Mark Pagel

My research program, the Contrast Agent Molecular Engineering Laboratory (CAMEL) develops chemical agents that change the contrast of biomedical images. These contrast agents are designed to respond to molecular biomarkers of biological process and pathologies. This molecular information is used to predict response to therapy before the therapy is applied, monitor the delivery of therapy to targeted tissues, and evaluate the early-stage effects of the therapy. These diagnostic methods that affect the choice of therapy are designed to provide personalized medicine for each individual patient.CAMEL primarily focuses on the development of contrast agents for Magnetic Resonance Imaging (MRI). In particular, CAMEL has developed a new type of MRI contrast agent that can detect molecular biomarkers through Chemical Exchange Saturation Transfer (CEST). CAMEL has also developed CEST MRI methods for pre-clinical and clinical studies, and has also developed methods that rapidly synthesize CEST contrast agents. CAMEL also develops contrast agents for optical imaging, particularly focusing on applications of optical imaging that use multiple agents to improve the specificity of molecular imaging. CAMEL is affiliated with the Department of Biomedical Engineering and the Biomedical Engineering Graduate Interdisciplinary Program, the Department of Chemistry and Biochemistry, the Department of Medical Imaging, the University of Arizona Cancer Center, and the Institute for Collaborative BioResearch (BIO5) at the University of Arizona in Tucson, AZ. These affiliations reflect the interdisciplinary research approach undertaken by CAMEL and the supportive environment for biomedical research at the University of Arizona. Teaching MissionCAMEL supports the teaching and training mission of the University of Arizona. The CAMEL laboratories provide an outstanding training environment for graduate and undergraduate students from a variety of disciplines, including biomedical engineering, chemistry & biochemistry, optical sciences, and computer science. In addition, I regularly teach a graduate-level course for biomedical engineers, BME 510: “Cell Biology for Engineers,” which covers basic cell biology from a quantitative, design-driven perspective. I also teach an undergraduate-level course for chemists and biochemists, CHEM 481: “Biophysical Chemistry” that covers quantum mechanics and spectroscopy as applied to biochemistry and biotechnology. These multidisciplinary teaching roles further strengthen the teaching mission of CAMEL.HistoryThe concept of CAMEL was inspired by the Imaging in 2020 meeting held in 2001 at the Jackson Lake Lodge, Jackson, WY. This meeting facilitates open and effective communication among basic and clinical researchers from many interdisciplinary fields, and evaluates the opportunities and challenges for the development & clinical translation of molecular imaging by 2020 and beyond. CAMEL is founded on open communication and interdisciplinary research that leads to the development & clinical translation of molecular imaging. CAMEL was first established in the Department of Biomedical Engineering at Case Western Reserve University in 2003. I started this research program after leaving the pharmaceutical industry to return to academia, to contribute to the high-risk high-reward field of molecular imaging. CAMEL pioneered the development of responsive CEST MRI contrast agents in 2003-2005, and demonstrated the first in vivo MRI studies with paramagnetic CEST agents in 2006-2007. CAMEL also developed new synthesis methods to create new types of MRI contrast agents.In 2008, I moved CAMEL to the University of Arizona, in Tucson AZ. This transition provided CAMEL with resources and opportunities to collaborate with cancer biology researchers in the University of Arizona Cancer Center, and access to resources in the Departments of Biomedical Engineering, Chemistry & Biochemistry, and Medical Imaging, and the BIO5 Institute. The combination of these diverse resources and multidisciplinary collaborators has been essential to the continued productivity of CAMEL. Furthermore, the collaborative research environment at the University of Arizona has greatly facilitated the expansion of CAMEL’s research interests into optical imaging and clinical imaging. CAMEL has found an ideal home in the desert!
			
Monitoring The Development Of Xenograft Triple Negative Breast Cancer Models Using Diffusion Weighted Magnetic Resonance Imaging. Source: Experimental Biology And Medicine (Maywood, N.J.)
