A fast screening model for drug permeability assessment based on native small intestinal extracellular matrix

Area of Science:

• Biomedical Engineering
• Pharmacology
• Cell Biology

Background:

• The Caco-2 cell monolayer is a standard model for predicting intestinal drug permeability.
• Conventional Caco-2 models require 21 days for maturation, limiting drug discovery throughput.
• There is a need for faster, more physiologically relevant drug permeability screening models.

Purpose of the Study:

• To develop and validate a rapid (7-day) Caco-2 cell model for drug permeability screening.
• To assess the physiological relevance and predictive capability of the accelerated model.
• To investigate the role of small intestinal submucosa (SIS) hydrogel in Caco-2 cell differentiation.

Main Methods:

• Integration of Caco-2 cells with a small intestinal submucosa (SIS) hydrogel to form a 7-day monolayer.
• Evaluation of monolayer integrity via paracellular resistance and alkaline phosphatase (ALP) activity.
• Assessment of transporter expression (PEPT1, OATP1A2, P-gp, BCRP, MRP2) and function.
• Correlation analysis of apparent permeability (Papp) values between the 7-day and 21-day models.

Main Results:

• The 7-day SIS-integrated model achieved comparable phenotype and function to the 21-day model.
• Enhanced expression and function of excretory transporters (BCRP, MRP2) were observed in the 7-day model.
• A strong correlation (r^2 = 0.9458) was found between drug permeability values in the 7-day and 21-day models.
• SIS hydrogel facilitated Caco-2 cell differentiation, enabling accelerated model development.

Conclusions:

• The 7-day SIS-integrated Caco-2 model is a rapid and physiologically relevant alternative to the conventional 21-day model.
• This accelerated model maintains predictive accuracy for drug permeability.
• The developed model offers a promising tool to enhance efficiency in drug discovery screening.