Natural D‐glucose as a biodegradable MRI contrast agent for detecting cancer

Abstract

Purpose Modern imaging technologies such as CT, PET, SPECT, and MRI employ contrast agents to visualize the tumor microenvironment, providing information on malignancy and response to treatment. Currently, all clinical imaging agents require chemical labeling, i.e. with iodine (CT), radioisotopes (PET/SPECT), or paramagnetic metals (MRI). The goal was to explore the possibility of using simple D-glucose as an infusable biodegradable MRI agent for cancer detection. Methods D-glucose signals were detected using chemical exchange saturation transfer (glucoCEST) MRI of its hydroxyl groups. Feasibility was established in phantoms as well as in vivo using two human breast cancer cell lines, MDA-MB-231 and MCF-7, implanted orthotopically in nude mice. PET and contrast-enhanced MRI were also acquired. Results Both tumor types exhibited significant glucoCEST signal enhancement during systemic sugar infusion (mild hyperglycemia), allowing their noninvasive visualization. GlucoCEST showed differences between types, while PET and CE-MRI did not. Data are discussed in terms of signal contributions from the increased vascular volume in tumors and especially from the acidic extracellular extravascular space (EES), where glucoCEST signal is expected to be enhanced due to a slow-down of hydroxyl proton exchange. Conclusions This observation opens up the possibility for using simple non-toxic sugars as contrast agents for cancer detection with MRI by employing hydroxyl protons as a natural label.

Imaging Brain Deoxyglucose Uptake and Metabolism by Glucocest MRI

“…31 P MRS were processed in TopSpin 3.0 (Bruker). An exponential line broadening factor of 20 Hz was applied before Fourier transformation of the data.…”

“…The signal decayed more slowly than under 1.0% isoflurane suggesting delayed 2DG6P production ( Figure 5B) under the latter conditions. Figure 5C shows the kinetics of 2DG6P change under the same levels of isoflurane measured by 31 P MRS. In a manner similar to glucoCEST, no difference in 2DG6P production was observed between 1.0% and 1.5% isoflurane, but the response was significantly delayed and reduced under 2.0% isoflurane.…”

“…20 As both isoflurane and hypercapnia can cause acidosis, 21,22 we evaluated their influence on blood and cellular pH. 31 P MRS enables the estimation of intracellular pH from the chemical shift of the inorganic phosphate (Pi) resonance or that of 2DG6P. 23,24 For all the experimental conditions, the brain pH estimated using the Pi resonance was constant at 7.15 ± 0.03, and there was no change before and after injection of 2DG.…”

“…7,8 These earlier studies showed that high doses (up to 0.5 g/kg) of 2DG are well tolerated by animals and reveal reaction kinetics similar to those of 14 C-2DG experiments. The phosphorylation of 2DG makes it detectable by 31 P NMR, thereby indirectly assessing glucose metabolism. 9 However, even at such high doses of 2DG, the sensitivity of in vivo NMR is still insufficient to allow spatial mapping of glucose metabolism.…”

Downfield‐NOE‐suppressed amide‐CEST‐MRI at 7 Tesla provides a unique contrast in human glioblastoma

“…The power of chemical exchange saturation transfer (CEST) MR imaging as a marker for tumor diseases is the indirect detection of intracellular compounds like functional metabolites (1)(2)(3)(4) or mobile proteins (5,6) in vivo by use of the exchange processes with water pool protons (7). Two distinct saturation transfer (ST) effects apparent in vivo are attributed to protons of mobile proteins: at 3.5 ppm the backbone amide signals with their base catalyzed proton transfer (APT) and at -3.5 ppm the nuclear Overhauser enhancement (NOE) mediated aliphatic proton magnetization transfer (so called exchangerelayed NOE or relayed-NOE (rNOE) ST) (8,9).…”