Development of a novel in vitro 3D intestinal model for permeability evaluations

Abstract

In this work, a new three-dimensional (3D) in vitro cell model was described, which was comprised of an epithelium, a subepithelial fibroblast network and an extracellular matrix, thereby more closely mimicking the morphology of the small intestine. Transmission electron microscopy studies clearly revealed the complex structure of the new in vitro model. In a comparative study of drug absorption in the 3D model and a conventional Caco-2 mono-culture cell model, the 3D model provided more physiological observations of transepithelial electrical resistance and alkaline phosphatase activity. The activities of two major intestinal xenobiotic efflux transporters, namely ABCB1 (P-glycoprotein, P-gp) and ABCG2 (Breast Cancer Resistance Protein, BCRP), were also studied, with the decreased ABCB1 activity and increased ABCG2 activity observed in the 3D model closer to the physiological characteristics of the human small intestine. A better correlation between drug permeability and human drug absorption was also observed from the 3D model, consistent with the better modelling of human intestine in structure and physiology.

Keywords:

• Caco-2
• 3D model
• TEER
• drug transporter
• drug permeability

Acknowledgements

The authors would like to acknowledge Dr. Aleksandr Mironov for assistance with transmission electron microscopic imaging and Mrs. Rehana Sung for assistance with HPLC.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

We thank the School of Physics and Astronomy, University of Manchester, for an overseas research studentship to JZ. This work also benefited from the grant support from EPSRC (EP/F062966/1) and Innovate UK (KTP009043).