Experimental and Computational Models of Transport of Galectin-3 Through Glycosylated Matrix.

Abstract

Altered extracellular matrix (ECM) production is a hallmark of many fibroproliferative diseases, including certain cancers. The high incidence of glycan-rich components within altered ECM makes the use of glycan-binding proteins such as Galectin-3 (G3) a promising therapeutic strategy. The complexity of ECM as a rich 3D network of proteins with varied glycosylation states makes it challenging to determine the retention of glycan-binding proteins in altered ECM environments. Computational models capable of predicting the transport of glycan-binding proteins in altered ECM can benefit the design and testing of such proteins and associated novel therapeutic strategies. However, such computational models require many kinetic parameters that cannot be estimated from traditional 2D pharmacokinetic assays. To validate transport properties of G3 in 3D ECM constructs, we developed a species transport model that includes diffusion and matrix-binding components to predict retention of G3 fusion proteins in glycan-rich ECM. By iteratively comparing our computational model to experimental results, we are able to determine a reasonable range of parameters for a robust computational model of G3 transport. We anticipate this overall approach to building a data-driven model is translatable to other ECM-targeting therapeutic strategies.