Dendrimer-like PEO glycopolymers exhibit anti-inflammatory properties

Abstract

A new class of high molecular weight polysulfated PEO dendrimer-like glycopolymer has been synthesized by a combination of arm-first and core-first methodologies followed by trichloroacetimidate glycosidation as a facile bioconjugation strategy. An L-selectin antagonist was identified that exhibits 103-fold greater activity than other multivalent sLex glycopolymers and 20-50 times greater potency than other linear heparinoids. A significant reduction in inflammatory cell recruitment was observed in vivo.

Figure 1

I) Selectin blockade using polyvalent branched glycoconjugates. II) Glycosidation of terminal hydroxyls on a PEO scaffold using lactose imidate (A).

Figure 2

Saccharide-functionalized PEO star and ‘dendrimer-like’ polymers as selectin ligands.

Figure 3

600 MHz ¹H NMR spectrum of 3a (2^nd generation, 12 end groups) recorded in CDCl₃ at 25 °C. Inset shows the MALDI-TOF spectra of the original hydroxyl-terminated phosphazene core-based PEO branched polymer and glycodendrimer 3a, confirming a high degree of sugar conjugation.

Figure 4

Neutrophil and macrophage content in thioglycollate-induced peritoneal inflammation (n = 6). A: Neutrophil. B: Macrophage. Significant differences were observed in neutrophil and macrophage content in mice treated with heparin and 3c compared with control mice that received saline (p < 0.05). Compounds 1c/2c did not exhibit in vivo activity. Each bar represents the average value ± SD.

Figure 5

Competitive inhibition of U937 cell adhesion to immobilized A) L- selectin, B) P-selectin. Neither heparin nor 3c exhibited inhibitory activity towards E-selectin. Inhibition was not observed in the absence of test compound or heparin. Data represents means of at least n = 3, SD < 10%).