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

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.

A Biomimetic Tumor Model of Heterogeneous Invasion in Pancreatic Ductal Adenocarcinoma

“…Creating tumor models that mimic this heterogeneity in a reliable manner is extremely challenging. Recent developments of engineered tumor models show a great promise to recapitulate a 3D microenvironment to study the TME. However, many of these in vitro models have used isogenic cancer cells, which significantly hamper the capability of mimicking true heterogeneity found in the disease.…”

Physical constraints on accuracy and persistence during breast cancer cell chemotaxis

“…Cell behaviors were captured every 15 minutes for 9 hours using an inverted microscope (Olympus IX71, Japan) equipped with a stage top incubator as described previously [56][57][58], so that the microfluidic platform could be maintained at 37 • C in a 5% CO 2 environment during imaging. The time-lapse imaging was started 3 hours after applying TGF-β1 solution in the source channel to have sufficient adjusting time.…”

Targeting CD44 by CRISPR-Cas9 in Multi-Drug Resistant Osteosarcoma Cells

“…CD44 expression is also considered as an important biomarker to predict the sensitivity of chemotherapy in ovarian cancer, fibrosarcoma and Gastric cancer [8,46,48]. And CD44 abnormal expression can directly affect the emergence of drug-resistant phenotype [49,50]. CD44 receptor levels in many drug-resistant cancer cells were significantly increased [51].…”