Differential response to doxorubicin in breast cancer subtypes simulated by a microfluidic tumor model

Altug Ozcelikkale, Kyeonggon Shin, Victoria Noe-Kim, Bennett D. Elzey, Zizheng Dong, Jian-Ting Zhang, Kwangmeyung Kim, Ick Chan Kwon, Kinam Park, Bumsoo Han

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Successful drug delivery and overcoming drug resistance are the primary clinical challenges for management and treatment of cancer. The ability to rapidly screen drugs and delivery systems within physiologically relevant environments is critically important; yet is currently limited due to lack of appropriate tumor models. To address this problem, we developed the Tumor-microenvironment-on-chip (T-MOC), a new microfluidic tumor model simulating the interstitial flow, plasma clearance, and transport of the drug within the tumor. We demonstrated T-MOC's capabilities by assessing the delivery and efficacy of doxorubicin in small molecular form versus hyaluronic acid nanoparticle (NP) formulation in MCF-7 and MDA-MB-231, two cell lines representative of different molecular subtypes of breast cancer. Doxorubicin accumulated and penetrated similarly in both cell lines while the NP accumulated more in MDA-MB-231 than MCF-7 potentially due to binding of hyaluronic acid to CD44 expressed by MDA-MB-231. However, the penetration of the NP was less than the molecular drug due to its larger size. In addition, both cell lines cultured on the T-MOC showed increased resistance to the drug compared to 2D culture where MDA-MB-231 attained a drug-resistant tumor-initiating phenotype indicated by increased CD44 expression. When grown in immunocompromised mice, both cell lines exhibited cell-type-dependent resistance and phenotypic changes similar to T-MOC, confirming its predictive ability for in vivo drug response. This initial characterization of T-MOC indicates its transformative potential for in vitro testing of drug efficacy towards prediction of in vivo outcomes and investigation of drug resistance mechanisms for advancement of personalized medicine.

Original languageEnglish (US)
Pages (from-to)129-139
Number of pages11
JournalJournal of Controlled Release
Volume266
DOIs
StatePublished - Nov 28 2017

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Microfluidics
Doxorubicin
Tumor Microenvironment
Breast Neoplasms
Drug Resistance
Pharmaceutical Preparations
Nanoparticles
Cell Line
Neoplasms
Hyaluronic Acid
Precision Medicine
Drug Delivery Systems
Phenotype

Keywords

  • Breast cancer
  • Cancer stem cell
  • Chemoresistance
  • Doxorubicin
  • Drug transport
  • Tumor-microenvironment-on-chip

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Differential response to doxorubicin in breast cancer subtypes simulated by a microfluidic tumor model. / Ozcelikkale, Altug; Shin, Kyeonggon; Noe-Kim, Victoria; Elzey, Bennett D.; Dong, Zizheng; Zhang, Jian-Ting; Kim, Kwangmeyung; Kwon, Ick Chan; Park, Kinam; Han, Bumsoo.

In: Journal of Controlled Release, Vol. 266, 28.11.2017, p. 129-139.

Research output: Contribution to journalArticle

Ozcelikkale, A, Shin, K, Noe-Kim, V, Elzey, BD, Dong, Z, Zhang, J-T, Kim, K, Kwon, IC, Park, K & Han, B 2017, 'Differential response to doxorubicin in breast cancer subtypes simulated by a microfluidic tumor model', Journal of Controlled Release, vol. 266, pp. 129-139. https://doi.org/10.1016/j.jconrel.2017.09.024
Ozcelikkale, Altug ; Shin, Kyeonggon ; Noe-Kim, Victoria ; Elzey, Bennett D. ; Dong, Zizheng ; Zhang, Jian-Ting ; Kim, Kwangmeyung ; Kwon, Ick Chan ; Park, Kinam ; Han, Bumsoo. / Differential response to doxorubicin in breast cancer subtypes simulated by a microfluidic tumor model. In: Journal of Controlled Release. 2017 ; Vol. 266. pp. 129-139.
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AU - Shin, Kyeonggon

AU - Noe-Kim, Victoria

AU - Elzey, Bennett D.

AU - Dong, Zizheng

AU - Zhang, Jian-Ting

AU - Kim, Kwangmeyung

AU - Kwon, Ick Chan

AU - Park, Kinam

AU - Han, Bumsoo

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AB - Successful drug delivery and overcoming drug resistance are the primary clinical challenges for management and treatment of cancer. The ability to rapidly screen drugs and delivery systems within physiologically relevant environments is critically important; yet is currently limited due to lack of appropriate tumor models. To address this problem, we developed the Tumor-microenvironment-on-chip (T-MOC), a new microfluidic tumor model simulating the interstitial flow, plasma clearance, and transport of the drug within the tumor. We demonstrated T-MOC's capabilities by assessing the delivery and efficacy of doxorubicin in small molecular form versus hyaluronic acid nanoparticle (NP) formulation in MCF-7 and MDA-MB-231, two cell lines representative of different molecular subtypes of breast cancer. Doxorubicin accumulated and penetrated similarly in both cell lines while the NP accumulated more in MDA-MB-231 than MCF-7 potentially due to binding of hyaluronic acid to CD44 expressed by MDA-MB-231. However, the penetration of the NP was less than the molecular drug due to its larger size. In addition, both cell lines cultured on the T-MOC showed increased resistance to the drug compared to 2D culture where MDA-MB-231 attained a drug-resistant tumor-initiating phenotype indicated by increased CD44 expression. When grown in immunocompromised mice, both cell lines exhibited cell-type-dependent resistance and phenotypic changes similar to T-MOC, confirming its predictive ability for in vivo drug response. This initial characterization of T-MOC indicates its transformative potential for in vitro testing of drug efficacy towards prediction of in vivo outcomes and investigation of drug resistance mechanisms for advancement of personalized medicine.

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