Scalable Multiplexed Drugâ Combination Screening Platforms Using 3D Microtumor Model for Precision Medicine

Abstract

Cancer heterogeneity is a notorious hallmark of this disease, and it is desirable to tailor effective treatments for each individual patient. Drug combinations have been widely accepted in cancer treatment for better therapeutic efficacy as compared to a single compound. However, experimental complexity and cost grow exponentially with more target compounds under investigation. The primary challenge remains to efficiently perform a largeâ scale drug combination screening using a small number of patient primary samples for testing. Here, a scalable, easyâ toâ use, highâ throughput drug combination screening scheme is reported, which has the potential of screening all possible pairwise drug combinations for arbitrary number of drugs with multiple logarithmic mixing ratios. A â Christmas tree mixerâ structure is introduced to generate a logarithmic concentration mixing ratio between drug pairs, providing a large drug concentration range for screening. A threeâ layer structure design and special inlets arrangement facilitate simple drug loading process. As a proof of concept, an 8â drug combination chip is implemented, which is capable of screening 172 different treatment conditions over 1032 3D cancer spheroids on a single chip. Using both cancer cell lines and patientâ derived cancer cells, effective drug combination screening is demonstrated for precision medicine.Combination drug treatment has been widely accepted for better cancer therapeutic efficacy, yet the discovery of combinations is hindered by experimental complexity. A combinatorial drug screening platform is developed, covering all pairwise combinations of 8 drugs with multiple mixing ratios in a linear/logarithmic scale. It facilitates the discovery of synergistic drug combinations by allowing over 1000 experiments per chip at once.