Probing drug delivery and mechanisms of action in 3D spheroid cells by quantitative analysis

Chae Eun Heo; Areum Hong; Minji Kim; Jong Wha Lee; Soo Yeon Chae; Ki Woong Sung; Ji Won Lee; Sung Woo Heo; Hugh I. Kim

doi:10.1039/d0an01518k

Probing drug delivery and mechanisms of action in 3D spheroid cells by quantitative analysis

Chae Eun Heo, Areum Hong, Minji Kim, Jong Wha Lee, Soo Yeon Chae, Ki Woong Sung, Ji Won Lee, Sung Woo Heo, Hugh I. Kim

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Human tumor cells in a 3-dimensional (3D) spheroid can reflect the characteristics of solid tumors by forming cell-cell interactions and microenvironments. This makes 3D cell culture useful for preclinical stability and drug efficacy tests. In this study, the drug delivery and action mechanisms in SK-N-SH neuroblastoma cells cultured in 3D spheroids were quantitatively compared to those cultured in 2D monolayers using confocal microscopy imaging and inductively coupled plasma-mass spectrometry. In the 3D spheroids, cisplatin only accessed the surface, accumulating in the cells on the spheroid exterior. As a result, an increased cellular amount of cisplatin was required to obtain similar cytotoxicity in the 3D spheroid cells to that in 2D monolayers. The mechanisms of reduction of drug efficacy by dimethyl sulfoxide (DMSO) in the 3D spheroid cells compared to those in the 2D monolayer cells were further investigated. DMSO reduced the drug cytotoxicity by forming stable DMSO-substituted compounds that inhibited the cellular uptake of cisplatin and DNA-Pt adduct formation. The quantitative analysis used in this study is promising for understanding drug delivery and drug action mechanisms in cells in various microenvironments.

Original language	English
Pages (from-to)	7687-7694
Number of pages	8
Journal	Analyst
Volume	145
Issue number	23
DOIs	https://doi.org/10.1039/d0an01518k
Publication status	Published - 2020 Dec 7

Bibliographical note

Funding Information:
This research was supported by the “Establishment of measurement standards for amount of substance” funded by the Korea Research Institute of Standards and Science (KRISS-2019-GP2019-0006). This work was also supported by the NRF of Korea (2019R1A2C2086193) and the Korea University Future Research Grant. In addition, it was supported by grants from the Korea Basic Science Institute (KBSI) National Research Facilities & Equipment Center (NFEC), funded by the Korean government (Ministry of Education) (2019R1A6C1010028). The authors acknowledge the Korea Research Institute of Standards and Science (KRISS) for ICP-MS measurements and Korea Basic Science Institute (KBSI) for confocal microscopy analysis.

Publisher Copyright:
© The Royal Society of Chemistry.

ASJC Scopus subject areas

Analytical Chemistry
Biochemistry
Environmental Chemistry
Spectroscopy
Electrochemistry

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10.1039/d0an01518k

Cite this

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title = "Probing drug delivery and mechanisms of action in 3D spheroid cells by quantitative analysis",

abstract = "Human tumor cells in a 3-dimensional (3D) spheroid can reflect the characteristics of solid tumors by forming cell-cell interactions and microenvironments. This makes 3D cell culture useful for preclinical stability and drug efficacy tests. In this study, the drug delivery and action mechanisms in SK-N-SH neuroblastoma cells cultured in 3D spheroids were quantitatively compared to those cultured in 2D monolayers using confocal microscopy imaging and inductively coupled plasma-mass spectrometry. In the 3D spheroids, cisplatin only accessed the surface, accumulating in the cells on the spheroid exterior. As a result, an increased cellular amount of cisplatin was required to obtain similar cytotoxicity in the 3D spheroid cells to that in 2D monolayers. The mechanisms of reduction of drug efficacy by dimethyl sulfoxide (DMSO) in the 3D spheroid cells compared to those in the 2D monolayer cells were further investigated. DMSO reduced the drug cytotoxicity by forming stable DMSO-substituted compounds that inhibited the cellular uptake of cisplatin and DNA-Pt adduct formation. The quantitative analysis used in this study is promising for understanding drug delivery and drug action mechanisms in cells in various microenvironments.",

author = "Heo, {Chae Eun} and Areum Hong and Minji Kim and Lee, {Jong Wha} and Chae, {Soo Yeon} and Sung, {Ki Woong} and Lee, {Ji Won} and Heo, {Sung Woo} and Kim, {Hugh I.}",

