Compound Screening – Capturing More Relevant Information More Efficiently
Article Feb 28, 2017 | By Vicki Glaser
Faster, cheaper, better – the mantra of the screening industry whether using high throughput screening (HTS) or high content screening (HCS) to identify leads and select new drug candidates to take forward into development. Screen compound libraries faster, perhaps using smaller, smarter sets of compounds tested in parallel. Reduce the cost of HTS and HCS through miniaturization. Improve the results of screening by using more relevant cell, tissue, and disease models and software tools that can integrate instrument systems and datasets.
Overall trends in HTS and HCS continue to focus on gathering more and better information in less time at less expense. Following are examples and perspectives on advances and challenges in screening technology.
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3D Tissue Models
Late last year, the U.S. National Institutes of Health awarded MIMETAS and the University of Pittsburgh a SBIR grant to support development of the company's liver-on-a-chip platform for high throughput discovery and development. The goal of the technology is to provide a liver tissue model in a microfluidic device to enable accurate prediction of hepatotoxicity without the need to screen drug compounds in animals.
"Pharma companies realize that most of the preclinical testing they have been doing just isn't good enough," says Jos Joore, PhD, Managing Director and co-founder of MIMETAS. As many as 9 in 10 drug candidates fail in clinical testing, and the majority of this attrition is due to toxicity and efficacy issues. In Joore's view, Pharma needs 3D tissue models that will better allow them to predict more accurately how a compound will function in humans.
Pharma first began evaluating MIMETAS's organ-on-a-chip technology in the toxicology and preclinical setting and has now increasingly been using it to identify new drug compounds with novel capabilities, according to Joore. "Over the last year-and-a-half, we have seen a significant trend toward Pharma wanting to model a specific disease phenotype -- such as vascular fibrosis or complex diseases like Parkinson's or Alzheimer's disease -- in an organ-on-a-chip device to screen compounds," Dr. Joore says. The company's OrganoPlate® technology enables co-culturing of layered levels of different cell types in extracellular matrix within separate but juxtaposed microchambers, allowing the cells to interact with each other and also be continuously perfused with medium.
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Zurich-based CellSpring is developing 3D Bloom® biomimetic microtissues for use in screening to predict the safety and efficacy of drug compounds. 3D Bloom technology is based on a chemical interaction between two biopolymers that crosslink as soon as they come in contact in a microplate well. When cells are added, such as hepatocytes or tumor cells, they become trapped in an environment that closely mimics the physiology and extracellular matrix present in vivo, forming liver or tumor microtissues, respectively, for example.
Cells grown in 2D cultures have very different expression patterns of genes, proteins, and potential drug targets compared to what those cells would be expressing in the body. In 2D culture, the cells are not exposed to the same mechanical influences, external signals, or rates of diffusion, which can all affect gene expression. These factors can be simulated in 3D microtissues. "Especially in tumors, there is a certain distance between the cells and the blood vessels that are carrying a drug," says Chris Millan, PhD, CTO and co-Founder of CellSpring. "You not only have to give the cells the right mechanical environment, but you also have to simulate the way they receive molecules from the vasculature."
The 3D Bloom technology is based on two biopolymers (3DB1 and 3DB2) that crosslink spontaneously after mixing in the presence of cells. After the 30 minutes (middle step), media can be added and a screening is initiated (right). The microscopy image is of human adipose cells stained with Oil red O to visualize their lipid droplets.
CellSpring worked with Tecan to automate the process of drug screening in 3D Bloom microtissues on the Freedom EVO® platform. Automation improves speed, consistency, and throughput, making it possible to screen larger numbers of compounds, and ensures that "there will be no human error so we can be a lot more confident with our results," says Dr. Millan.
The biggest challenge at present is creating microtissue models that incorporate cells typically found in the blood -- white blood cells and other types of immune cells -- the natural environment of which differs from that of solid tumor cells or organs. "It is hard to have properties of both in a simplified in vitro model," says Dr. Millan. "That is where the challenge is, but also where the focus is, and I think it will be solved."
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