Clickable polyamidosaccharides

Hyaluronic acid (HA) binds the transmembrane glycoprotein cluster of differentiation-44 (CD44), a highly expressed surface receptor that plays a critical role in tumor growth, invasion, and metastasis. Approaches to target CD44 utilize biologically sourced HA which inherently suffers from molecular weight (Mw) heterogeneity and biological contaminants. Fully synthetic approaches to HA are attractive and circumvent these biological contaminants; however, readily accessing oligomers of six monosaccharides or more, as is required for CD44 binding, is challenging. To this end, we report the synthesis of carbohydrate-based glycopolymers functionalized with HA disaccharide pendant chains. These well-defined and chemoselective polymers consist of glucose monomers linked via -1,2 amide bonds, termed polyamidosaccharides, functionalized with branched HA disaccharide moieties interspersed throughout via a strain-promoted azide-alkyne cycloaddition. Among these homopolymers and copolymers, two of the polymers bearing the highest HA disaccharide conjugation bind CD44 with nanomolar affinity. Assays using a rhodamine-labeled polymer reveal a positive relationship between cellular internalization and CD44 expression levels in breast cancer cells. Conjugation of paclitaxel to the polymer results in enhanced paclitaxel efficacy in CD44-expressing cancer cells compared to free paclitaxel.