Drug Toxicity Screening
In recent years, the number of new chemical entities and screenable drug targets has increased rapidly, but only a few have succeeded. Due to the adverse biological consequences of drug metabolism and induced toxicity, more than 40% of marketed drug candidates were terminated. Early prediction of metabolism and its toxicity is an essential part of the drug development process. By developing in vitro models with better potential for drug toxicity screening and prediction, the pharmacokinetics/pharmacodynamics (PK-PD) and biological activities of potential new compounds can be predicted more accurately.
Current in Vitro Models
Conventional static 2D cell culture includes Petri dishes, well plates, and cell culture flasks. Although they are very powerful tools for rapid and high-throughput screening of one or more parameters, they have the following disadvantages:
- Conventional in vitro models cannot generalize the habitat of cells in vivo, which leads to unreliable toxicity results;
- Conventional 2D models cannot imitate many functions of cells, including cell-to-cell and cell-to-matrix interactions.
- It takes a long time to manually collect metabolites for offline measurement;
- A large number of cells, reagents, and complicated sample pre-processing are required.
Recently, more advanced models incorporating microfluidic technology have been developed to create a biologically relevant environment for cell culture.
Microfluidics has the following advantages: low reagent consumption, easy control, rapid analysis, miniaturization, high integration, and high throughput. It is considered to be an excellent platform for cell-based assays, such as drug metabolism, cell interaction, etc. More importantly, the characterization of drug metabolism and cytotoxicity determination can be achieved on a single device, which will greatly speed up the drug development process.
Multilayer Microfluidic Device for Drug Metabolism and Cytotoxicity
Cytochrome P450 enzymes play a central role in drug metabolism, and more than 75% of human drug enzymatic reactions are catalyzed by them. Human liver microsomes (HLM) are commonly used as carriers for P450. Studies have shown that HLM may be trapped in biocompatible materials. In the 3D microenvironment, higher levels of cell-specific functions can be better retained, which makes the experimental results more reliable and accurate.
Based on new technologies related to drug metabolism and cytotoxicity determination, an integrated microfluidic device has been developed. The device has three functional parts, which can be used for drug metabolism in HLM and high-throughput cell cytotoxicity screening in a 3D culture system.
Fig.1 Microfluidic device for drug metabolism in HLM and high-throughput cell cytotoxicity screening in the 3D culture system. (Wu Q, et al. 2014)
The part containing the micropores is sandwiched between the upper PDMS plate and the PC membrane with a diameter of 0.4 μm for loading HLM. The second part consists of the main channel, a cell culture chamber, and a medium channel connected to a lower height channel for 3D cell culture and drug stimulation. The third part is the integrated micro solid-phase extraction (SPE) channel for sample purification and concentration before mass spectrometry analysis. Using this device can obtain the ability to test drug metabolism and cytotoxicity determination in the same experiment.
Microfluidic Liver-on-A-Chip for Drug Toxicity Testing
In vitro models are essential for screening the absorption, distribution, metabolism, excretion, and toxicity of new formulations. Only a small part of the drugs that showed appropriate ADME toxicity behavior and moved to the next phase of testing eventually appeared on the market. The reason for the failure may be due to the insufficient ability of preclinical in vitro models and animal tests to predict the toxicity levels of new compounds. Therefore, more complex in vitro models of organs affected by drugs is needed, such as the liver.
Fig.2 The microfluidic live-proximal tubule two-organ-chip. (A) Expanded view of the device comprising the PDMS-glass chip. (B) The experimental setup of cocultivation of liver microtissues and renal proximal tubule barriers in the MOC. (Lin N, et al. 2020)
The important feature of the microfluidic tissue chip is the control of the microenvironment and the flow of nutrients and culture media, which can customize the biologically relevant environment according to the needs of the experiment. A liver-on-a-chip device is an excellent example of these microfluidic chips. In a monolithic liver, hepatocytes or co-cultures of hepatocytes and other types of cells in the liver are cultured under highly supervised conditions in a microfluidic chamber. The cells on the liver slice can then be exposed to various compounds and their response can be monitored in real-time.
Do you need to develop a microfluidic chip model for drug toxicity screening, or learn more about the application of microfluidics for toxicity screening? Alfa Chemistry can help you!
- Wu Q, et al. (2014). "Development of A Novel Multi-layer Microfluidic Device Towards Characterization of Drug Metabolism and Cytotoxicity for Drug Dcreening." Chem. Commun. 50: 2762-2764.
- Lin N, et al. (2020). "Repeated Dose Multi-drug Testing Using a Microfluidic Chip-based Coculture of Human Liver and Kidney Proximal Tubules Equivalents." Scientific Reports. 10: 8879.
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