contrast, and the CEST agent was stable without enzyme treatment. These results established that this diamagnetic CEST MRI contrast agent is a platform technology with a modular design that can be potentially exploited to detect other combinations of enzyme activities, which can expand the armamentarium of contrast agents for molecular imaging.
Co-reporter:Edward A. Randtke;Kyle M. Jones;Christine M. Howison;Julio Cárdenas-Rodríguez;Mark D. Pagel;Patricia J. Sime;Matthew R. Kottmann
Molecular Imaging and Biology 2015 Volume 17( Issue 2) pp:
Publication Date(Web):2015/04/01
DOI:10.1007/s11307-014-0784-6
A feed-forward loop involving lactic acid production may potentially occur during the formation of idiopathic pulmonary fibrosis. To provide evidence for this feed-forward loop, we used acidoCEST MRI to measure the extracellular pH (pHe), while also measuring percent uptake of the contrast agent, lesion size, and the apparent diffusion coefficient (ADC).We developed a respiration-gated version of acidoCEST MRI to improve the measurement of pHe and percent uptake in lesions. We also used T2-weighted MRI to measure lesion volumes and diffusion-weighted MRI to measure ADC.The longitudinal changes in average pHe and % uptake of the contrast agent were inversely related to reduction in lung lesion volume. The average ADC did not change during the time frame of the study.The increase in pHe during the reduction in lesion volume indicates a role for lactic acid in the proposed feed-forward loop of IPF
Co-reporter:Christine M. Howison;Edward A. Randtke;Kyle M. Jones;Brianna F. Moon;Mark D. Pagel;Liu Qi Chen
Molecular Imaging and Biology 2015 Volume 17( Issue 4) pp:
Publication Date(Web):2015/08/01
DOI:10.1007/s11307-014-0816-2
We aimed to develop pixelwise maps of tumor acidosis to aid in evaluating extracellular tumor pH (pHe) in cancer biology.MCF-7 and MDA-MB-231 mouse models were imaged during a longitudinal study. AcidoCEST MRI and a series of image processing methods were used to produce parametric maps of tumor pHe, and tumor pHe was also measured with a pH microsensor.Sufficient contrast-to-noise for producing pHe maps was achieved by using standard image processing methods. A comparison of pHe values measured with acidoCEST MRI and a pH microsensor showed that acidoCEST MRI measured tumor pHe with an accuracy of 0.034 pH units. The MCF-7 tumor model was found to be more acidic compared to the MDA-MB-231 tumor model. The pHe was not related to tumor size during the longitudinal study.These results show that acidoCEST MRI can create pixelwise tumor pHe maps of mouse models of cancer.
Co-reporter:Liu Qi Chen;Christine M. Howison;Justin J. Jeffery;Ian F. Robey;Phillip H. Kuo;Mark D. Pagel
Magnetic Resonance in Medicine 2014 Volume 72( Issue 5) pp:1408-1417
Publication Date(Web):
DOI:10.1002/mrm.25053
Purpose
A practical, noninvasive method is needed to measure the extracellular pH (pHe) within in vivo tumors to longitudinally monitor tumor acidosis. We have optimized a biomedical imaging method, termed acidoCEST MRI, to provide noninvasive assessments of tumor pHe in preclinical models of mammary carcinoma.
Methods
A CEST-FISP MRI method was optimized to detect the chemical exchange saturation transfer (CEST) of two amide protons of a clinically approved CT contrast agent, iopromide. The ratio of the two CEST effects was used to measure pH. Routes of administration of iopromide were evaluated to ensure sufficient delivery of the agent to the tumor. The optimized acidoCEST MRI method was then used to evaluate the change in tumor pHe following alkalinizing bicarbonate treatment.
Results
The acidoCEST MRI protocol measured pH between 6.2 and 7.2 pH units. Greater delivery of iopromide was shown to improve the precision of the measurement of tumor pHe, but the agent did not influence the tumor pHe. AcidoCEST MRI was used to longitudinally monitor the effect of bicarbonate treatment on the pHe of tumors and bladders.
Conclusion
This study demonstrates that an optimized acidoCEST MRI method is a practical, noninvasive method for assessing changes in tumor acidosis. Magn Reson Med 72:1408–1417, 2014. © 2013 Wiley Periodicals, Inc.
