Characterization of tumor vascular permeability using natural dextrans and CEST MRI

Li, Yuguo; Qiao, Yuan; Chen, Hanwei; Bai, Ren-Yuan; Staedtke, Verena; Zheng, Han; Xu, Jiadi; Chan, Kannie W. Y.; Yadav, Nirbhay N.; Bulte, Jeff W.M.; Zhou, Shibin; Zijl, Peter van; Liu, Guanshu

doi:10.1002/mrm.27014

Cited by 37 publications

(66 citation statements)

References 67 publications

(72 reference statements)

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“…Previously, several variations of CEST, such as amide proton transfer (APT), glutamate CEST, creatine CEST, CEST imaging of glucose and its derivatives, paramagnetic agent CEST, and acidoCEST, have been developed to detect endogenous and exogenous agents. To further quantify the exchange rate, which is relevant to the intracellular or extracellular pH, a ratiometric approach, using the ratio of two CEST signals that have different dependences on the exchange rate but the same dependences on other non‐specific factors (e.g., solute pool concentration), was also developed .…”

Section: Introductionmentioning

confidence: 99%

Ratiometric NOE(−1.6) contrast in brain tumors

2018

NMR in Biomedicine

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Recently, a new nuclear Overhauser enhancement (NOE)‐mediated saturation transfer effect at around −1.6 ppm from water, termed NOE(−1.6), was reported to show hypointense signals in brain tumors. Similar to chemical exchange saturation transfer or magnetization transfer (MT) effects, which depend on the solute pool concentration, the exchange/coupling rate, the solute transverse relaxation rate, etc., the NOE(−1.6) effect should also depend on these factors. Since the exchange rate is relevant to tissue pH, and the coupling rate and the solute transverse relaxation rate are relevant to the motional property of the coupled molecules, further studies to quantify the contribution from only the exchange/coupling rate and the solute transverse relaxation rate are always interesting. The purpose of this paper is to apply a ratiometric approach to the NOE(−1.6) effect to obtain a metric that is more specific to the NOE coupling rate and the solute transverse relaxation rate than the NOE(−1.6) signal amplitude. Simulations indicate that the ratiometric approach allows us to rule out nearly all of the non‐specific factors including the solute pool concentration, solute and water longitudinal relaxation rates, direct water saturation, and semi‐solid MT effects, and provides a more specific NOE coupling rate‐ and solute transverse relaxation rate‐weighted signal. Animal studies show that the ratiometric NOE(−1.6) decreases dramatically in brain tumors, which suggests that the change in the NOE(−1.6) coupling rate and/or the solute transverse relaxation rate are major contributors to the previously observed hypointense NOE(−1.6) signal in tumors.

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Section: Introductionmentioning

confidence: 99%

Ratiometric NOE(−1.6) contrast in brain tumors

2018

NMR in Biomedicine

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“…Second, the sensitivity of high MW dextrans is higher than that of small molecules. According to our previous study, the detectability (defined as the minimal concentration of a contrast agent to generate 5% signal change) of Dex150 at physiological pH is only 3.2 µM per dextran molecule (3 mM per glucose), indicating an approximately 1000 times higher sensitivity enhancement as compared to its monomer glucose.…”

Section: Discussionmentioning

confidence: 97%

“…One potential drawback in the application of CEST signal of hydroxyl proton is its relatively small chemical shift (~ 1 ppm) that can be possibly ‘contaminated’ by endogenous CEST species. Using a dynamic CEST MRI acquisition scheme can measure specifically the changes in dexCEST signal at 1 ppm by normalizing the background CEST signal generated by endogenous molecules . Thus, the background OH signals in the tissue are subtracted and will not cause errors in the MRI quantification of tumor uptake of dextrans.…”

Section: Discussionmentioning

confidence: 99%

“…Full Z spectra were acquired by sweeping the saturation offsets from ‐3 ppm to +3 ppm (step size 0.2 ppm) using a fat‐suppressed RARE sequence with a continuous wave presaturation pulse of B 1 = 1.8 µT and 3 s with acquisition parameters: T R /T E = 5000/5 ms, RARE factor = 10, number of averages = 2, slice number = 1, slice thickness = 1 mm, matrix size = 64 × 64 with partial FT acceleration to 64 × 40, field of view = 25 mm × 25 mm 2 , total acquisition time = 20.7 min. It should be noted that a weaker B 1 (i.e., 1.8 µT) was used for in vivo studies than that used for in vitro studies (i.e., 3.6 µT) to reduce the unwanted saturation caused by the MT effect . To correct B 0 inhomogeneity, WASSR‐based B 0 maps (acquisition time = 2.1 min) were acquired before and after CEST acquisition as described previously …”

