Hyaluronan Brush-like Copolymers Promote CD44 Declustering in Breast Cancer Cells

We report on the synthesis of hyaluronan (HA) brush-like copolymers and their application as antagonists of tumorigenic CD44-HA interactions. HA (4.8 kDa, ca. 24 saccharides) was grafted on 2-hydrohyethyl methacrylate (HEMA) by end-on oxime ligation. The obtained copolymers were compared with low and high molecular weight HA in terms of hydrolysis kinetics in the presence of hyaluronidase (isothermal titration calorimetry) and interactions with CD44 (surface plasmon resonance). The results evidenced that the high molecular weight HA and HA-<i>g</i>-HEMA have a much higher affinity to CD44 than low molecular weight HA. Additionally, slower enzymatic degradation was observed for the copolymer, making it an excellent candidate for active targeting of tumorigenic CD44-HA interactions. We, therefore, investigated the effect of the copolymer on cancer cell lines with different expression of CD44 and observed an efficient declustering of CD44 that is usually associated with reduction of metastasis and drug resistance.