Quantification of Methotrexate in Human Serum Using Surface-Enhanced Raman Scattering—Toward Therapeutic Drug Monitoring

Yaman Göksel; Kinga Zor; Tomas Rindzevicius; Bodil Elise Thorhauge Als-Nielsen; Kjeld Schmiegelow; Anja Boisen

doi:10.1021/acssensors.1c00643

Quantification of Methotrexate in Human Serum Using Surface-Enhanced Raman Scattering—Toward Therapeutic Drug Monitoring

Yaman Göksel^*, Kinga Zor, Tomas Rindzevicius, Bodil Elise Thorhauge Als-Nielsen, Kjeld Schmiegelow, Anja Boisen

^*Corresponding author for this work

Department of Health Technology

University of Copenhagen

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

Therapeutic drug monitoring (TDM) can improve clinical care when using drugs with pharmacokinetic variability and a narrow therapeutic window. Rapid, reliable, and easy-to-use detection methods are required in order to decrease the time of analysis and can also enable TDM in resource-limited settings or even at bedside. Monitoring methotrexate (MTX), an anticancer drug, is critical since it is needed to follow the drug clearance rate and decide how to administer the rescue drug, leucovorin (LV), in order to avoid toxicity and even death. We show that with the optimized nanopillar-assisted separation (NPAS) method using surface-enhanced Raman scattering, we were able to measure MTX in PBS and serum in the linear range of 5-150 μM and confirmed that MTX detection can be carried out even in the presence of LV. Additionally, when NPAS was combined with centrifugal filtration, a quantification limit of 2.1 μM for MTX in human serum sample was achieved. The developed detection method enables fast detection (10 min) and quantification of MTX from human serum (>90% accuracy). Furthermore, we show the potential of the developed method for TDM, when quantifying MTX from clinical samples, collected from patients who are undergoing high-dose MTX therapy.

Original language	English
Journal	ACS Sensors
Volume	6
Issue number	7
Pages (from-to)	2664-2673
ISSN	2379-3694
DOIs	https://doi.org/10.1021/acssensors.1c00643
Publication status	Published - 2021

Bibliographical note

Funding Information:
Y.G. acknowledges Elodie Dumont, Ph.D. for guidance and advice provided during the quantification of MTX from clinical samples and Lasse H. E. Thamdrup for SERS substrate fabrication and optimization. Y.G., K.Z., T.R., and A.B. acknowledge financial support from the Danish National Research Foundation (DNRF122), the Villum Fonden (grant no. 9301) for Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics (IDUN), and the BioInnovation Institute Foundation for Therapeutic Drug Monitoring (grant no. NNF20SA0063552). K.S. acknowledges financial support from the Danish Cancer Society (grant no. R257-A14720) and the Danish Childhood Cancer Foundation (grant nos. 2019-5934 and 2020-6759).

Keywords

Methotrexate
Patient samples
Point-of-care detection
Quantitative SERS
Surface-enhanced Raman scattering
Therapeutic drug monitoring

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title = "Quantification of Methotrexate in Human Serum Using Surface-Enhanced Raman Scattering—Toward Therapeutic Drug Monitoring",

abstract = "Therapeutic drug monitoring (TDM) can improve clinical care when using drugs with pharmacokinetic variability and a narrow therapeutic window. Rapid, reliable, and easy-to-use detection methods are required in order to decrease the time of analysis and can also enable TDM in resource-limited settings or even at bedside. Monitoring methotrexate (MTX), an anticancer drug, is critical since it is needed to follow the drug clearance rate and decide how to administer the rescue drug, leucovorin (LV), in order to avoid toxicity and even death. We show that with the optimized nanopillar-assisted separation (NPAS) method using surface-enhanced Raman scattering, we were able to measure MTX in PBS and serum in the linear range of 5-150 μM and confirmed that MTX detection can be carried out even in the presence of LV. Additionally, when NPAS was combined with centrifugal filtration, a quantification limit of 2.1 μM for MTX in human serum sample was achieved. The developed detection method enables fast detection (10 min) and quantification of MTX from human serum (>90% accuracy). Furthermore, we show the potential of the developed method for TDM, when quantifying MTX from clinical samples, collected from patients who are undergoing high-dose MTX therapy.",

keywords = "Methotrexate, Patient samples, Point-of-care detection, Quantitative SERS, Surface-enhanced Raman scattering, Therapeutic drug monitoring",

author = "Yaman G{\"o}ksel and Kinga Zor and Tomas Rindzevicius and {Thorhauge Als-Nielsen}, {Bodil Elise} and Kjeld Schmiegelow and Anja Boisen",

