Poly-Amido-Saccharides (PASs): Functional Synthetic Carbohydrate Polymers Inspired by Nature

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS:Carbohydrates are ubiquitous in nature, playing vital roles in all organisms ranging from metabolism to intercellular signaling. Polysaccharides, repeating units of small molecule carbohydrates, are hydrophilic, densely functionalized, stereoregular, and rigid macromolecules, and these characteristics are simultaneously advantageous in biomedical applications while presenting major hurdles for synthetic methodology and development of structure property relationships. While naturally obtained polysaccharides are widely utilized in the biochemical and medical literature, their poor physicochemical definition and the potential for contaminated samples hinders the clinical translation of this work. To address the need for new methods to synthesize carbohydrate polymers, we reported a novel class of biomaterials (Poly-Amido-Saccharides; PAS) in 2012. PASs share many properties with natural polysaccharides, such as hydrophilicity, dense hydroxyl functionality, stereoregularity, and a rigid backbone. PASs are connected by an α-1,2-amide linkage, instead of an ether linkage, that confers resistance to enzymatic and hydrolytic degradation and leads to a unique helical conformation. Importantly, our synthetic methodology affords control over molecular weight distribution resulting in pure, welldefined polymers. This Account provides an overview of the development of PAS, from the factors that initially motivated our research to current efforts to translate functional PAS to biomedical applications. We detail the synthesis of glucose-and galactosebased PAS and their biophysical properties including conformation analysis, lectin interactions, cell internalization, and water solubility. Additionally, we describe postpolymerization modification strategies to afford PASs that act as protein stabilizers. We also highlight our recent efforts toward a mechanistic understanding of monomer synthesis via [2 + 2] cycloaddition reactions in order to develop novel monomers with different stereochemistry and amine or alkyl functionality, thereby accessing functional carbohydrate polymers. Throughout our work, we apply computational and theoretical analysis to explain how properties at the monomer level (e.g., stereochemistry, functionality) significantly impact polymer properties, helical conformation, and bioactivities. Collectively, the results from the theoretical, synthetic, and applied aspects of this research advance us toward our goal of utilizing PASs in key biomedical applications as alternatives to natural polysaccharides. The importance of carbohydrates in nature and the versatility of their functions continue to inspire our investigation of new monomers, polymers, and copolymers, leveraging the advantageous properties of PAS to develop potential therapies.

Carbohydrate-Based Macromolecular Biomaterials

“…56,61 A recent advance in PASs has been reviewed by Grinstaff's group. 230 It is noteworthy that, to the best of our knowledge, the other subtype of naturally derived synthetic polysaccharides, namely, poly(saccharide carbonate)s, is more distant from tissue-engineering applications than PASs. This could be partially due to the fact that the development of such polymers is still in its infancy.…”

“…Very recently, Grinstaff and co-workers successfully synthesized a new type of cationic PASs with controlled molecular weight and low polydispersity, which can mimic the chitosan structure and bind to mucin in solution and on ex vivo tissue samples. This example implicates that such PASs have great potential in tissue-engineering applications. , A recent advance in PASs has been reviewed by Grinstaff’s group . It is noteworthy that, to the best of our knowledge, the other subtype of naturally derived synthetic polysaccharides, namely, poly­(saccharide carbonate)­s, is more distant from tissue-engineering applications than PASs.…”

The Microstructure, Antibacterial and Antitumor Activities of Chitosan Oligosaccharides and Derivatives

“…In the review of Anant S. Balijepalli and Mark W. Grinstaff [27], it was proposed that carbohydrates have their key structural characteristics. COSs, which are also carbohydrates, have diversified biological activities due to their unique chemical structure.…”

Synthesis and Biopharmaceutical Applications of Sugar-Based Polymers: New Advances and Future Prospects

“…PASs share many properties with natural polysaccharides, such as hydrophilicity, dense hydroxyl functionality, stereoregularity, and a rigid backbone. − PASs with a unique helical conformation connected by an α-1,2-amide linkage, instead of an ether linkage, become resistant to enzymatic and hydrolytic degradation. Good control over the molecular weight distributions results in well-defined polymers.…”