Molecular Imaging of Brain Tumors and Drug Delivery Using CEST MRI: Promises and Challenges

BACKGROUND: Noninvasive imaging of molecular alterations after intracerebral hemorrhage (ICH) could provide valuable information to guide and monitor treatments. Chemical exchange saturation transfer (CEST) magnetic resonance imaging has demonstrated promises in identifying proliferation, necrosis, and changes in cellularity in brain tumors. Here, we applied CEST magnetic resonance imaging to monitor molecular changes in hematoma without and with treatment noninvasively over 2 weeks at 3T using endogenous contrast. METHODS: CEST contrast related to proteins at 3.5 ppm (amide proton transfer) and proteins/lipids at −3.5 ppm (relayed nuclear overhauser effect [rNOE]) were examined over 14 days in a collagenase-induced ICH mouse model. Imaging findings were validated with immunohistochemistry based on the ICH neuropathology. We also examined iron-containing phantoms that mimicked iron concentrations in hematoma to ensure the iron will not attenuate the CEST contrast during disease progression. Based on the validity of the CEST contrast of hematoma, we further examined related molecular alterations under iron-chelation treatment with deferoxamine. RESULTS: We observed the temporal and spatial differences of CEST contrasts between rNOE at −3.5 ppm and amide proton transfer at 3.5 ppm, in which the core and perihematoma could be identified by rNOE on day 3 and day 14, and amide proton transfer on day 1, day 7, and day 14. Moreover, we observed a 25.7% significant reduction ( P <0.05) of rNOE contrast after deferoxamine treatment to the ICH mice on day 3, which was not observable in amide proton transfer contrast. Our histology data indicated that rNOE primarily correlated with the myelin pathology, and amide proton transfer could reflect the cellularity increase at hematoma up to day 7. CONCLUSIONS: Significant rNOE changes correlated well with histologic findings, especially myelin lipids, and regional characteristics in hematoma indicate the uniqueness of CEST magnetic resonance imaging in monitoring molecular changes during ICH and treatment.

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“…22 APT and rNOE are commonly used in the clinic to evaluate brain tumors. 51 These indicate that our recent study could be applied clinically.…”

Section: Discussionmentioning

confidence: 73%

Chemical Exchange Saturation Transfer Magnetic Resonance Imaging for Longitudinal Assessment of Intracerebral Hemorrhage and Deferoxamine Treatment at 3T in a Mouse Model

Lai

Liu

Yang

et al. 2023

Stroke

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“…Moreover, the injection of Iop-lipobeads could induce inflammation in mice without tumors, which was supported by the NOE increase at the microbead periphery (Figure f) and the histology results (Figure c). NOE is sensitive to lipids/proteins, especially lipid-rich structures, e.g., the cell membrane and myelin . Inflammation typically results in acidosis, thus reducing the pH of normal tissue to less than 7.0. , The B 1 power of 1.6 μT was applied for following in vivo experiments.…”

Section: Resultsmentioning

confidence: 99%

“…NOE is sensitive to lipids/ proteins, especially lipid-rich structures, e.g., the cell membrane and myelin. 25 Inflammation typically results in acidosis, thus reducing the pH of normal tissue to less than 7.0. 63,64 The B 1 power of 1.6 μT was applied for following in vivo experiments.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…The emerging MR approaches could solve the limitations associated with spatial and temporal resolution, especially CEST MRI that enables the use of endogenous contrast and/or exogeneous agents approved for clinical use to support frequent assessments. For example, the natural exchangeable protons of computed tomography (CT) CAs have been successfully repurposed as pH-sensitive CEST CAs for tumor pH imaging. , The endogenous CEST contrast of tumors, such as the amide proton transfer (APT) at around 3.5 ppm, has been applied to identify acute stroke and radiation necrosis from tumor recurrence. − APT is more sensitive to alterations in the concentration of proteins than pH, thus it will be challenging to monitor pHe independently using an endogenous APT signal. , …”

Section: Introductionmentioning

confidence: 99%

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Monitor Tumor pHe and Response Longitudinally during Treatment Using CEST MRI-Detectable Alginate Microbeads

