Search

For treating cancer at various stages, chemotherapy drugs administered in combination provide better treatment results with lower side effects compared to single-drug therapy. However, finding the potential drug combinations has been challenging due to the large numbers of possible combinations from approved drugs and the failure of in vitro 2D well plate-based cancer models. 3D spheroid-based high-throughput microfluidic platforms recapitulate some of the important features of native tumor tissue and offer a promising alternative to evaluate the combinatory effects of the drugs. This study develops a novel polydimethylsiloxane (PDMS) based microfluidic design with a dynamic environment and strategically placed U-shaped wells for testing all seven possible combinations (three single-drug treatments, three pairwise combinations, treatment with all three drugs) of three chemotherapy drugs (Paclitaxel, Vinorelbine, and Etoposide) on lung tumor spheroids. The design of U-shaped wells has been validated with computational results. Firstly, we test all combinations of drugs on the conventional well plate in static conditions with 3D tumor spheroids. Based on static drug testing results, we show a proof-of-concept by testing the most effective drug combination on the microfluidic device in a dynamic environment. The concentration of the drugs used in combination falls below the maximum tolerated dose (MTD) of the individual drugs, towards low dose metronomic (LDM) chemotherapy. LDM combinatorial chemotherapy identified in this study can potentially lower toxicity and provide better treatment results in cancer patients. The device can be further used to culture patient-specific tumor spheroids and identify synergistic drug combinations for personalized medicine., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

[Display omitted] • Osteo-specific matrix directs osteogenic differentiation and immunomodulation. • Osteoniche-on-a-chip demonstrates invasion in absence of exogenous chemoattractants. • The co-culture reveals differential invasive phenotypes and drug resistance. • Personalized osteotropism of CSCs revealed at the inter-tumor level. Cancer cell invasion to the surrounding extracellular matrix contributes to distant metastasis. There are no predictive models that focus on the accuracy of secondary site-infiltrative pattern. The degree of cancer invasion is regulated by receptive pre-metastatic niche. Herein, we show the feasibility of real time three-dimensional (3D) tissue-specific invasion of cancer stem like-cells (CSCs) from two different primary tumors employing a microfluidic device. An osteo-specific matrix (Osteomatrix-Collagen I, Os-Col) allows 3D osteogenic culture proven by differentiation of human adipose derived mesenchymal cells (ADSCs) into an osteoblastic lineage. In vitro enriched CSC-like cells (EpCAM+/CD44+/CD24− phenotype) derived from primary culture of oral squamous carcinoma and breast adenocarcinoma were used to demonstrate the differential strategy adopted for tumor progression. Morphological and viability parameters of the CSCs were monitored to assess the robustness as a realistic platform for in vitro osteotropic assay. Spatio-temporal elevated invasion into the osteo-specific matrix was evident in Os-Col compared to conventional collagen gel. Drug screening on co-cultures of CSC-like cells and osteoblasts exhibited drug resistance. Overall, this work demonstrates that the proposed microfluidic chip with bone-specific ECM can efficiently replicate in vitro biochemical conditions for distinguishing tissue-specific invasive phenotype and screening drug resistance. This may serve as a tool to systematically examine the contribution of the bone microenvironment on the progression of various primary cancers to predict its invasive form, advancing personalized therapies. [ABSTRACT FROM AUTHOR]