Instantaneous Degelling Thermoresponsive Hydrogel

Abstract

Responsive polymeric hydrogels have found wide application in the clinic as injectable, biocompatible, and biodegradable materials capable of controlled release of therapeutics. In this article, we introduce a thermoresponsive polymer hydrogel bearing covalent disulfide bonds. The cold aqueous polymer solution forms a hydrogel upon heating to physiological temperatures and undergoes slow degradation by hydrolytic cleavage of ester bonds. The disulfide functionality allows for immediate reductive cleavage of the redox-sensitive bond embedded within the polymer structure, affording the option of instantaneous hydrogel collapse. Poly(ethylene glycol)-b-poly(lactic acid)-S-S-poly(lactic acid)-b-poly(ethylene glycol) (PEG-PLA-SS-PLA-PEG) copolymer was synthesized by grafting PEG to PLA-SS-PLA via urethane linkages. The aqueous solution of the resultant copolymer was a free-flowing solution at ambient temperatures and formed a hydrogel above 32 °C. The immediate collapsibility of the hydrogel was displayed via reaction with NaBH₄ as a relatively strong reducing agent, yet stability was displayed even in glutathione solution, in which the polymer degraded slowly by hydrolytic degradation. The polymeric hydrogel is capable of either long-term or immediate degradation and thus represents an attractive candidate as a biocompatible material for the controlled release of drugs.

Keywords: PEG-PLA; redox-sensitive; thermoresponsive hydrogel.

Figure 1

PEG-PLA-PEG triblock copolymers with embedded disulfide bonds immediately collapse upon addition of reducing agent NaBH₄. Disulfide-bearing polymer hydrogels afford controlled hydrogel collapsibility due to S–S bond cleavage.

Figure 2

(A) Synthesis by Jeong et al. of a PEG-PLA-PEG triblock copolymer with urethane linkages [24]. (B) Synthesis of PEG-PLA-PEG with urethane linkages between polymer blocks and one embedded disulfide bond.

Figure 3

(a) 1H NMR spectra of PLA(SS) with peak assignments.; (b) 1H NMR spectra of PEG-PLA-SS-PLA-PEG with peak assignments.

Figure 3

(a) 1H NMR spectra of PLA(SS) with peak assignments.; (b) 1H NMR spectra of PEG-PLA-SS-PLA-PEG with peak assignments.

Figure 4

Heating (red) and cooling (blue) viscosity curves of 25% w/w PEG-PLA-SS-PLA-PEG aqueous solutions.

Figure 5

Sensitivity of the embedded disulfide bond in PEG-PLA-PEG triblock copolymer was confirmed by reaction with NaBH₄ and subsequent reduction in molecular weight by half. A chemical analog lacking the disulfide bond retained most of its molecular weight under the same conditions, indicating the role of disulfide bond cleavage in molecular weight reduction. Error bars represent the standard deviation of experiments performed in triplicate.

Figure 6

Degradation of PEG-PLA-SS-PLA-PEG hydrogel in distilled water or 1% glutathione solution displayed a slow hydrolytic degradation for two weeks with near-constant PDI values.

Figure 7

Three-dimensional structure of a physically crosslinked hydrogel may be instantaneously collapsed by exposure to reducing conditions.