note = "Funding Information: This research was supported by the “Establishment of measurement standards for amount of substance” funded by the Korea Research Institute of Standards and Science (KRISS-2019-GP2019-0006). This work was also supported by the NRF of Korea (2019R1A2C2086193) and the Korea University Future Research Grant. In addition, it was supported by grants from the Korea Basic Science Institute (KBSI) National Research Facilities & Equipment Center (NFEC), funded by the Korean government (Ministry of Education) (2019R1A6C1010028). The authors acknowledge the Korea Research Institute of Standards and Science (KRISS) for ICP-MS measurements and Korea Basic Science Institute (KBSI) for confocal microscopy analysis. Publisher Copyright: {\textcopyright} The Royal Society of Chemistry.",

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T1 - Probing drug delivery and mechanisms of action in 3D spheroid cells by quantitative analysis

AU - Heo, Chae Eun

AU - Hong, Areum

AU - Kim, Minji

AU - Lee, Jong Wha

AU - Chae, Soo Yeon

AU - Sung, Ki Woong

AU - Lee, Ji Won

AU - Heo, Sung Woo

AU - Kim, Hugh I.

N1 - Funding Information: This research was supported by the “Establishment of measurement standards for amount of substance” funded by the Korea Research Institute of Standards and Science (KRISS-2019-GP2019-0006). This work was also supported by the NRF of Korea (2019R1A2C2086193) and the Korea University Future Research Grant. In addition, it was supported by grants from the Korea Basic Science Institute (KBSI) National Research Facilities & Equipment Center (NFEC), funded by the Korean government (Ministry of Education) (2019R1A6C1010028). The authors acknowledge the Korea Research Institute of Standards and Science (KRISS) for ICP-MS measurements and Korea Basic Science Institute (KBSI) for confocal microscopy analysis. Publisher Copyright: © The Royal Society of Chemistry.

PY - 2020/12/7

Y1 - 2020/12/7

N2 - Human tumor cells in a 3-dimensional (3D) spheroid can reflect the characteristics of solid tumors by forming cell-cell interactions and microenvironments. This makes 3D cell culture useful for preclinical stability and drug efficacy tests. In this study, the drug delivery and action mechanisms in SK-N-SH neuroblastoma cells cultured in 3D spheroids were quantitatively compared to those cultured in 2D monolayers using confocal microscopy imaging and inductively coupled plasma-mass spectrometry. In the 3D spheroids, cisplatin only accessed the surface, accumulating in the cells on the spheroid exterior. As a result, an increased cellular amount of cisplatin was required to obtain similar cytotoxicity in the 3D spheroid cells to that in 2D monolayers. The mechanisms of reduction of drug efficacy by dimethyl sulfoxide (DMSO) in the 3D spheroid cells compared to those in the 2D monolayer cells were further investigated. DMSO reduced the drug cytotoxicity by forming stable DMSO-substituted compounds that inhibited the cellular uptake of cisplatin and DNA-Pt adduct formation. The quantitative analysis used in this study is promising for understanding drug delivery and drug action mechanisms in cells in various microenvironments.

AB - Human tumor cells in a 3-dimensional (3D) spheroid can reflect the characteristics of solid tumors by forming cell-cell interactions and microenvironments. This makes 3D cell culture useful for preclinical stability and drug efficacy tests. In this study, the drug delivery and action mechanisms in SK-N-SH neuroblastoma cells cultured in 3D spheroids were quantitatively compared to those cultured in 2D monolayers using confocal microscopy imaging and inductively coupled plasma-mass spectrometry. In the 3D spheroids, cisplatin only accessed the surface, accumulating in the cells on the spheroid exterior. As a result, an increased cellular amount of cisplatin was required to obtain similar cytotoxicity in the 3D spheroid cells to that in 2D monolayers. The mechanisms of reduction of drug efficacy by dimethyl sulfoxide (DMSO) in the 3D spheroid cells compared to those in the 2D monolayer cells were further investigated. DMSO reduced the drug cytotoxicity by forming stable DMSO-substituted compounds that inhibited the cellular uptake of cisplatin and DNA-Pt adduct formation. The quantitative analysis used in this study is promising for understanding drug delivery and drug action mechanisms in cells in various microenvironments.

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Probing drug delivery and mechanisms of action in 3D spheroid cells by quantitative analysis

Abstract

Bibliographical note

ASJC Scopus subject areas

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