Investigation of the Impact of Hydrolytically Cleavable Groups on the Stability of Poly(ethylene glycol) Based Hydrogels Cross‐Linked via the Inverse Electron Demand Diels–Alder (iEDDA) Reaction

Abstract

Eight-armed poly(ethylene glycol) (PEG) hydrogels cross-linked via inverse electron demand Diels-Alder reaction between norbornene and tetrazine groups are promising materials for long-term protein delivery. While a controlled release over 265 days is achieved for 15% w/v hydrogels in the previous study, the material shows high stability over 500 days despite having cleavable ester linkages between the PEG macromonomers and their functionalities. In this study, the hydrolyzable ester linkers in the PEG-norbornene precursor structure are exchanged to reduce the degradation time. To this end, 3,6-epoxy-1,2,3,6-tetrahydrophthalimide, phenyl carbamate, carbonate ester, and phenyl carbonate ester are introduced as degradable functional groups. Oscillatory shear experiments reveal that they are not affected the in situ gelation. All hydrogel types have gel points of less than 20 s even at a low polymer concentration of 5% w/v. Hydrogels with varying polymer concentrations have similar mesh sizes, all of which fell in the range of 4-12 nm. The inclusion of phenyl carbonate ester accelerates degradation considerably, with complete dissolution of 15% w/v hydrogels after 302 days of incubation in phosphate buffer (pH 7.4). Controlled release of 150 kDa fluorescein isothiocyanate-dextran over a period of at least 150 days is achieved with 15% w/v hydrogels.

Injectable Anhydrous Poly(ethylene glycol) Polymer Liquids Form Protein Depot for Extended Controlled Release Applications Via Rapid In Situ Gelation

“…In our previous work, we incorporated different hydrolytically cleavable linkers into the backbone of conventional hydrogels to accelerate degradation . Phenyl carbamate, carbonate, and phenyl carbonate were used as designated breaking points.…”

“…4armPEG2k-amine (4armPEG2k-NH 2 ) was prepared according to a previously published procedure for 4armPEG10k-NH 2 . 4armPEG2k-phenyl carbamate-Nb, 4armPEG2k-carbonate-Nb, and 4armPEG2k-phenyl carbonate-Nb were synthesized according to the protocols for 8armPEG10k derivatives . The degree of end-group conversion was 85% for 4armPEG2k-phenyl carbamate-Nb, 81% for 4armPEG2k-carbonate-Nb, and 71% for 4armPEG2k-phenyl carbonate-Nb, as determined by 1 H NMR spectroscopy (Scheme ).…”

“…In our previous work, we incorporated different hydrolytically cleavable linkers into the backbone of conventional hydrogels to accelerate degradation. 24 Phenyl carbamate, carbonate, and phenyl carbonate were used as designated breaking points. Incorporation of phenyl carbonate groups resulted in faster degradation, whereas carbonate and phenyl carbamate linkers did not reduce degradation time.…”

“…The goal of this study was to utilize our prior knowledge of melt polymerization, iEDDA reaction, and degrading linkers to design a water-free system that forms immediately after combining two liquid polymers. ,, In this way, we aimed to develop an injectable, water-free, in situ gelling system that forms at low temperature to serve as a depot for the controlled long-term release of high-molecular-weight proteins. Its major advantage over existing hydrogel-type polymers should be that it avoids all major stability compromising aspects of similar polymer systems such as protein dissolution during manufacturing, presence of water, elevated temperature, and lack of bio-orthogonality.…”

Degradable and Multifunctional PEG-Based Hydrogels Formed by iEDDA Click Chemistry with Stable Click-Induced Supramolecular Interactions

“…14 Even with hydrolytically labile groups (e.g., a phenyl carbonate functional group at the cross-linking site) installed in the polymer backbone, the fastest in vitro degradation time achieved with 8arm PEGs was approximately 150 days. 15 Further, utilizing lower functionality PEG did not accelerate the hydrolytic degradation time. 16 However, hydrogels cross-linked by the iEDDA click reaction can still be rendered more hydrolytically labile using a degradable polymer backbone.…”