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Glycomimetics via radical polymerization: The effect of saccharide identity, connectivity, and architecture on biological interactions

  • Author(s): Liau, Walter Tsu-i
  • Advisor(s): Kasko, Andrea M
  • et al.
Abstract

Polysaccharides are polymeric chains comprised of saccharides connected through glycosidic bonds that have important biological functions, such as energy storage, structure, and cell signaling. Although polysaccharides are ubiquitous in nature, there are limited tools for examining their roles due to the complexity of polysaccharide synthesis. In order to synthesize well-defined polysaccharides, selective protection/deprotection techniques are employed that require tedious purification at each intermediate. In order to facilitate the creation of high molecular weight saccharide-bearing polymers, glycopolymers can be created as an alternative. Glycopolymers emulate the interactions observed in natural polysaccharides through the use of synthetic analogues.

Glycopolymers are synthetic polymers that present saccharide side groups. Although glycopolymers have been produced with control over saccharide identity and molecular weight, only limited investigations have been conducted to incorporate cationic charge or control branched architecture. Currently, cationic charge is incorporated through the copolymerization of cationic monomers with glycomonomers, but the inclusion of cationic monomers has led to increased cytotoxicity. There have been no examples of glycopolymers utilizing the inherent charge available on amino-sugars, such as glucosamine. In addition, branched glycopolymers have previously been studied using atom-transfer radical polymerization, but the polymerization technique is incompatible with amine-containing monomers and requires removal of the copper catalyst. Reversible addition-fragmentation chain transfer (RAFT) polymerization is an alternative technique for glycopolymer synthesis, but branching has only been introduced using crosslinkers that result in gelation at high degrees of incorporation. To address these limitations, new cationic glycomonomers and RAFT branching units have been synthesized.

Using these new tools, in addition to those currently available for glycopolymer synthesis, a number of biomedical applications were investigated: bacterial attachment on glycopolymer-modified surfaces, lectin interaction with 3D constructs that present saccharides at different densities, antibacterial activity of a cationic glycopolymer, and potential usage of a cationic glycopolymer in gene transfection.

Using a set of four glycomonomers synthesized from glucose, galactose, mannose, and N acetyl glucosamine, glycopolymer of various saccharide identities were polymerized via RAFT polymerization and conjugated to gold surfaces to investigate the attachment of Shewanella oneidensis and Vibrio cholerae. Polymeric mannose was seen to encourage significantly more attachment than monomeric mannose, polymeric galactose, and polymeric N acetyl glucosamine.

Using a RAFT branching unit, amphiphilic glycopolymers were polymerized and self-assembled into nanoparticles with control over the surface saccharide density without affecting size and morphology. The nanoparticles with increased branching bound more lectin compared to nanoparticles without branching and glycopolymers in solution.

Using a cationic glycomonomer, a chitosan-mimic was polymerized and investigated for similarities in bioactivity. In antibacterial studies, the cationic glycopolymer closely mimicked the ability of chitosan to inhibit bacterial growth above a threshold molecular weight. Unlike chitosan, the glycopolymer was also soluble in neutral and basic buffer and maintained its ability to inhibit bacterial growth. As a transfection agent, the glycopolymer was able to induce gene expression with less cytotoxicity than poly(ethylenimine), the standard synthetic transfection agent, but with more cytotoxicity than chitosan. With optimization, the chitosan-mimic can be an efficient transfection agent with low cytotoxicity.

We have described the addition of new synthetic tools for creating cationic glycopolymers and hyperbranched glycopolymers. The applications presented demonstrate the importance of control over saccharide identity, branching, and charge in glycomimetic systems and can be applied to the design of new therapeutics and devices.

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