Xiao

Huang

Han

et al. 2022

ACS Appl. Mater. Interfaces

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Imaging pHe of the tumor microenvironment has paramount importance for characterizing aggressive, invasive tumors, as well as therapeutic responses. Here, a robust approach to image pH changes in the tumor microenvironment longitudinally and during sodium bicarbonate treatment was reported. The pH-sensing microbeads were designed and prepared based on materials approved for clinical use, i.e., alginate microbeadcontaining computed tomography (CT) contrast-agent (iopamidol)-loaded liposomes (Iop-lipobeads). This Iop-lipobead prepared using a customized microfluidic device generated a CEST contrast of 10.6% at 4.2 ppm at pH 7.0, which was stable for 20 days in vitro. The CEST contrast decreased by 11.8% when the pH decreased from 7.0 to 6.5 in vitro. Optimized Iop-lipobeads next to tumors showed a significant increase of 19.7 ± 6.1% (p < 0.01) in CEST contrast at 4.2 ppm during the first 3 days of treatment and decreased to 15.2 ± 4.8% when treatment stopped. Notably, percentage changes in Iop-lipobeads were higher than that of amide CEST (11.7% and 9.1%) in tumors during and after treatment. These findings demonstrated that the Iop-lipobead could provide an independent and sensitive assessment of the pHe changes for a noninvasive and longitudinal monitoring of the treatment effects using multiple CEST contrast.

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“…It is important to acknowledge that the use of IP injection requires a longer acquisition time, adding an extra 15–20 min in the protocol compared with the IV injection. Long acquisition times, concern related to specific absorption rate (SAR) due to the radiofrequency power used, B 1 and B 0 inhomogeneities and motion artifacts are the main vulnerabilities, but they can be addressed with specific sequence designs and postprocessing analyses [ 10 , 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

Intraperitoneal Delivery of Iopamidol to Assess Extracellular pH of Orthotopic Pancreatic Tumor Model by CEST-MRI

Jardim‐Perassi

Irrera

Lau

et al. 2023

Contrast Media & Molecular Imaging

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The extracellular pH (pHe) of solid tumors is often acidic, as a consequence of the Warburg effect, and an altered metabolic state is often associated with malignancy. It has been shown that acidosis can promote tumor progression; thus, many therapeutic strategies have been adopted against tumor metabolism; one of these involves alkalinization therapies to raise tumor pH to inhibit tumor progression, improve immune surveillance, and overcome resistance to chemotherapies. Chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) is a noninvasive technique that can measure pH in vivo using pH-sensitive contrast agents. Iopamidol, an iodinated contrast agent, clinically used for computed tomography (CT), contains amide group protons with pH-dependent exchange rates that can reveal the pHe of the tumor microenvironment. In this study, we optimized intraperitoneal (IP) delivery of iopamidol to facilitate longitudinal assessments of orthotopic pancreatic tumor pHe by CEST-MRI. Following IV-infusion and IP-bolus injections, we compared the two protocols for assessing tumor pH. Time-resolved CT imaging was used to evaluate the uptake of iopamidol in the tumor, revealing that IP-bolus delivered a high amount of contrast agent 40 min postinjection, which was similar to the amounts reached with the IV-infusion protocol. As expected, both IP and IV injection protocols produced comparable measurements of tumor pHe, showing no statistically significant difference between groups ( p = 0.16 ). In addition, we showed the ability to conduct longitudinal monitoring of tumor pHe using CEST-MRI with the IP injection protocol, revealing a statistically significant increase in tumor pHe following bicarbonate administration ( p < 0.001 ). In conclusion, this study shows the capability to measure pHe using an IP delivery of iopamidol into orthotopic pancreatic tumors, which is important to conduct longitudinal studies.

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Molecular Imaging of Brain Tumors and Drug Delivery Using CEST MRI: Promises and Challenges

Cited by 15 publications

References 206 publications

Chemical Exchange Saturation Transfer Magnetic Resonance Imaging for Longitudinal Assessment of Intracerebral Hemorrhage and Deferoxamine Treatment at 3T in a Mouse Model

Chemical Exchange Saturation Transfer Magnetic Resonance Imaging for Longitudinal Assessment of Intracerebral Hemorrhage and Deferoxamine Treatment at 3T in a Mouse Model

Monitor Tumor pHe and Response Longitudinally during Treatment Using CEST MRI-Detectable Alginate Microbeads

Intraperitoneal Delivery of Iopamidol to Assess Extracellular pH of Orthotopic Pancreatic Tumor Model by CEST-MRI

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