A novel strategy for the development of next-generation biomaterials for tissue engineering revolves around the use of supramolecular polymers which rely on non-covalent interactions to self-assemble into larger polymer networks. In our research group, supramolecular assembly has been achieved by end-functionalization of prepolymers with ureidopyrimidinone (UPy) units, which dimerize through strong and specific quadruple hydrogen bonding. Furthermore, the introduction of a urea functionality adjacent to the UPy moiety, results in the formation of additional hydrogen bonds which direct lateral stacking into nanofibers |1l In a modular approach, the bulk material properties can be carefully tuned by selection of the type of prepolymer, resulting in the formation of either hydrogel systems or elastomeric materials. Additionally, the material properties can be enhanced through the introduction of UPy-guest molecules which are complementary to the UPy-modified host polymer and can be decorated at the carboxylic acid with a wide variety of functional handles (figure 1). We designed the UPy-guest molecules in such a way that they consist of both a hydrophillic and a hydrophobic part. The hydrophobic spacer, in conjunction with the UPy moiety, steers the lateral stacking. The hydrophilic oligofethylene glycol) part, on the other hand, is required to make the introduced functional group (in this case the carboxylic acid) more accessible for conjugation and/or exposure to the aqueous environment. Figure 1. Chemical structure of UPy-guest molecule. Our goal is to see how the design and decoration of the guest molecule can be used to endow additional properties to the material in a modular approach. More specifically, it is of special interest to determine how the ratio of hydrophobic alkyl spacer vs. hydrophilic OEG spacer influences the effect of the introduced functionality. A small library of four different UPy-guest molecules, consisting of either a smaller (C6), larger (C12) hydrophobic block, in combination with a smaller (OEG6) or larger (OEG12) hydrophilic spacer was synthesized. Figure 2. Synthesis of UPy-guest molecule. In general, the library of the guest molecules was prepared by reaction of a monoprotected alkyl spacer with the CDI-activated oligo(ethylene glycol) chain. Then the benzyl protecting group is removed using standard hydrogenation. Subsequently, the UPy moiety is coupled using isocyanate chemistry. Varying functional groups can be introduced after deprotection of the carboxylic acid. This synthetic strategy enables the preparation of the guest molecules at a scale exceeding a gram. Several functional groups have been coupled to the carboxylic acid of the guest molecule though standard amide bond formation using HATU as a coupling agent. Besides various peptides (such as a heparin binding sequence, RGD peptide, etc.), these groups also include smaller moieties such as tetrazines, and metal-binding ligands. The tetrazines serve as handles onto which proteins can be conjugated via the inverse electron demand Diels-Alder click chemistry reaction. The guest molecules described here allow enhancing the properties of UPy-based supramolecular materials by adding bioactivity.
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