Targeting Galectin-3 in Tumors with Carbohydrate-Polymer Conjugates
Introduction
Lectins (i.e., carbohydrate-binding proteins) are involved in numerous biological processes, including the immune response, cellular signaling, gene expression, and disease. Galectins comprise a class of multivalent lectins that selectively recognize b-galactoside carbohydrates. Galectin-3 (Gal-3) plays an active role in immune suppression in tumors. Therefore, strategies to inhibit the function of this protein in cancer are attractive as new therapeutic targets. Motivated by this, we have developed carbohydrate-polymer conjugates (CPCs) that contain b-galactosides for binding to Gal-3 in liver cancer.
Methods
To probe Gal-3 binding to polymer structure, we synthesized a small library of monomers amenable to ring-opening metathesis polymerization (ROMP). Polymerization was completed and the polymers were characterized via gel-permeation chromatography and dynamic light scattering. The CPCs were then subjected to binding studies with Gal-3 using microscale thermophoresis.
Results
We have developed and synthesized a small library of ROMP-amenable glycomonomers that vary in the linker length as well as the sugar residue. Additionally, the selected monomers were subjected to polymerization, which afforded polymers with low dispersity at several degrees of polymerization. The polymerization results also suggest that the increased number of free hydroxyl groups in lactose leads to loss in polymerization control, as evidenced by the increased dispersity. Lastly, when analyzing binding avidity to Galectin-3 we found that lactose containing polymers bound Galectin-3 better than polymers with galactose-based monomers. With longer polymers and more dense polymers binding the best to Galectin-3.
Conclusion
As the length of the polymer increases, the binding strength to Galectin-3 also increases. Additionally, the density of the carbohydrates on the polymer strongly affects Galectin-3 binding with a denser polymer binding better than less dense polymers.