Noninvasive <i>In vivo</i> Detection of Glutathione Metabolism in Tumors

Thelwall, Peter E.; Yemin, Avner Y.; Gillian, Theresa L.; Simpson, Nicholas E.; Kasibhatla, Mohit S.; Rabbani, Zahid N.; Macdonald, Jeffrey M.; Blackband, Stephen J.; Gamcsik, Michael P.

doi:10.1158/0008-5472.can-05-1781

Cited by 30 publications

(34 citation statements)

References 16 publications

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“…Although redox chemistry is a central feature of cellular processes, existing methods to interrogate coupled oxidation/ reduction reactions in vivo have significant limitations, including poor tissue penetration (as is the case for optical probes) and prohibitively long scan times (20,21). Here we describe a MR imaging agent, hyperpolarized [1-13 C] DHA, which is rapidly converted to [1-13 C] Vitamin C in vivo, at levels suitable for magnetic resonance spectroscopic imaging (MRSI) (Fig.…”

Section: Mri | Molecular Imaging | Probe | Kineticsmentioning

confidence: 99%

Hyperpolarized ¹³ C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Keshari

Kurhanewicz

Bok

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

149

159

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Reduction and oxidation (redox) chemistry is involved in both normal and abnormal cellular function, in processes as diverse as circadian rhythms and neurotransmission. Intracellular redox is maintained by coupled reactions involving NADPH, glutathione (GSH), and vitamin C, as well as their corresponding oxidized counterparts. In addition to functioning as enzyme cofactors, these reducing agents have a critical role in dealing with reactive oxygen species (ROS), the toxic products of oxidative metabolism seen as culprits in aging, neurodegenerative disease, and ischemia/ reperfusion injury. Despite this strong relationship between redox and human disease, methods to interrogate a redox pair in vivo are limited. Here we report the development of [1-13 C] dehydroascorbate [DHA], the oxidized form of Vitamin C, as an endogenous redox sensor for in vivo imaging using hyperpolarized 13 C spectroscopy. In murine models, hyperpolarized [1-13 C] DHA was rapidly converted to [1-13 C] vitamin C within the liver, kidneys, and brain, as well as within tumor in a transgenic prostate cancer mouse. This result is consistent with what has been previously described for the DHA/Vitamin C redox pair, and points to a role for hyperpolarized [1-13 C] DHA in characterizing the concentrations of key intracellular reducing agents, including GSH. More broadly, these findings suggest a prognostic role for this new redox sensor in determining vulnerability of both normal and abnormal tissues to ROS.MRI | molecular imaging | probe | kinetics

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Section: Mri | Molecular Imaging | Probe | Kineticsmentioning

confidence: 99%

Hyperpolarized ¹³ C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Keshari

Kurhanewicz

Bok

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

149

159

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“…In this study, we used glutathione (GSH, reduced form) as a coating agent for the surface modification of TOPO/HDA capped QDs [30-32]. GSH is a natural thiol compound (γ- L -glutanyl- L -cystenylglycine) that exists in most organs at mM levels [33,34], and the compound is not harmful like synthetic thiol compounds (e.g. mercaptoacetic acid and mercapotethanol).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Characterization of Anti-HER2 Antibody Conjugated CdSe/CdZnS Quantum Dots for Fluorescence Imaging of Breast Cancer Cells

