Sulfation Modulates the Targeting Properties of Hyaluronic Acid to P-Selectin and CD44

Abstract

Many targeting strategies can be employed to direct nanoparticles to tumors for imaging and therapy. However, tumors display a dynamic, heterogeneous microenvironment that undergoes spatiotemporal changes, including the expression of targetable cell-surface biomarkers. Here, we develop a nanoparticle system to effectively target two receptors overexpressed in the microenvironment of aggressive tumors. Hyaluronic acid (HA) was regioselectivity modified using a multi-step synthetic approach to alter binding specificities for CD44 and P-selectin to tumor cell interaction. The dual-targeting strategy utilizes sulfate modifications on HA that targets P-selectin, in addition to native targeting of CD44, which exploits spatiotemporal alterations in the expression patterns of these two receptors in cancer sites. Using biophysical characterization and <i>in vitro</i> studies, we demonstrate that modified HA nanoparticles effectively targets both P-selectin⁺ and CD44⁺ cells, which lays the groundwork for future <i>in vivo</i> biomedical applications.