A Hybrid In Silico and Tumor-on-a-Chip Approach to Model Targeted Protein Behavior in 3D Microenvironments

Cancers

Valentina Palacio-Castañeda¹  ThijmenJ. Wijgers¹  WouterP. R. Verdurmen¹  Philipp Albrecht¹  Stéphanie Descroix²  Simon Dumas² 

[1] Department of Biochemistry, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands;Physico-Chemistry Curie, Institut Curie, PSL Research University, CNRS UMR168, Sorbonne University, 75005 Paris, France;

关键词: tumor-on-a-chip;    spheroid;    DARPin;    protein diffusion;    tumor targeting;   

DOI  :  10.3390/cancers13102461

来源: DOAJ

【 摘 要 】

To rationally improve targeted drug delivery to tumor cells, new methods combining in silico and physiologically relevant in vitro models are needed. This study combines mathematical modeling with 3D in vitro co-culture models to study the delivery of engineered proteins, called designed ankyrin repeat proteins (DARPins), in biomimetic tumor microenvironments containing fibroblasts and tumor cells overexpressing epithelial cell adhesion molecule (EpCAM) or human epithelial growth factor receptor (HER2). In multicellular tumor spheroids, we observed strong binding-site barriers in combination with low apparent diffusion coefficients of 1 µm²·s⁻¹ and 2 µm² ·s⁻¹ for EpCAM- and HER2-binding DARPin, respectively. Contrasting this, in a tumor-on-a-chip model for investigating delivery in real-time, transport was characterized by hindered diffusion as a consequence of the lower local tumor cell density. Finally, simulations of the diffusion of an EpCAM-targeting DARPin fused to a fragment of Pseudomonas aeruginosa exotoxin A, which specifically kills tumor cells while leaving fibroblasts untouched, correctly predicted the need for concentrations of 10 nM or higher for extensive tumor cell killing on-chip, whereas in 2D models picomolar concentrations were sufficient. These results illustrate the power of combining in vitro models with mathematical modeling to study and predict the protein activity in complex 3D models.

【 授权许可】

Unknown