Selective Fluorination Affords Hydrophilic Synthetic Glycoconjugates Stable In Vivo

Abstract

Therapeutics based on native carbohydrates such as lactose often suffer from short circulation half-lives in vivo due to their rapid clearance from the bloodstream by hepatic C-type lectin receptors, which limits their therapeutic efficacy. A common counter-strategy is to develop structurally distinct glycomimetics by introducing aromatic substituents. However, these modifications often increase hydrophobicity and, in multivalent conjugates, may promote nanoaggregation in the bloodstream, adversely affecting their pharmacokinetic and pharmacodynamic properties. In our conceptually distinct approach, strategic fluorine substitution in the native carbohydrate scaffold modulates pharmacokinetics while preserving high water solubility and bioavailability. The prepared highly water-soluble multivalent glycopolymers fluorinated at the 3′- and 4′-positions based on a biocompatible polyoxazoline scaffold exhibited circulation times comparable to the unmodified macromolecular carrier and substantially longer than native lactose-terminated analogues. We establish site-selective carbohydrate fluorination as a broadly applicable platform to improve the pharmacokinetic properties of soluble glycan-based therapeutics, useful for targeting biomedically important lectins, such as β-galactoside-binding galectins.