CD44 is a widely distributed type I transmembrane glycoprotein which binds hyaluronic acid (HA) in most cell types including astrocytes, primary tumor cells, cancer-initiating cells, and have roles in cell migration, cell-cell and, cell-matrix adhesion. HA, a non-sulfated glycosaminoglycan, is comprised of disaccharide repeat units of alternating (1-3)-β linked N-acetyl-D-glucosamine and (1-4)-β linked D-glucuronic acid. Our group and other labs have used HA-based nanoparticles for delivery of drugs and imaging agents to tumors, targeting the CD44 receptor as a source of recognition of cancer cells. Altering the crucial interactions of HA with CD44 active site holds significant importance in tuning targeting ability of hyaluronic acid to other cancer types which primarily do not express the CD44 receptor. This presents an alternative approach in using modified HA-based systems for drug delivery/imaging applications for non-CD44 expressing tumors. Synthetic strategies were exploited included deacetylation of the N-acetyl group and selectively sulfating the C6 primary hydroxyl group which are involved in forming critical interactions with the CD44 active site. Interactions confirmed by molecular modeling were hydrogen bonding of the C6-OH with Tyr109 and hydrophobic interaction of the N-acetyl group with Tyr46, 83 and Ile 92. Combining synthetic modifications, in vitro, and molecular modeling techniques enabled us to rationally modify HA after careful understanding the interactions it holds with the CD44 receptor. Flow cytometry and fluorescence polarization techniques, as well as docking, molecular dynamics and binding calculations by MM-PBSA approach were used. Results of these studies were in good agreement showing that HA binding properties were successfully modified. We aim to prepare nanoparticles from these modified polymers which will open avenues for exploration of future applications in the field of image-guided surgery.

Tuning hyaluronic acid binding properties to CD44 using synthetic, in vitro and in silico approaches

253rd National Meeting (2017)

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