AcidoCEST MRI Evaluates the Bone Microenvironment in Multiple Myeloma

Lombardi, Alecio; Wong, Jonathan; High, Rachel; Ma, Yajun; Jerban, Saeed; Tang, Qingbo; Frost, Patrick; Pagel, Mark; Chang, Eric Y.

doi:10.1007/s11307-021-01611-2

Cited by 6 publications

(6 citation statements)

References 40 publications

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“…For in vivo assessment of tumor pHe, 4 T1 breast or H292 lung tumor bearing mice ( n = 4 per group; NSPS vs vehicle saline) described above were imaged via magnetic resonance imaging (MRI) at 7 Tesla using the chemical exchange saturation transfer (CEST) approach, an established method for measuring extracellular pH 42 , 43 , 44 , 45 , 46 , 47 in vivo. Clinical grade iohexol; 300 mg/mL Iodine (300 mgI/mL Omnipaque, GE Healthcare, purchased from VUMC pharmacy) was injected (0.2 mL) intraperitoneally and another 0.2 mL were injected directly into the tumors similar to Chen et al 43 The mice were scanned at baseline and immediately following an intravenous injection, via jugular vein catheter, of either a test dose of 25 mg/kg (0.6 mg) NSPS in 0.05 mL saline or vehicle (0.05 mL saline).…”

Section: Methodsmentioning

confidence: 99%

Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift

Tantawy,

McIntyre,

Yull

et al. 2024

Cancer Medicine

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BackgroundIt has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth. Additionally, acidosis in the TME has been reported to play a key role in selecting for a more aggressive tumor phenotype, drug resistance and desensitization to immunotherapy for many types of cancers. TME‐HAP is an attractive target for tumor detection and treatment development since HAP is generally absent from normal soft tissue. We provide strong evidence that dissolution of hydroxyapatite (HAP) within the tumor microenvironment (TME‐HAP) using a novel therapeutic can be used to kill cancer cells both in vitro and in vivo with minimal adverse effects.MethodsWe developed an injectable cation exchange nano particulate sulfonated polystyrene solution (NSPS) that we engineered to dissolve TME‐HAP, inducing localized acute alkalosis and inhibition of tumor growth and glucose metabolism. This was evaluated in cell culture using 4T1, MDA‐MB‐231 triple negative breast cancer cells, MCF10 normal breast cells, and H292 lung cancer cells, and in vivo using orthotopic mouse models of cancer that contained detectable microenvironment HAP including breast (MMTV‐Neu, 4T1, and MDA‐MB‐231), prostate (PC3) and colon (HCA7) cancer using 18F‐NaF for HAP and 18F‐FDG for glucose metabolism with PET imaging. On the other hand, H292 lung tumor cells that lacked detectable microenvironment HAP and MCF10a normal breast cells that do not produce HAP served as negative controls. Tumor microenvironment pH levels following injection of NSPS were evaluated via Chemical Exchange Saturation (CEST) MRI and via ex vivo methods.ResultsWithin 24 h of adding the small concentration of 1X of NSPS (~7 μM), we observed significant tumor cell death (~ 10%, p < 0.05) in 4T1 and MDA‐MB‐231 cell cultures that contain HAP but ⟨2% in H292 and MCF10a cells that lack detectable HAP and in controls. Using CEST MRI, we found extracellular pH (pHe) in the 4T1 breast tumors, located in the mammary fat pad, to increase by nearly 10% from baseline before gradually receding back to baseline during the first hour post NSPS administration. in the tumors that contained TME‐HAP in mouse models, MMTV‐Neu, 4T1, and MDA‐MB‐231, PC3, and HCA7, there was a significant reduction (p<0.05) in 18F‐Na Fuptake post NSPS treatment as expected; 18F‐ uptake in the tumor = 3.8 ± 0.5 %ID/g (percent of the injected dose per gram) at baseline compared to 1.8 ±0.5 %ID/g following one‐time treatment with 100 mg/kg NSPS. Of similar importance, is that 18F‐FDG uptake in the tumors was reduced by more than 75% compared to baseline within 24 h of treatment with one‐time NSPS which persisted for at least one week. Additionally, tumor growth was significantly slower (p < 0.05) in the mice treated with one‐time NSPS. Toxicity showed no evidence of any adverse effects, a finding attributed to the absence of HAP in normal soft tissue and to our therapeutic NSPS having limited penetration to access HAP within skeletal bone.ConclusionDissolution of TME‐HAP using our novel NSPS has the potential to provide a new treatment paradigm to enhance the management of cancer patients with poor prognosis.