December 14th, 2012 PMID: 23239438 Emmanuelle Meuillet Mark Pagel
Evaluations of tumor growth rates and molecular biomarkers are traditionally used to assess new mouse models of human breast cancers. This study investigated the utility of diffusion weighted (DW)-magnetic resonance imaging (MRI) for evaluating cellular proliferation of new tumor models of triple-negative breast cancer, which may augment traditional analysis methods. Eleven human breast cancer cell lines were used to develop xenograft tumors in severe combined immunodeficient mice, with two of these cell lines exhibiting sufficient growth to be serially passaged. DW-MRI was performed to measure the distributions of the apparent diffusion coefficient (ADC) in these two tumor xenograft models, which showed a correlation with tumor growth rates and doubling times during each passage. The distributions of the ADC values were also correlated with expression of Ki67, a biomarker of cell proliferation, and hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor receptor-2 (VEGFR2), which are essential proteins involved in regulating aerobic glycolysis and angiogenesis that support tumor cell proliferation. Although phosphatase and tensin homolog (PTEN) levels were different between the two xenograft models, AKT levels did not differ nor did they correlate with tumor growth. This last result demonstrates the complexity of signaling protein pathways and the difficulty in interpreting the effects of protein expression on tumor cell proliferation. In contrast, DW-MRI may be a more direct assessment of tumor growth and cancer cell proliferation.<br /><br />
A Linear Algorithm Of The Reference Region Model For Dce Mri Is Robust And Relaxes Requirements For Temporal Resolution. Source: Magnetic Resonance Imaging
December 7th, 2012 PMID: 23228309 Mark Pagel
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.<br /><br />
Imaging Biomarkers To Monitor Response To The Hypoxia Activated Prodrug Th 302 In The Mia Pa Ca2 Flank Xenograft Model. Source: Magnetic Resonance Imaging
May 1st, 2012 PMID: 22554971 Mark Pagel
TH-302, a hypoxia-activated anticancer prodrug, was evaluated for antitumor activity and changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in a mouse model of pancreatic cancer. TH-302 monotherapy resulted in a significant delay in tumor growth compared to vehicle-treated controls. TH-302 treatment was also associated with a significant decrease in the volume transfer constant (K(trans)) compared to vehicle-treated controls 1 day following the first dose measured using DCE-MRI. This early decrease in K(trans) following the first dose as measured is consistent with selective killing of the hypoxic fraction of cells which are associated with enhanced expression of hypoxia inducible transcription factor-1 alpha that regulates expression of permeability and perfusion factors including vascular endothelial growth factor-A. No changes were observed in DW-MRI following treatment with TH-302, which may indicate that this technique is not sensitive enough to detect changes in small hypoxic fractions of the tumor targeted by TH-302. These results suggest that changes in tumor permeability and/or perfusion may be an early imaging biomarker for response to TH-302 therapy.<br /><br />
Fluorescent And Lanthanide Labeling For Ligand Screens, Assays, And Imaging. Source: Methods In Molecular Biology (Clifton, N.J.)
The use of fluorescent (or luminescent) and metal contrast agents in high-throughput screens, in vitro assays, and molecular imaging procedures has rapidly expanded in recent years. Here we describe the development and utility of high-affinity ligands for cancer theranostics and other in vitro screening -studies. In this context, we also illustrate the syntheses and use of heteromultivalent ligands as targeted imaging agents.<br><br>
A Self Calibrating Paracest Mri Contrast Agent That Detects Esterase Enzyme Activity. Source: Contrast Media & Molecular Imaging
November 30th, 2010 PMID: 21861282 Mark Pagel
The CEST effect of many PARACEST MRI contrast agents changes in response to a molecular biomarker. However, other molecular biomarkers or environmental factors can influence CEST, so that a change in CEST is not conclusive proof for detecting the biomarker. To overcome this problem, a second control CEST effect may be included in the same PARACEST agent, which is responsive to all factors that alter the first CEST effect except for the biomarker to be measured. To investigate this approach, a PARACEST MRI contrast agent was developed with one CEST effect that is responsive to esterase enzyme activity and a second control CEST effect. The ratio of the two CEST effects was independent of concentration and T(1) relaxation, so that this agent was self-calibrating with respect to these factors. This ratiometric method was dependent on temperature and was influenced by MR coalescence as the chemical exchange rates approached the chemical shifts of the exchangable protons as temperature was increased. The two CEST effects also showed evidence of having different pH dependencies, so that this agent was not self-calibrating with respect to pH. Therefore, a self-calibrating PARACEST MRI contrast agent can more accurately detect a molecular biomarker such as esterase enzyme activity, as long as temperature and pH are within an acceptable physiological range and remain constant.<br /><br />
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