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

Abstract

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-g-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.

Sniping Cancer Stem Cells with Nanomaterials

“…As previously elucidated, CSCs overexpress defined biomarkers that can serve as discerning therapeutic targets to precisely delineate and eliminate CSCs populations . Given this, CD44, assumes a pivotal function in propelling tumor metastasis and invasion, encompassing its ability to avidly engage its principal ligand, HA . Joseph et al developed a dual-targeted therapeutic nanocarrier chemically conjugated with HA, precise homes in on CSCs overexpressing CD44, and folate, directly targets tumor cells, thus enabling precise eradication of chemoresistant cancer cells and CSCs (Figure A) .…”

“…193 Given this, CD44, assumes a pivotal function in propelling tumor metastasis and invasion, encompassing its ability to avidly engage its principal ligand, HA. 194 Joseph et al developed a dual-targeted therapeutic nanocarrier chemically conjugated with HA, precise homes in on CSCs overexpressing CD44, and folate, directly targets tumor cells, thus enabling precise eradication of chemoresistant cancer cells and CSCs (Figure 3A). 195 Additionally, Rao et al constructed a doxorubicin (DOX)-coated polymer nanoparticle decorated with chitosan, which specifically target the CD44 receptor overexpressed on CSCs, but not normal stem cells (Figure 3B).…”