Non-invasive Investigation of Tumor Metabolism and Acidosis by MRI-CEST Imaging (original) (raw)
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Molecular imaging of tumors and metastases using chemical exchange saturation transfer (CEST) MRI
Scientific Reports, 2013
The two glucose analogs 2-deoxy-D-glucose (2-DG) and 2-fluoro-2-deoxy-D-glucose (FDG) are preferentially taken up by cancer cells, undergo phosphorylation and accumulate in the cells. Owing to their exchangeable protons on their hydroxyl residues they exhibit significant chemical exchange saturation transfer (CEST) effect in MRI. Here we report CEST-MRI on mice bearing orthotopic mammary tumors injected with 2-DG or FDG. The tumor exhibited an enhanced CEST effect of up to 30% that persisted for over one hour. Thus 2-DG/FDG CEST MRI can replace PET/CT or PET/MRI for cancer research in laboratory animals, but also has the potential to be used in the clinic for the detection of tumors and metastases, distinguishing between malignant and benign tumors and monitoring tumor response to therapy as well as tumors metabolism noninvasively by using MRI, without the need for radio-labeled isotopes.
In vivo imaging of tumour metabolism and acidosis by combining PET and MRI-CEST pH imaging
Cancer research, 2016
The vast majority of cancers exhibit increased glucose uptake and glycolysis regardless of oxygen availability. This metabolic shift leads to an enhanced production of lactic acid that decreases extracellular pH (pHe), a hallmark of the tumour microenvironment. In this way, dysregulated tumour pHe and up-regulated glucose metabolism are linked tightly and their relative assessment may be useful to gain understanding of the underlying biology. Here we investigated non-invasively the in vivo correlation between tumour (18)F-FDG uptake and extracellular pH values in a murine model of HER2+ breast cancer. Tumour extracellular pH and perfusion were assessed by acquiring MRI-CEST (Chemical Exchange Saturation Transfer) images on a 3T scanner after intravenous administration of a pH-responsive contrast agent (iopamidol). Static PET images were recorded immediately after MRI acquisitions to quantify the extent of (18)F-FDG uptake. We demonstrated the occurrence of tumour pHe changes that re...
Increased lactate production through glycolysis in aerobic conditions is a hallmark of cancer. Some anticancer drugs have been designed to exploit elevated glycolysis in cancer cells. For example, lonidamine (LND) inhibits lactate transport, leading to intracellular acidification in cancer cells. Chemical exchange saturation transfer (CEST) is a novel MRI contrast mechanism that is dependent on intracellular pH. Amine and amide concentration-independent detection (AACID) and apparent amide proton transfer (APT*) represent two recently developed CEST contrast parameters that are sensitive to pH. The goal of this study was to compare the sensitivity of AACID and APT* for the detection of tumor-selective acidification after LND injection. Using a 9.4-T MRI scanner, CEST data were acquired in mice approximately 14 days after the implantation of 10 5 U87 human glioblastoma multiforme (GBM) cells in the brain, before and after the administration of LND (dose, 50 or 100 mg/kg). Significant dose-dependent LND-induced changes in the measured CEST parameters were detected in brain regions spatially correlated with implanted tumors. Importantly, no changes were observed in T 1 -and T 2 -weighted images acquired before and after LND treatment. The AACID and APT* contrast measured before and after LND injection exhibited similar pH sensitivity. Interestingly, LND-induced contrast maps showed increased heterogeneity compared with pre-injection CEST maps. These results demonstrate that CEST contrast changes after the administration of LND could help to localize brain cancer and monitor tumor response to chemotherapy within 1 h of treatment. The LND CEST experiment uses an anticancer drug to induce a metabolic change detectable by endogenous MRI contrast, and therefore represents a unique cancer detection paradigm which differs from other current molecular imaging techniques that require the injection of an imaging contrast agent or tracer.
Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine, 2014
To evaluate the feasibility to detect tumors and metastases by the chemical exchange saturation transfer (CEST) MRI technique using 3-O-Methyl-D-glucose (3OMG), a nonmetabolizable derivative of glucose that is taken up rapidly and preferentially by tumors and is entirely excreted by the kidneys. In vivo CEST MRI experiments were performed on a Bruker 7 Tesla Biospec on implanted orthotopic mammary tumors of mice before and following i.p. injection of 3OMG. The CEST images were generated by a series of gradient-echo images collected from a single 1 mm coronal slice after a 1.2 s presaturation pulse, applied at offsets of ±1.2 ppm from the water and at B(1) power of 2.5 µT. Following 3OMG (1.5 g/kg) i.p. injection, an enhanced CEST effect of approximately 20% was visualized at the tumor within a few minutes. The signal slowly declined reaching half of its maximum at approximately 80 min. Due to the large CEST effect of 3OMG and its low toxicity 3OMG-CEST may serve for the detection of...