Tiwari

Tanaka

Inouye

et al. 2009

Sensors

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The early detection of HER2 (human epidermal growth factor receptor 2) status in breast cancer patients is very important for the effective implementation of anti-HER2 antibody therapy. Recently, HER2 detections using antibody conjugated quantum dots (QDs) have attracted much attention. QDs are a new class of fluorescent materials that have superior properties such as high brightness, high resistance to photo-bleaching, and multi-colored emission by a single-light source excitation. In this study, we synthesized three types of anti-HER2 antibody conjugated QDs (HER2Ab-QDs) using different coupling agents (EDC/sulfo-NHS, iminothiolane/sulfo-SMCC, and sulfo-SMCC). As water-soluble QDs for the conjugation of antibody, we used glutathione coated CdSe/CdZnS QDs (GSH-QDs) with fluorescence quantum yields of 0.23∼0.39 in aqueous solution. Dispersibility, hydrodynamic size, and apparent molecular weights of the GSH-QDs and HER2Ab-QDs were characterized by using dynamic light scattering, fluorescence correlation spectroscopy, atomic force microscope, and size-exclusion HPLC. Fluorescence imaging of HER2 overexpressing cells (KPL-4 human breast cancer cell line) was performed by using HER2Ab-QDs as fluorescent probes. We found that the HER2Ab-QD prepared by using SMCC coupling with partially reduced antibody is a most effective probe for the detection of HER2 expression in KPL-4 cells. We have also studied the size dependency of HER2Ab-QDs (with green, orange, and red emission) on the fluorescence image of KPL-4 cells.

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“…It should be noted that NMR is one of the few and by far the most versatile technique that can be employed for real time stable isotope tracer studies in vivo due to its noninvasive mode of measurement. In either case, the tracer can be administered as a bolus orally (Mason, Petersen et al 2002) or intraperitoneally, via ad libitum food or water intake, via tail vein injection, (Fan, Lane et al 2011; Lane, Fan et al 2011), or by continuous infusion via a cannula (Thelwall, Yemin et al 2005; Mason, Petersen et al 2007; Thelwall, Simpson et al 2011). The continuous infusion approach has the advantage of achieving a much higher and constant level of the tracer.…”

Section: Application Of Nmr To Stable Isotope Tracer Studiesmentioning

confidence: 99%

Stable isotope-resolved metabolomics and applications for drug development

Fan

Lorkiewicz

Sellers

et al. 2012

Pharmacology & Therapeutics

189

169

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Advances in analytical methodologies, principally nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS), during the last decade have made large-scale analysis of the human metabolome a reality. This is leading to the reawakening of the importance of metabolism in human diseases, particularly cancer. The metabolome is the functional readout of the genome, functional genome, and proteome; it is also an integral partner in molecular regulations for homeostasis. The interrogation of the metabolome, or metabolomics, is now being applied to numerous diseases, largely by metabolite profiling for biomarker discovery, but also in pharmacology and therapeutics. Recent advances in stable isotope tracer-based metabolomic approaches enable unambiguous tracking of individual atoms through compartmentalized metabolic networks directly in human subjects, which promises to decipher the complexity of the human metabolome at an unprecedented pace. This knowledge will revolutionize our understanding of complex human diseases, clinical diagnostics, as well as individualized therapeutics and drug response. In this review, we focus on the use of stable isotope tracers with metabolomics technologies for understanding metabolic network dynamics in both model systems and in clinical applications. Atom-resolved isotope tracing via the two major analytical platforms, NMR and MS, has the power to determine novel metabolic reprogramming in diseases, discover new drug targets, and facilitates ADME studies. We also illustrate new metabolic tracer-based imaging technologies, which enable direct visualization of metabolic processes in vivo. We further outline current practices and future requirements for biochemoinformatics development, which is an integral part of translating stable isotope-resolved metabolomics into clinical reality.

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Noninvasive In vivo Detection of Glutathione Metabolism in Tumors

Cited by 30 publications

References 16 publications

Hyperpolarized ¹³ C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Hyperpolarized ¹³ C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Synthesis and Characterization of Anti-HER2 Antibody Conjugated CdSe/CdZnS Quantum Dots for Fluorescence Imaging of Breast Cancer Cells

Stable isotope-resolved metabolomics and applications for drug development

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Noninvasive In vivo Detection of Glutathione Metabolism in Tumors

Cited by 30 publications

References 16 publications

Hyperpolarized 13 C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Hyperpolarized 13 C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Synthesis and Characterization of Anti-HER2 Antibody Conjugated CdSe/CdZnS Quantum Dots for Fluorescence Imaging of Breast Cancer Cells

Stable isotope-resolved metabolomics and applications for drug development

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Product

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Hyperpolarized ¹³ C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging

Hyperpolarized ¹³ C dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging