Scalable Multiplexed Drug‐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 large‐scale drug combination screening using a small number of patient primary samples for testing. Here, a scalable, easy‐to‐use, high‐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 “Christmas tree mixer” structure is introduced to generate a logarithmic concentration mixing ratio between drug pairs, providing a large drug concentration range for screening. A three‐layer structure design and special inlets arrangement facilitate simple drug loading process. As a proof of concept, an 8‐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 patient‐derived cancer cells, effective drug combination screening is demonstrated for precision medicine.

Advanced Devices for Tumor Diagnosis and Therapy

“…A logarithmic concentration gradient producer was proposed, providing a wider dynamic concentration range rather than a linear gradient producer. [78] Akay et al reported the use of a brain cancer chip to release two clinical drugs in the treatment of glioblastoma. The concentration gradient generated by the multiple microfluidic channels in the chip allowed the delivery of anticancer drugs at different concentrations.…”

Phenotype-related drug sensitivity analysis of single CTCs for medicine evaluation

“…Most drug screening approaches generally rely on large-scale studies in populations with heterogeneity in individual patient differences. [4][5][6] However, this approach is still not ideal, because the results are obtained based on bulk analysis of a large number of cells, which neglects cellular heterogeneity within a patient, leading to the masking of specic cell information. To solve this problem, several single-cell drug screening systems for the analysis of cancer cell lines were established.…”

A simple microsphere‐based mold to rapidly fabricate microwell arrays for multisize 3D tumor culture

“…Over the past decades, traditional cell culture methods such as surface modification (Cui et al, 2019; Fukuda & Nakazawa, 2011), spinner flask (Friedrich, Ebner, & Kunz‐Schughart, 2007), microfluidic (Jin, Cho, Gu, Kim, & Oh, 2011; Liu et al, 2016; Zhang et al, 2018), handing drop (Antunes et al, 2019; Kwak, Lee, Lee, Lee, & Lim, 2018; Liu, Sun et al, 2019; Zhao et al, 2017), and liquid marbles (Vadivelu, Kamble, Munaz, & Nguyen, 2017; Vadivelu et al, 2015) have been widely applied to generate 3D tumors. However, each method has advantages and limitations (Breslin & O'Driscoll, 2013).…”