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Section: Methodsmentioning

confidence: 99%

Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift

Tantawy,

McIntyre,

Yull

et al. 2024

Cancer Medicine

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“…AcidoCEST MRI has demonstrated effectiveness in measuring pHe through many preclinical studies [6][7][8][9][10][11][12][13][14][15][16][17][18][19] and preliminary clinical tests. [20][21][22][23] The image contrast of chemical exchange saturation transfer (CEST) MRI is dependent on the chemical exchange rate, k ex , of a proton that transfers from an exogenous or endogenous agent to water.…”

Section: Introductionmentioning

confidence: 99%

“…To address these limitations, we have developed an advanced analysis method using the Bloch-McConnell equations that include k ex when describing the evolution of magnetization during MRI acquisition methods. [15][16][17][18][19]23 We have modified these equations to substitute pH for k ex , so that we can iteratively fit our modified Bloch-McConnell equations to Z-spectra from acidoCEST MR image acquisitions. This method has the advantage of employing the entire Z-spectrum for the analysis, rather than only using the CEST contrast at 4.2 and 5.6 ppm.…”

Section: Introductionmentioning

confidence: 99%

A machine learning approach that measures pH using acidoCEST MRI of iopamidol

Li,

Cárdenas‐Rodríguez,

Trakru

et al. 2023

NMR in Biomedicine

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Tumor acidosis is an important biomarker for aggressive tumors, and extracellular pH (pHe) of the tumor microenvironment can be used to predict and evaluate tumor responses to chemotherapy and immunotherapy. AcidoCEST MRI measures tumor pHe by exploiting the pH‐dependent chemical exchange saturation transfer (CEST) effect of iopamidol, an exogenous CT agent repurposed for CEST MRI. However, all pH fitting methodologies for acidoCEST MRI data have limitations. Herein we present results of the application of machine learning for extracting pH values from CEST Z‐spectra of iopamidol. We acquired 36,000 experimental CEST spectra from 200 phantoms of iopamidol prepared at five concentrations, five T1 values, and eight pH values at five temperatures, acquired at six saturation powers and six saturation times. We also acquired T1, T2, B1 RF power, and B0 magnetic field strength supplementary MR information. These MR images were used to train and validate machine learning models for the tasks of pH classification and pH regression. Specifically, we tested the L1‐penalized logistic regression classification (LRC) model and the random forest classification (RFC) model for classifying the CEST Z‐spectra for thresholds at pH 6.5 and 7.0. Our results showed that both RFC and LRC were effective for pH classification, although the RFC model achieved higher predictive value, and improved the accuracy of classification accuracy with CEST Z‐spectra with a more limited set of saturation frequencies. Furthermore, we used LASSO and random forest regression (RFR) models to explore pH regression, which showed that the RFR model achieved higher accuracy and precision for estimating pH across the entire pH range of 6.2–7.3, especially when using a more limited set of features. Based on these results, machine learning for analysis of acidoCEST MRI is promising for eventual in vivo determination of tumor pHe.

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“…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%

“…For example, the natural exchangeable protons of computed tomography (CT) CAs have been successfully repurposed as pH-sensitive CEST CAs for tumor pH imaging. 20,21 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 22 and radiation necrosis from tumor recurrence. 23−25 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%

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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AcidoCEST MRI Evaluates the Bone Microenvironment in Multiple Myeloma

Cited by 6 publications

References 40 publications

Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift

Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift

A machine learning approach that measures pH using acidoCEST MRI of iopamidol

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

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