Synthesis of Biocompatible PEG Hydrogels by pH-Sensitive Potassium Acyltrifluoroborate (KAT) Amide Ligations

Abstract

The synthesis of novel PEG-based hydrogel via chemoselective potassium acyl trifluoroborate (KAT) and O-carbamoyl hydroxylamines amide ligation is reported. The gelation kinetics, determined by dynamic rheometry, is pH dependent and allows fine-tuning of the gelation time. For a 4 wt % PEG hydrogel, at low acidic pHs (3 to 6) gelation proceeds rapidly within few minutes, comparable or existing the faster known gelation times. At neutral and physiological pHs (7 and 7.4) the reaction is slower, forming a hydrogel in ca. 80 min. The gels are suitable for the encapsulation of bovine chondrocytes with the high viability (96% after 2 days), demonstrating the biocompatibility of the KAT ligation for the first time.

Potassium Acyltrifluoroborate (KAT) Ligations are Orthogonal to Thiol‐Michael and SPAAC Reactions: Covalent Dual Immobilization of Proteins onto Synthetic PEG Hydrogels

“…The KAT ligation of potassium acyl trifluoroborates and hydroxylamines offers unique functional group partners, water‐compatibility, the formation of amide bond, biocompatibility and useful pH‐dependent kinetics . We have previously shown that it is suitable for hydrogel formation in presence of living cells and demonstrates remarkable chemoselectivity for the conjugation of peptides and other biomolecules . We therefore prepared linkers containing either O ‐diethylcarbamoyl hydroxylamine or a KAT as the second functional group for incorporation into hydrogel.…”

“…[36] We have previously shown that it is suitable for hydrogel formation in presence of living cells and demonstrates remarkable chemoselectivity for the conjugation of peptides and other biomolecules. [35] [43] We therefore prepared linkers containing either O-diethylcarbamoyl hydroxylamine or a KAT as the second functional group for incorporation into hydrogel. This was achieved by the synthesis and use of hydroxylamine thiol 4 and KAT 5 during the hydrogel formation (Scheme 2).…”

PEGylation and Dimerization of Expressed Proteins under Near Equimolar Conditions with Potassium 2-Pyridyl Acyltrifluoroborates

“…Provided these studies were successful, we also sought to apply this chemistry to protein dimerization, as the requisite multivalent PEG-KATs are easily prepared in one step. 10 , 27 …”

Cell‐Surface Engineering for Advanced Cell Therapy

“…[182,[190][191][192] In addition to cycloaddition reactions, other organic reactions have also been used for cell encapsulation in covalent cross-linked hydrogels, including Staudinger ligation, [193] oxime/hydrazone formation, [194,195] phenylboronic acid-polyol reaction, [196] urea bond formation, [197] and KATl igation (amide bond formation of hydroxylamines and potassium acyltrifluoroborates). [198] From the standpoint of control of degradation, severalc ovalenth ydrogels whose degradation is triggered by light, [199,200] enzymes, [147,201] or natural hydrolysis [197] have been developed. In addition to alginate-based ionotropich ydrogels and covalently cross-linked hydrogels, other chemical interac- tions have been introduced to encapsulate cells.…”