Design of thiol- and light-sensitive degradable hydrogels using Michael-type addition reactions

Abstract

Injectable depots that respond to exogenous and endogenous stimuli present an attractive strategy for tunable, patient-specific drug delivery. Here, the design of injectable and multimodal degradable hydrogels that respond to externally applied light and physiological stimuli, specifically aqueous and reducing microenvironments, is reported. Rapid hydrogel formation was achieved using a thiol-maleimide click reaction between multifunctional poly(ethylene glycol) macromers. Hydrogel degradation kinetics in response to externally applied cytocompatible light, reducing conditions, and hydrolysis were characterized, and degradation of the gel was controlled over multiple time scales from seconds to days. Further, tailored release of an encapsulated model cargo, fluorescent nanobeads, was demonstrated.

Controlling the Release of Small, Bioactive Proteins via Dual Mechanisms with Therapeutic Potential

“…Building upon our prior success with aryl-thiol-based thioether succinimide linkages for GSH-responsive release, [13, 14] we conjugated aryl-thiol groups to amine-end-functionalized PEG (PEG-4-NH 2 ) using carbodiimide chemistry (Fig. 1B).…”

“…The o -NB moiety undergoes irreversible photoisomerization in response to externally applied cytocompatible doses of light. [15] In our previous work, we incorporated an ester-linked maleimide o -NB moiety onto a four-arm PEG macromer; [13] however, this formulation presented challenges due to hydrolysis of the maleimide ring during monomer synthesis in addition to the rapid hydrolysis (k = 6.84 × 10 −4 min −1 ) of esters within the resulting hydrogels in aqueous solution. To address these issues, a new amide-linked MPA o -NB was synthesized on PEG-4-NH 2 (Scheme S1).…”

“…In our previous studies, hydrogel degradation was achieved using externally applied light; however, the incorporation of ester bonds caused rapid and uncontrolled ester hydrolysis. [13] The presence of esters in that hydrogel system, consequently, presented significant challenges for future applications in drug delivery, where long-term release (days to weeks) is needed. Hence, we sought to replace the labile ester linkages within the macromers with amide linkages.…”

Spatiotemporal hydrogel biomaterials for regenerative medicine

“…208,209 This strategy was combined with an ester-containing photodegradable hydrogel to create a network with three modes of degradation that varied across large time scales: photodegradation (minutes), thiol exchange (hours), and ester hydrolysis (days). 210 In another study, photolysis was combined with cell-directed degradation by combining the o NB functionality into an MMP-sensitive peptide. 211 The peptide was end-functionalized with azido groups for incorporation into a click-based network.…”

Responsive hybrid (poly)peptide–polymer conjugates

“…140–142,231–233 Similarly, Wieduwild et al reported the use of a series of tagged peptide-polymer conjugates (KA7-starPEG/heparin hydrogel) for antithrombin III (ATIII) release. 234 In another approach, a cysteine-linked antibody drug conjugated with an N-phenyl maleimide was reported.…”