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.

Understanding progression of breast cancers to invasive ductal carcinoma (IDC) can significantly improve breast cancer treatments. However, it is still difficult to identify genetic signatures and the role of tumor microenvironment to distinguish pathological stages of preinvasive lesion and IDC. Presence of multiple subtypes of breast cancers makes the assessment more challenging. In this study, an in-vitro microfluidic assay was developed to quantitatively assess the subtype-specific invasion potential of breast cancers. The developed assay is a microfluidic platform in which a ductal structure of epithelial cancer cells is surrounded with a three-dimensional (3D) collagen matrix. In the developed platform, two triple negative cancer subtypes (MDA-MB-231 and SUM-159PT) invaded into the surrounding matrix but the luminal A subtype, MCF-7, did not. Among invasive subtypes, SUM-159PT cells showed significantly higher invasion and degradation of the surrounding matrix than MDA-MB-231. Interestingly, the cells cultured on the platform expressed higher levels of CD24 than in their conventional 2D cultures. This microfluidic platform may be a useful tool to characterize and predict invasive potential of breast cancer subtypes or patient-derived cells.

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