**1. Introduction**

Biodegradable polymers are ubiquitous across the pharmaceutical industry. These materials often constitute the primary platform for the delivery of therapeutic agents, as their slow degradation in vivo allows for sustained drug release over an extended period of time without the need for subsequent removal of the delivery vehicle. 'Smart' polymers capable of responding to external stimuli were developed to afford targeted drug release based on the presence of the relevant stimulus. These materials bear functional groups capable of a quick response to small changes in temperature, pH, or light, which lead to a physical change in the polymer that triggers drug release [1].

Polymeric hydrogels describe polymers capable of absorbing large amounts of water to form a gel due to crosslinking of the polymer chains. Smart thermoresponsive hydrogels were developed to undergo a sol–gel transition in response to temperature variation [2]. This feature enables a liquid solution to be injected into a physiological environment and form a gel in situ at the point of injection due to the temperature change. The molecular structures of such polymers determine their gelling temperatures as well as important features such as biocompatibility [3,4].

Copolymers of poly (lactic-co-glycolic acid) (PLGA) and poly (ethylene glycol) (PEG) were described at length as biocompatible and biodegradable polymers capable of forming thermoresponsive hydrogels in water [5]. Triblock copolymers, either with the morphology PLA-PEG-PLGA or PEG-PLGA-PEG, are soluble in water and reversibly form hydrogels upon heating [6–8]. The gelling behavior of the hydrogels formed from these copolymers is affected by overall polymer molecular weight, the ratio between polymer blocks, and

**Citation:** Steinman, N.Y.; Domb, A.J. Instantaneous Degelling Thermoresponsive Hydrogel. *Gels* **2021**, *7*, 169. https://doi.org/ 10.3390/gels7040169

Academic Editor: Yang Liu

Received: 4 October 2021 Accepted: 12 October 2021 Published: 14 October 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

the concentration of the polymer in solution [3,9–11]. Hence, the rational design of each element of the polymer structure is critical to achieving desired gel properties. sign of each element of the polymer structure is critical to achieving desired gel properties. Inspired by the crucial role of cysteine–cysteine bonds and cleavage thereof in bio-

blocks, and the concentration of the polymer in solution [3,9–11]. Hence, the rational de-

*Gels* **2021**, *7*, x FOR PEER REVIEW 2 of 12

Inspired by the crucial role of cysteine–cysteine bonds and cleavage thereof in biological processes, the disulfide (S–S) bonds were exploited in a variety of functional materials due to their redox responsiveness. Materials containing disulfide bonds may undergo specific cleavage under reductive conditions, particularly upon exposure to the reductive intracellular space, rendering redox-responsive functionality to polymers. Disulfide bonds were incorporated in polyurethanes to afford self-healing properties [12], in electrochemical polymers and devices [13,14], and in drug carriers to render reduction-specific crosslinking or drug binding [15–17] for the controlled release of antitumor drugs due to high concentrations of reducing agents in the tumor microenvironment [18], to reduce toxicity in gene delivery platforms [19–22], and in supramolecular polymer applications [23]. The opportunity to incorporate disulfide bonds in biocompatible thermoreversible hydrogels may render these materials dual-responsiveness to both temperature and reduction. logical processes, the disulfide (S–S) bonds were exploited in a variety of functional materials due to their redox responsiveness. Materials containing disulfide bonds may undergo specific cleavage under reductive conditions, particularly upon exposure to the reductive intracellular space, rendering redox-responsive functionality to polymers. Disulfide bonds were incorporated in polyurethanes to afford self-healing properties [12], in electrochemical polymers and devices [13,14], and in drug carriers to render reductionspecific crosslinking or drug binding [15–17] for the controlled release of antitumor drugs due to high concentrations of reducing agents in the tumor microenvironment [18], to reduce toxicity in gene delivery platforms [19–22], and in supramolecular polymer applications [23]. The opportunity to incorporate disulfide bonds in biocompatible thermoreversible hydrogels may render these materials dual-responsiveness to both temperature and reduction.

In this work, we describe a triblock PEG-PLA-PEG copolymer bearing one disulfide bond per molecule. The thermoresponsiveness of the polymer solution afforded a fully water-soluble material at cool temperatures, which formed a gel between 32 and 40 ◦C. The polymer possesses a cleavable disulfide bond capable of cleavage upon exposure to strong reducing agents, thereby rendering immediate hydrogel collapse. This proof of concept was displayed by the cleavage of the disulfide bond in the presence of hydride. A synthetic analog without a disulfide bond was stable as a hydrogel even under harsh reductive conditions. The work here represents, to the best of our knowledge, the first report of a thermoresponsive hydrogel capable of controlled instantaneous collapse, in this example upon exposure to reducing conditions (Figure 1). In this work, we describe a triblock PEG-PLA-PEG copolymer bearing one disulfide bond per molecule. The thermoresponsiveness of the polymer solution afforded a fully water-soluble material at cool temperatures, which formed a gel between 32 and 40 °C. The polymer possesses a cleavable disulfide bond capable of cleavage upon exposure to strong reducing agents, thereby rendering immediate hydrogel collapse. This proof of concept was displayed by the cleavage of the disulfide bond in the presence of hydride. A synthetic analog without a disulfide bond was stable as a hydrogel even under harsh reductive conditions. The work here represents, to the best of our knowledge, the first report of a thermoresponsive hydrogel capable of controlled instantaneous collapse, in this example upon exposure to reducing conditions (Figure 1).

age.

**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 cleav-**Figure 1.** PEG-PLA-PEG triblock copolymers with embedded disulfide bonds immediately collapse upon addition of reducing agent NaBH<sup>4</sup> . Disulfide-bearing polymer hydrogels afford controlled hydrogel collapsibility due to S–S bond cleavage.
