A Novel Acid‐Degradable PEG Crosslinker for the Fabrication of pH‐Responsive Soft Materials

Abstract

The design and synthesis of a novel acid‐degradable polyethylene glycol‐based N‐hydroxysuccinimide (NHS) ester‐activated crosslinker is reported. The crosslinker is reactive towards nucleophiles and features a central ketal functional group that is stable at pH > 7.5 and rapidly hydrolyses at pH > 6.0. The crosslinker is used to (i) fabricate acid‐degradable polysaccharide hydrogels that exhibit controlled degradation upon exposure to an acidic environment or via endogenous enzyme activity; and (ii) construct hydrogel‐filled protein‐polymer microcompartments (termed proteinosomes) capable of pH‐dependent membrane disassembly. Taken together the results provide new opportunities for the fabrication of pH‐responsive soft materials with potential applications in drug delivery, tissue engineering, and soft‐matter bioengineering.

Crosslinkers for polysaccharides and proteins: Synthesis conditions, mechanisms, and crosslinking efficiency, a review

“…For instance, PEG (M n = 1000 g/ mol) was modified in order create an acid-degradable crosslinker, as represented in Fig. 29 3) was used for the crosslinking of carboxymethyl chitosan chains by the reaction between chitosan amino groups and (3) N-hydroxysuccinimide ester groups, creating hydrogels stable at pH 7.5, but readily degradable at pH < 6.0, due to the presence of ketal moieties in the macromolecular structure [311].…”

“…[311]. PEG was first transformed into bis(succinic acid ester)polyethylene glycol, which reacted with EDC to yield O,O′-bis[2-(N-succinimidyl-succinate)]polyethylene glycol (1).…”

“…The acetal moieties and the reactive Nhydroxysuccinimide ester groups are highlighted in red and blue, respectively. Adapted from Ref [311]…”

Concurrent Ring-Opening/Ring-Closing Polymerization of Glycidyl Acetate to Acid-Degradable Poly(ether-co-orthoester) Materials Using a Mono(μ-alkoxo)bis(alkylaluminum) Initiator

“…Previously reported strategies of synthesizing degradable polyethers involve the incorporation of heterofunctionality into the polyether backbone through copolymerization of epoxides with lactones or anhydrides, − the incorporation of acetal linkages through end-group modification followed by intermolecular condensation, , or vinyl ethers derived from copolymerization followed by postpolymerization modification. − In all of these applications, either careful selection of catalytic method for balanced comonomer reactivity or postpolymerization modification is required.…”

“…The GPC system was equipped with an Agilent 1260 Infinity refractometer, and molecular weights were evaluated using a polystyrene standard calibration. 1 H and 13 C NMR spectroscopy were performed on a 400 MHz Agilent MR spectrometer or a Bruker AVANCE III 500 MHz spectrometer at room temperature in CDCl 3 or CD 2 Cl 2 . The chemical shift was referenced to the residual solvent signal of CHCl 3 or CHDCl 2 ( 1 H NMR: 7.26 and 5.32 ppm, 13 C NMR: 77.16 and 53.50 ppm, respectively).…”