Dynamic Imine Bonding Facilitates Mannan Release from a Nanofibrous Peptide Hydrogel

Abstract

Recently, there has been increased interest in using mannan as an immunomodulatory bioconjugate. Despite notable immunological and functional differences between the reduced (R-Man) and oxidized (O-Man) forms of mannan, little is known about the impact of mannan oxidation state on its in vivo persistence or its potential controlled release from biomaterials that may improve immunotherapeutic or prophylactic efficacy. Here, we investigate the impact of oxidation state on the in vitro and in vivo release of mannan from a biocompatible and immunostimulatory multidomain peptide hydrogel, K 2 (SL) 6 K 2 (abbreviated as K 2 ), that has been previously used for the controlled release of protein and small molecule payloads. We observed that O-Man released more slowly from K 2 hydrogels in vitro than R-Man. In vivo, the clearance of O-Man from K 2 hydrogels was slower than O-Man alone. We attributed the slower release rate to the formation of dynamic imine bonds between reactive aldehyde groups on O-Man and the lysine residues on K 2 . This imine interaction was also observed to improve K 2 + O-Man hydrogel strength and shear recovery without significantly influencing secondary structure or peptide nanofiber formation. There were no observed differences in the in vivo release rates of O-Man loaded in K 2 , R-Man loaded in K 2 , and R-Man alone. These data suggest that, after subcutaneous injection, R-Man naturally persists longer in vivo than O-Man and minimally interacts with the peptide hydrogel. These results highlight a potentially critical, but previously unreported, difference in the in vivo behavior of O-Man and R-Man and demonstrate that K 2 can be used to normalize the release of O-Man to that of R-Man. Further, since K 2 itself is an adjuvant, a combination of O-Man and K 2 could be used to enhance the immunostimulatory effects of O-Man for applications such as infectious disease vaccines and cancer immunotherapy.

Advances in Functional Hydrogel Wound Dressings: A Review

“…Imine bonds have a dynamic reversible property. The dynamic reversible covalent bonds between these functional groups are the dominant driving force for the self-healing of hydrogels, as opposed to the simple physical adhesion among the broken hydrogel interfaces [44]. Hydrogel dressings dynamically crosslinked by imine bonds have excellent injectability and efficient self-healing ability [45].…”

Orthogonal Self-Assembly of Amphiphilic Peptide Hydrogels and Liposomes Results in Composite Materials with Tunable Release Profiles

“…13 These rheological properties allow for syringe-directed aspiration and subsequent injection at the site of interest, where they localize and persist as an elastic solid. [8][9][10][11]14 MDP hydrogels are advantageous as drug delivery systems due to their ease of chemical tunability and self-healing properties, making them chemically diverse and localizable depots for drugs. Despite the multiple examples of MDP hydrogels as drug delivery systems, 7−11 there are limitations that can be improved upon.…”

“…Nature′s ability to control biological processes using supramolecular structures has inspired the synthesis of self-assembling systems for a myriad of biomedical applications. In particular, the field of drug delivery has greatly benefited from self-assembled materials due to their ability to control drug release kinetics through supramolecular interactions. − MultiDomain Peptides (MDPs) are a class of amphiphilic peptide assemblers, which have been shown to delay the release of small molecule drugs and biologics. − MDPs are designed with alternating hydrophobic and hydrophilic amino acid residues in the middle of the primary sequence and charged amino acids flanking the termini . In aqueous solution, the hydrophobic residues of two peptide molecules pack together, helping to stabilize an antiparallel β-sheet (Figure a).…”

“…Nanofiber entanglement causes the formation of a shear-thinning, self-healing hydrogel (Figure c) . These rheological properties allow for syringe-directed aspiration and subsequent injection at the site of interest, where they localize and persist as an elastic solid. − , …”

“…MDP hydrogels are advantageous as drug delivery systems due to their ease of chemical tunability and self-healing properties, making them chemically diverse and localizable depots for drugs. Despite the multiple examples of MDP hydrogels as drug delivery systems, − there are limitations that can be improved upon. Certain MDP-drug combinations may undergo initial burst release.…”