Section: Methodsmentioning

confidence: 99%

“…Moreover, dextrans are polymers composed of tens to thousands of glucose units, providing a greatly boosted sensitivity for in vivo applications, such as imaging of prostate‐specific membrane antigen . Because dextrans are available in a variety of different molecular sizes, dexCEST MRI has the potential to characterize differential vascular permeability of tumors to particles in different size ranges . Dextrans are available in clinical‐grade for intravenous injection, which have a proven safety profile, allowing repeated use without fear of accumulation and toxicity.…”

Section: Introductionmentioning

confidence: 99%

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CEST MRI monitoring of tumor response to vascular disrupting therapy using high molecular weight dextrans

Chen

Liu

et al. 2019

Magnetic Resonance in Med

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Purpose Vascular disrupting therapy of cancer has become a promising approach not only to regress tumor growth directly but also to boost the delivery of chemotherapeutics in the tumor. An imaging approach to monitor the changes in tumor vascular permeability, therefore, has important applications for monitoring of vascular disrupting therapies. Methods Mice bearing CT26 subcutaneous colon tumors were injected intravenously with 150 kD dextran (Dex150, diameter, d~ 20 nm, 375 mg/kg), tumor necrosis factor‐alpha (TNF‐α; 1 µg per mouse), or both (n = 3 in each group). The Z‐spectra were acquired before and 2 h after the injection, and the chemical exchange saturation transfer (CEST) signals in the tumors as quantified by asymmetric magnetization transfer ratio (MTRasym) at 1 ppm were compared. Results The results showed a significantly stronger CEST contrast enhancement at 1 ppm (∆MTRasym = 0.042 ± 0.002) in the TNF‐α‐treated tumors than those by Dex150 alone (∆MTRasym = 0.000 ± 0.005, P = 0.0229) or TNF‐α alone (∆MTRasym = 0.002 ± 0.004, P = 0.0264), indicating that the TNF‐α treatment strongly augmented the tumor uptake of 150 kD dextran. The MRI findings were verified by fluorescence imaging and immunofluorescence microscopy. Conclusions High molecular weight dextrans can be used as safe and sensitive CEST MRI contrast agents for monitoring tumor response to vascular disrupting therapy and, potentially, for developing dextran‐based theranostic drug delivery systems.

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Close to Real: Large‐Volume 3D Cell Spheroids on a Superamphiphobic Surface

Dai

Wang

et al. 2021

Adv Materials Inter

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3D cell spheroids with native cell‐to‐cell junctions and cell‐extracellular matrix interactions can recapitulate the comprehensive physiological environments in vivo, providing new platforms for preclinical drug screening. However, the applications of 3D cell spheroids are limited by the unmatched size, deficient cell abundance, and short service time. In this work, a novel upward culture method on a porous silica superamphiphobic biointerface (SABI) is developed to fully overcome these technical hurdles. Cell suspensions maintain in a state of aquatic marble, accelerating cellular self‐aggregation. Contributing to the upward culture model, this strategy overcomes the shortages of size limitation and media refreshing in the classical methods. Herein, large‐volume 3D cell spheroids with the size of over 1500 µm can be efficiently established within 2 days and subsequently long‐term cultured for more than 20 days. For a close to real biomimetic microenvironment, breast tumor 3D spheroid is applied as a proof of concept, simultaneously employing MCF‐7 cell, cancer‐associated fibroblast (clone 8), and vascular endothelial cell (HUVEC). The large‐volume tumor spheroid with close‐to‐real microenvironment services as a unique paradigm for all‐in‐one biological relevant researches, including the capacity of in situ observation, long‐term incubation, drug screening, and recyclability.

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Characterization of tumor vascular permeability using natural dextrans and CEST MRI

Cited by 37 publications

References 67 publications

Ratiometric NOE(−1.6) contrast in brain tumors

Ratiometric NOE(−1.6) contrast in brain tumors

CEST MRI monitoring of tumor response to vascular disrupting therapy using high molecular weight dextrans

Close to Real: Large‐Volume 3D Cell Spheroids on a Superamphiphobic Surface

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