note = "Funding Information: Y.G. acknowledges Elodie Dumont, Ph.D. for guidance and advice provided during the quantification of MTX from clinical samples and Lasse H. E. Thamdrup for SERS substrate fabrication and optimization. Y.G., K.Z., T.R., and A.B. acknowledge financial support from the Danish National Research Foundation (DNRF122), the Villum Fonden (grant no. 9301) for Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics (IDUN), and the BioInnovation Institute Foundation for Therapeutic Drug Monitoring (grant no. NNF20SA0063552). K.S. acknowledges financial support from the Danish Cancer Society (grant no. R257-A14720) and the Danish Childhood Cancer Foundation (grant nos. 2019-5934 and 2020-6759). ",

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AU - Göksel, Yaman

AU - Zor, Kinga

AU - Rindzevicius, Tomas

AU - Thorhauge Als-Nielsen, Bodil Elise

AU - Schmiegelow, Kjeld

AU - Boisen, Anja

N1 - Funding Information: Y.G. acknowledges Elodie Dumont, Ph.D. for guidance and advice provided during the quantification of MTX from clinical samples and Lasse H. E. Thamdrup for SERS substrate fabrication and optimization. Y.G., K.Z., T.R., and A.B. acknowledge financial support from the Danish National Research Foundation (DNRF122), the Villum Fonden (grant no. 9301) for Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics (IDUN), and the BioInnovation Institute Foundation for Therapeutic Drug Monitoring (grant no. NNF20SA0063552). K.S. acknowledges financial support from the Danish Cancer Society (grant no. R257-A14720) and the Danish Childhood Cancer Foundation (grant nos. 2019-5934 and 2020-6759).

PY - 2021

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N2 - Therapeutic drug monitoring (TDM) can improve clinical care when using drugs with pharmacokinetic variability and a narrow therapeutic window. Rapid, reliable, and easy-to-use detection methods are required in order to decrease the time of analysis and can also enable TDM in resource-limited settings or even at bedside. Monitoring methotrexate (MTX), an anticancer drug, is critical since it is needed to follow the drug clearance rate and decide how to administer the rescue drug, leucovorin (LV), in order to avoid toxicity and even death. We show that with the optimized nanopillar-assisted separation (NPAS) method using surface-enhanced Raman scattering, we were able to measure MTX in PBS and serum in the linear range of 5-150 μM and confirmed that MTX detection can be carried out even in the presence of LV. Additionally, when NPAS was combined with centrifugal filtration, a quantification limit of 2.1 μM for MTX in human serum sample was achieved. The developed detection method enables fast detection (10 min) and quantification of MTX from human serum (>90% accuracy). Furthermore, we show the potential of the developed method for TDM, when quantifying MTX from clinical samples, collected from patients who are undergoing high-dose MTX therapy.

AB - Therapeutic drug monitoring (TDM) can improve clinical care when using drugs with pharmacokinetic variability and a narrow therapeutic window. Rapid, reliable, and easy-to-use detection methods are required in order to decrease the time of analysis and can also enable TDM in resource-limited settings or even at bedside. Monitoring methotrexate (MTX), an anticancer drug, is critical since it is needed to follow the drug clearance rate and decide how to administer the rescue drug, leucovorin (LV), in order to avoid toxicity and even death. We show that with the optimized nanopillar-assisted separation (NPAS) method using surface-enhanced Raman scattering, we were able to measure MTX in PBS and serum in the linear range of 5-150 μM and confirmed that MTX detection can be carried out even in the presence of LV. Additionally, when NPAS was combined with centrifugal filtration, a quantification limit of 2.1 μM for MTX in human serum sample was achieved. The developed detection method enables fast detection (10 min) and quantification of MTX from human serum (>90% accuracy). Furthermore, we show the potential of the developed method for TDM, when quantifying MTX from clinical samples, collected from patients who are undergoing high-dose MTX therapy.

KW - Methotrexate

KW - Patient samples

KW - Point-of-care detection

KW - Quantitative SERS

KW - Surface-enhanced Raman scattering

KW - Therapeutic drug monitoring

U2 - 10.1021/acssensors.1c00643

DO - 10.1021/acssensors.1c00643

M3 - Journal article

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SN - 2379-3694

VL - 6

SP - 2664

EP - 2673

JO - ACS Sensors

JF - ACS Sensors

IS - 7

ER -

Quantification of Methotrexate in Human Serum Using Surface-Enhanced Raman Scattering—Toward Therapeutic Drug Monitoring

Abstract

Bibliographical note

Keywords

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