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

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 multistep 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 target 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 in vitro studies, we demonstrate that modified HA nanoparticles effectively target both P-selectin⁺ and CD44⁺ cells, which lays the groundwork for future in vivo biomedical applications.