Co-reporter:Edward A. Rtke;Liu Qi Chen;L. Rene Corrales;Mark D. Pagel
Magnetic Resonance in Medicine 2014 Volume 71( Issue 4) pp:1603-1612
Publication Date(Web):
DOI:10.1002/mrm.24792
Purpose
Contrast agents for chemical exchange saturation transfer MRI often require an accurate measurement of the chemical exchange rate. Many analysis methods have been reported that measure chemical exchange rates. Additional analysis methods were derived as part of this study. This report investigated the accuracy and precision of each analysis method.
Methods
Chemical exchange saturation transfer spectra were simulated using the Bloch-McConnell equations modified for chemical exchange. Chemical exchange saturation transfer spectra of iopromide were obtained with a range of saturation times, saturation powers, and concentrations. These simulated and experimental results were used to estimate the chemical exchange rate using the QUESP, QUEST, Omega Plot (LB-QUESP), EH-QUESP, HW-QUESP, LB-Conc, EH-Conc, and HW-Conc methods.
Results
Bloch fitting produced the most precise estimates of chemical exchange rates, although substantial expertise and computation time were required to achieve these results. Of the more simplistic analysis methods, the HW-QUESP method produced the most accurate and precise estimates of fast exchange rates. The QUEST and LB-QUESP methods produced the most accurate estimates of slow exchange rates, especially with samples that have short T1w relaxation times.
Conclusions
HW-QUESP is a simplistic analysis method that should be used when fast chemical exchange rates need to be estimated from chemical exchange saturation transfer MRI results. Magn Reson Med 71:1603–1612, 2014. © 2013 Wiley Periodicals, Inc.
Co-reporter:Byunghee Yoo;Vipul R. Sheth;Christine M. Howison;Matthew J. K. Douglas;Carlos T. Pineda;Erin A. Maine;Ama F. Baker;Mark D. Pagel
Magnetic Resonance in Medicine 2014 Volume 71( Issue 3) pp:1221-1230
Publication Date(Web):
DOI:10.1002/mrm.24763
Purpose
CatalyCEST MRI compares the detection of an enzyme-responsive chemical exchange saturation transfer (CEST) agent with the detection of an unresponsive “control” CEST agent that accounts for other conditions that influence CEST. The purpose of this study was to investigate the feasibility of in vivo catalyCEST MRI.
Methods
CEST agents that were responsive and unresponsive to the activity of urokinase plasminogen activator were shown to have negligible interaction with each other. A CEST-fast imaging with steady state precession (FISP) MRI protocol was used to acquire MR CEST spectroscopic images with a Capan-2 pancreatic tumor model after intravenous injection of the CEST agents. A function of (super)-Lorentzian line shapes was fit to CEST spectra of a region-of-interest that represented the tumor.
Results
The CEST effects from each agent showed the same initial uptake into tumor tissues, indicating that both agents had the same pharmacokinetic transport rates. Starting 5 min after injection, CEST from the enzyme-responsive agent disappeared more quickly than CEST from the unresponsive agent, indicating that the enzyme responsive agent was being catalyzed by urokinase plasminogen activator, while both agents also experienced net pharmacokinetic washout from the tumor.
Conclusion
CatalyCEST MRI demonstrates that dynamic tracking of enzyme-responsive and unresponsive CEST agents during the same in vivo MRI study is feasible. Magn Reson Med 71:1221–1230, 2014. © 2013 Wiley Periodicals, Inc.
Co-reporter:Dina V. Hingorani;Dr. Byunghee Yoo;Adam S. Bernstein;Dr. Mark D. Pagel
Chemistry - A European Journal 2014 Volume 20( Issue 32) pp:9840-9850
Publication Date(Web):
DOI:10.1002/chem.201402474
Abstract
This review focuses on exogenous magnetic resonance imaging (MRI) contrast agents that are responsive to enzyme activity. Enzymes can catalyze a change in water access, rotational tumbling time, the proximity of a 19F-labeled ligand, the aggregation state, the proton chemical-exchange rate between the agent and water, or the chemical shift of 19F, 31P, 13C or a labile 1H of an agent, all of which can be used to detect enzyme activity. The variety of agents attests to the creativity in developing enzyme-responsive MRI contrast agents.
