TY - JOUR
T1 - Differential response to doxorubicin in breast cancer subtypes simulated by a microfluidic tumor model
AU - Ozcelikkale, Altug
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
PY - 2017/11/28
Y1 - 2017/11/28
N2 - 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.
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.
KW - Breast cancer
KW - Cancer stem cell
KW - Chemoresistance
KW - Doxorubicin
KW - Drug transport
KW - Tumor-microenvironment-on-chip
UR - http://www.scopus.com/inward/record.url?scp=85030453124&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85030453124&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2017.09.024
DO - 10.1016/j.jconrel.2017.09.024
M3 - Article
C2 - 28939108
AN - SCOPUS:85030453124
VL - 266
SP - 129
EP - 139
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -