*Article* **Instantaneous Degelling Thermoresponsive Hydrogel**

**Noam Y. Steinman and Abraham J. Domb \***

The Alex Grass Center for Drug Design and Synthesis and Center for Cannabis Research, Faculty of Medicine, Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel; noam.steinman@mail.huji.ac.il

**\*** Correspondence: avid@ekmd.huji.ac.il

**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 NaBH<sup>4</sup> 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; thermoresponsive hydrogel; redox-sensitive
