Abstract
Biodegradable hydrogels were prepared from furan- and maleimide-functionalized eight-armed poly(ethylene glycol) with an average molecular mass of 40 000 Da (8armPEG40k-furan and 8armPEG40k-maleimide) using the Diels-Alder (DA) reaction as a cross-linking mechanism. Hydrophobic 6-aminohexanoic acid (C6) and 12-aminododecanoic acid (C12) spacers were introduced between the polymer backbone and the functional end-groups; the influence on the gel properties was studied. Modification with C6 and C12 spacers induced hydrophobic interactions between the macromonomers leading to association and increased viscosity of the polymer solutions; both effects were influenced by the spacer length. In combination with DA cross-linking, hydrophobic derivatives of 8armPEG40k-furan and 8armPEG40k-maleimide led to hydrogels with improved properties. Upon introduction of C12 spacers, gelation of 8armPEG40k hydrogels occurred twice as fast. Interestingly, no effect was observed when only one of the two components had been modified. Our experiments suggest that the association of macromonomers by hydrophobic interactions facilitates chemical cross-linking via DA chemistry. This hypothesis is supported by calculations of the network mesh size and the Young's modulus of compression, which showed an increased cross-linking density of hydrophobically modified hydrogels. As a consequence of the increased cross-linking density, the degradation stability of C12-modified hydrogels increased by a factor of 4. Moreover, hydrophobic modification improved the hydrolytic resistance of maleimides; this also contributes to gel stability. The in vitro release of bevacizumab, which served as a model antibody, could be delayed for almost 60 days using modification with C12. Similar trends were observed for C6-modified 8armPEG40k hydrogels; however, the effects were considerably weaker. In summary, utilizing hydrophobic association and chemical cross-linking in tandem is a promising approach to create biodegradable hydrogels for delayed antibody release.
Highlights
Since the introduction of recombinant insulin[1] more than three decades ago, the steady progress in pharmaceutical biotechnology has resulted in the launch of numerous biologics
Hydrophobic modification improved the hydrolytic resistance of maleimides; this contributes to gel stability
Utilizing hydrophobic association and chemical cross-linking in tandem is a promising approach to create biodegradable hydrogels for delayed antibody release
Summary
Since the introduction of recombinant insulin[1] more than three decades ago, the steady progress in pharmaceutical biotechnology has resulted in the launch of numerous biologics. In 2014 alone, 12 new biologics, such as recombinant proteins and monoclonal antibodies, were approved by the US Food and Drug Administration.[2] Among these, monoclonal antibodies are exceptionally promising therapeutics as they provide great specificity and affinity toward their clinical targets.[3,4,5] therapeutic antibodies have significantly advanced the treatment of severe diseases, Among these drug delivery systems, hydrogels are suitable for controlled antibody release.[13] Firstly, hydrogels can act as a drug depot that protects the incorporated protein from degradation. The release rate can be tailored to the specific therapeutic needs; for example, hydrogels can prolong the dosing intervals by providing sustained or delayed antibody release. Hydrogels can be prepared from a wide range of natural
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