Co-reporter:Dina V. Hingorani ; Edward A. Randtke ;Mark D. Pagel
Journal of the American Chemical Society 2013 Volume 135(Issue 17) pp:6396-6398
Publication Date(Web):April 19, 2013
DOI:10.1021/ja400254e
CatalyCEST MRI can detect enzyme activity by employing contrast agents that are detected through chemical exchange saturation transfer (CEST). A CEST agent, Tm-DO3A-cadaverine, has been designed to detect the catalytic activity of transglutaminase (TGase), which creates a covalent bond between the agent and the side chain of a glutamine amino acid residue. CEST appeared at −9.2 ppm after TGase conjugated Tm-DO3A-cadaverine to albumin, which also caused a decrease in CEST from albumin at +4.6 ppm. Studies with model peptides revealed similar appearances and decreases in detectable CEST effects following TGase-catalyzed conjugation of the contrast agent and peptide. The MR frequencies and amplitudes of these CEST effects were dependent on the peptide sequence, which demonstrated the sensitivity of CEST agents to ligand conformations that may be exploited to create more responsive molecular imaging agents. The chemical exchange rates of the substrates and conjugated products were measured by fitting modified Bloch equations to CEST spectra, which demonstrated that changes in exchange rates can also be used to detect the formation of a covalent bond by catalyCEST MRI.
Co-reporter:Vipul R. Sheth;Yuguo Li;Liu Qi Chen;Christine M. Howison;Chris A. Flask;Mark D. Pagel
Magnetic Resonance in Medicine 2012 Volume 67( Issue 3) pp:760-768
Publication Date(Web):
DOI:10.1002/mrm.23038
Abstract
Paramagnetic chemical exchange saturation transfer (PARACEST) MRI contrast agents have been developed that can measure pH in solution studies, but these agents have not previously been detected in vivo. To use the PARACEST agent Yb-DO3A-oAA to measure the extracellular pH (pHe) in tumor tissue, a chemical exchange saturation transfer fast imaging with steady state precession MRI protocol was developed, the saturation period was optimized for sensitive chemical exchange saturation transfer (CEST) detection, and median filtering was used to remove artifacts in CEST spectra. These improvements were used to correlate pH with a ratio of two CEST effects of Yb-DO3A-oAA at a 7 T magnetic field strength (R2 = 0.99, standard deviation of precision = 0.011 pH units). The PARACEST agent could not be detected in tumor tissue following i.v. injection due to the low sensitivity of in vivo CEST MRI. Yb-DO3A-oAA was detected in tumor tissue and leg muscle after directly injecting the PARACEST agent into these tissues. The measured CEST effects were used to measure a tumor pH of 6.82 ± 0.21 and a leg muscle pH of 7.26 ± 0.14, and parametric pH maps were also generated from these tissue regions. These results demonstrated that tumor pHe can be measured with a PARACEST agent and a rapid CEST-MRI protocol. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.
Co-reporter:Byunghee Yoo, Vipul R. Sheth, Mark D. Pagel
Tetrahedron Letters 2009 50(31) pp: 4459-4462
Publication Date(Web):
DOI:10.1016/j.tetlet.2009.05.061
Co-reporter:Julio Cárdenas-Rodríguez, Christine M. Howison, Mark D. Pagel
Magnetic Resonance Imaging (May 2013) Volume 31(Issue 4) pp:497-507
Publication Date(Web):1 May 2013
DOI:10.1016/j.mri.2012.10.008
Dynamic contrast enhanced MRI (DCE-MRI) has utility for improving clinical diagnoses of solid tumors, and for evaluating the early responses of anti-angiogenic chemotherapies. The Reference Region Model (RRM) can improve the clinical implementation of DCE-MRI by substituting the contrast enhancement of muscle for the Arterial Input Function that is used in traditional DCE-MRI methodologies. The RRM is typically fitted to experimental results with a non-linear least squares algorithm. This report demonstrates that this algorithm produces inaccurate and imprecise results when DCE-MRI results have low SNR or slow temporal resolution. To overcome this limitation, a linear least-squares algorithm has been derived for the Reference Region Model. This new algorithm improves accuracy and precision of fitting the Reference Region Model to DCE-MRI results, especially for voxel-wise analyses. This linear algorithm is insensitive to injection speeds, and has 300- to 8000-fold faster calculation speed relative to the non-linear algorithm. The linear algorithm produces more accurate results for over a wider range of permeabilities and blood volumes of tumor vasculature. This new algorithm, termed the Linear Reference Region Model, has strong potential to improve clinical DCE-MRI evaluations.