Molecular imaging of tumors by chemical exchange saturation transfer MRI of glucose analogs
Quantitative Imaging in Medicine and Surgery, 2019
Early detection of the cancerous process would benefit greatly from imaging at the cellular and molecular level. Increased glucose demand has been recognized as one of the hallmarks of cancerous cells (the "Warburg effect"), hence glucose and its analogs are commonly used for cancer imaging. One example is FDG-PET technique, that led to the use of chemical exchange saturation transfer (CEST) MRI of glucose ("glucoCEST") for tumor imaging. This technique combines high-resolution MRI obtained by conventional imaging with simultaneous molecular information obtained from the exploitation of agents with exchangeable protons from amine, amide or hydroxyl residues with the water signal. In the case of glucoCEST, these agents are based on glucose or its analogs. Recently, preclinical glucoCEST studies demonstrated the ability to increase the sensitivity of MRI to the level of metabolic activity, enabling identification of tumor staging, biologic potential, treatment planning, therapy response and local recurrence, in addition to guiding target biopsy for clinically suspected cancer. However, natural glucose limits this method because of its rapid conversion to lactic acid, leading to reduced CEST effect and short signal duration. For that reason, a variety of glucose analogs have been tested as alternatives to the original glucoCEST. This review discusses the merits of these analogs, including new data on glucose analogs heretofore not reported in the literature. This summarized preclinical data may help strengthen the translation of CEST MRI of glucose analogs into the clinic, improving cancer imaging to enable early intervention without the need for invasive techniques. The data should also broaden our knowledge of fundamental biological processes.
In vivo imaging of glucose uptake and metabolism in tumors
Nature Medicine, 2013
Tumors have a greater reliance on anaerobic glycolysis for energy production than normal tissues. We developed a noninvasive method for imaging glucose uptake in vivo that is based on magnetic resonance imaging and allows the uptake of unlabeled glucose to be measured through the chemical exchange of protons between hydroxyl groups and water. This method differs from existing molecular imaging methods because it permits detection of the delivery and uptake of a metabolically active compound in physiological quantities. We show that our technique, named glucose chemical exchange saturation transfer (glucoCEST), is sensitive to tumor glucose accumulation in colorectal tumor models and can distinguish tumor types with differing metabolic characteristics and pathophysiologies. The results of this study suggest that glucoCEST has potential as a useful and cost-effective method for characterizing disease and assessing response to therapy in the clinic.
BioMed Research International, 2014
Cancer is known to have unique metabolic features such as Warburg effect. Current cancer therapy has moved forward from cytotoxic treatment to personalized, targeted therapies, with some that could lead to specific metabolic changes, potentially monitored by imaging methods. In this paper we addressed the important aspects to study cancer metabolism by using image techniques, focusing on opportunities and challenges of magnetic resonance spectroscopy (MRS), dynamic nuclear polarization (DNP)-MRS, positron emission tomography (PET), and mass spectrometry imaging (MSI) for mapping cancer metabolism. Finally, we highlighted the future possibilities of an integrated in vivo PET/MR imaging systems, together with an in situ MSI tissue analytical platform, may become the ultimate technologies for unraveling and understanding the molecular complexities in some aspects of cancer metabolism. Such comprehensive imaging investigations might provide information on pharmacometabolomics, biomarker discovery, and disease diagnosis, prognosis, and treatment response monitoring for clinical medicine.
Disease Markers, 2004
Cancer cells display heterogeneous genetic characteristics, depending on the tumor dynamic microenvironment. Abnormal tumor vasculature and poor tissue oxygenation generate a fraction of hypoxic tumor cells that have selective advantages in metastasis and invasion and often resist chemo- and radiation therapies. The genetic alterations acquired by tumors modify their biochemical pathways, which results in abnormal tumor metabolism. An elevation in glycolysis known as the “Warburg effect” and changes in lipid synthesis and oxidation occur. Magnetic resonance spectroscopy (MRS) has been used to study tumor metabolism in preclinical animal models and in clinical research on human breast, brain, and prostate cancers. This technique can identify specific genetic and metabolic changes that occur in malignant tumors. Therefore, the metabolic markers, detectable by MRS, not only provide information on biochemical changes but also define different metabolic tumor phenotypes. When combined wi...
NMR in Biomedicine, 2020
Glucosamine (GlcN) was recently proposed as an agent with an excellent safety profile to detect cancer with the chemical exchange saturation transfer (CEST) MRI technique. Translation of the GlcN CEST method to the clinical application requires evaluation of its sensitivity to the different frequency regions of irradiation. Hence, imaging of the GlcN signal was established for the full Z spectra recorded following GlcN administration to mice bearing implanted 4T1 breast tumors. Significant CEST effects were observed at around 1.5, 3.6 and −3.4 ppm, corresponding to the hydroxyl, amine/amide exchangeable protons and for the Nuclear Overhauser Enhancement (NOE), respectively. The sources of the observed CEST effects were investigated by identifying the GlcN metabolic products as observed by 13 C NMR spectroscopy studies of extracts from the same tumor model following treatment with [UL-13 C]-GlcNÁHCl. The CEST contribution can be attributed to several phosphorylated products of GlcN, including uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc), which is a substrate for the O-linked and N-linked glycosylated proteins that may be associated with the increase of the NOE signal. The observation of a significant amount of lactate among the metabolic products hints at acidification as one of the sources of the enhanced CEST effect of GlcN. The proposed method may offer a new approach for clinical molecular imaging that enables the detection of metabolically active tumors and may play a role in other diseases.