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Biomacromolecules 2008, 9, 208–215
Structure–Property Studies on Carbohydrate-Derived Polymers for Use as Protein-Resistant Biomaterials Mark Metzke and Zhibin Guan* Department of Chemistry, 1102 Natural Sciences 2, University of California, Irvine, California 92697-2025 Received September 11, 2007; Revised Manuscript Received October 24, 2007
Here we describe structure–property studies on our carbohydrate-derived side-chain ether polymers as proteinresistant biomaterials. A series of side-chain ether polymers, including two polyesters and two polyamides, were prepared by condensation polymerization of monomers derived from simple carbohydrates. The two side-chain permethoxylated polyesters having different stereochemical repeating units demonstrate excellent resistance toward nonspecific protein adsorption as shown by surface plasmon resonance, indicating that the polymer stereochemistry does not have much effect on its protein-resistant properties. The introduction of amide bonds to polymer backbones leads to more pronounced effects. While the polymer degradation stability is significantly enhanced by replacing ester with amide linkages, the protein resistance for the polymer is greatly reduced by introduction of amide bonds. Finally, our results suggest that free hydroxyl and amide groups, while both are hydrogen-bond donors, seem to have different effects on protein resistant properties for polymers. It appears that free amide groups have more detrimental effect on protein resistance than free hydroxyl groups. These results show that the proteinresistant properties of this family of polymers can be tailored by modifying the backbone and side chain functionalities. In combination with the biodegradability and functionalizability, this family of carbohydratederived polymers shows promise as versatile biomaterials for biomedical applications.
Introduction Currently there is an increasing effort toward the design of novel biomaterials that combine biodegradability, biocompatibility, and low toxicity. A material’s ability to resist nonspecific protein adsorption is an important indicator of its biological inertness1 and therefore biocompatibility. Applications of protein-resistant materials include not only surface coating of medical implants and medical devices2 but also cell cultures,3 tissue regeneration,4 drug delivery,5 and polymer therapeutics. Poly(ethylene glycol) (PEG) is a commonly used biomaterial in drug2,3 and gene delivery formulations,3–6 largely because of its exceptionally high resistance to nonspecific protein binding and unsurpassed biocompatibility.7 PEG has also found much use as a coating for other materials to endow them with proteinresistant, “stealth” biological properties. A commonly used strategy in biomaterials studies is to PEGylate a selected material that meets other desirable chemical, physical, and mechanical properties.8,9 Though the molecular mechanism for protein resistance is not fully understood,10–13 important progress has been made in this area for the past decade. The Whitesides11–13 and Mrksich14 groups have extensively surveyed the protein resistance of many model self-assembled monolayer (SAM) surfaces displaying various functional groups and molecular species, from which the following commonalities among proteinresistant substrates were generalized: (1) hydrophilicity, (2) the ability to accept hydrogen bonding, (3) the inability to donate hydrogen bonds, and (4) a net neutral charge. Though a number of “protein-resistant” motifs have been identified (Chart 1), including saccharides, permethoxylated saccharides, phospholipids, tertiary amine oxides, sulfobetaine-based polyurethanes, and polyglycerol polymer surfaces,11,15–19 none have found as frequent use as PEG. As a simple main-chain polyether, however, PEG lacks versatility as it can be functionalized only * Corresponding author:
[email protected].
Chart 1. Protein-Resistant Motifs Including Tri(ethylene glycol) (1), Methylated Sorbitol (2), and our D-Dulcitol-Derived Side-Chain Permethoxylated Polyester (DPMPE)
at its chain ends, and it is not biodegradable. For many biomedical applications, biodegradability and the flexibility to incorporate various functionalities throughout a material are desirable.20 Biomaterials that combine protein resistance, biodegradability, and functionalizability are therefore in high demand. Our group recently became interested in synthesizing biomaterials having excellent protein resistance like PEG, but with the added features of biodegradability and functional versatility along the polymer main chain. In our initial studies, we designed the dulcitol-derived side-chain permethylated polyester (DPMPE) shown in Chart 1, modeled after proteinresistant motifs with similar chemical structures. The design of our polymer as a protein-resistant biomaterial was based on several considerations. First, based on the structural resemblance between our monomeric units and the methylated sorbitol motif shown by Whitesides et al.,11–13 we envisioned the DPMPE would demonstrate good protein resistance. Second, the repeat units in polymer DPMPE were connected with ester linkages which should be cleaved by acid, base, or enzymatic hydrolysis. Third, carbohydrate starting materials are naturally abundant and can be functionalized with various substituents making our
10.1021/bm701013y CCC: $40.75 2008 American Chemical Society Published on Web 12/14/2007
Carbohydrate-Derived Protein-Resistant Polymers
polymer highly versatile. Finally, copolymerization with other sugar monomers carrying desired functional groups should serve to introduce additional functional groups to the polymer. The ability to functionalize the polymer should allow for a more diverse range of applications.20,21 As we reported previously, our DPMPE polymer indeed displays excellent protein resistance that is competitive to that of PEG. For both fibrinogen and lysozyme our DPMPE-coated surface exhibits