Co-reporter:Julio Cárdenas-Rodríguez, Christine M. Howison, Terry O. Matsunaga, Mark D. Pagel
Magnetic Resonance Imaging (July 2013) Volume 31(Issue 6) pp:900-910
Publication Date(Web):1 July 2013
DOI:10.1016/j.mri.2012.12.002
Dynamic Contrast Enhancement (DCE) MRI has been used to measure the kinetic transport constant, Ktrans, which is used to assess tumor angiogenesis and the effects of anti-angiogenic therapies. Standard DCE MRI methods must measure the pharmacokinetics of a contrast agent in the blood stream, known as the Arterial Input Function (AIF), which is then used as a reference for the pharmacokinetics of the agent in tumor tissue. However, the AIF is difficult to measure in pre-clinical tumor models and in patients. Moreover the AIF is dependent on the Fahraeus effect that causes a highly variable hematocrit (Hct) in tumor microvasculature, leading to erroneous estimates of Ktrans. To overcome these problems, we have developed the Reference Agent Model (RAM) for DCE MRI analyses, which determines the relative Ktrans of two contrast agents that are simultaneously co-injected and detected in the same tissue during a single DCE-MRI session. The RAM obviates the need to monitor the AIF because one contrast agent effectively serves as an internal reference in the tumor tissue for the other agent, and it also eliminates the systematic errors in the estimated Ktrans caused by assuming an erroneous Hct. Simulations demonstrated that the RAM can accurately and precisely estimate the relative Ktrans (RKtrans) of two agents. To experimentally evaluate the utility of RAM for analyzing DCE MRI results, we optimized a previously reported multiecho 19F MRI method to detect two perfluorinated contrast agents that were co-injected during a single in vivo study and selectively detected in the same tumor location. The results demonstrated that RAM determined RKtrans with excellent accuracy and precision.
Co-reporter:Renu M. Stephen, Abhinav K. Jha, Denise J. Roe, Theodore P. Trouard, Jean-Philippe Galons, Matthew A. Kupinski, Georgette Frey, Haiyan Cui, Scott Squire, Mark D. Pagel, Jeffrey J. Rodriguez, Robert J. Gillies, Alison T. Stopeck
Magnetic Resonance Imaging (December 2015) Volume 33(Issue 10) pp:1267-1273
Publication Date(Web):1 December 2015
DOI:10.1016/j.mri.2015.08.006
PurposeTo assess the value of semi-automated segmentation applied to diffusion MRI for predicting the therapeutic response of liver metastasis.MethodsConventional diffusion weighted magnetic resonance imaging (MRI) was performed using b-values of 0, 150, 300 and 450 s/mm2 at baseline and days 4, 11 and 39 following initiation of a new chemotherapy regimen in a pilot study with 18 women with 37 liver metastases from primary breast cancer. A semi-automated segmentation approach was used to identify liver metastases. Linear regression analysis was used to assess the relationship between baseline values of the apparent diffusion coefficient (ADC) and change in tumor size by day 39.ResultsA semi-automated segmentation scheme was critical for obtaining the most reliable ADC measurements. A statistically significant relationship between baseline ADC values and change in tumor size at day 39 was observed for minimally treated patients with metastatic liver lesions measuring 2–5 cm in size (p = 0.002), but not for heavily treated patients with the same tumor size range (p = 0.29), or for tumors of smaller or larger sizes. ROC analysis identified a baseline threshold ADC value of 1.33 μm2/ms as 75% sensitive and 83% specific for identifying non-responding metastases in minimally treated patients with 2–5 cm liver lesions.ConclusionQuantitative imaging can substantially benefit from a semi-automated segmentation scheme. Quantitative diffusion MRI results can be predictive of therapeutic outcome in selected patients with liver metastases, but not for all liver metastases, and therefore should be considered to be a restricted biomarker.
