Redox-Degradable Biocompatible Hyperbranched Polyglycerols: Synthesis, Copolymerization Kinetics, Degradation, and Biocompatibility

Abstract

Polymers that are biocompatible and degrade in response to stimuli are highly desirable as smart drug-delivery carriers. We report the first novel redox-degradable hyperbranched polyglycerols. A glycerol monomer containing a disulfide bond, i.e., 2-((2-(oxiran-2-ylmethoxy)ethyl)disulfanyl)ethan-1-ol (SSG), was designed and polymerized through anionic ring-opening multibranching polymerization to yield a series of redox-degradable hyperbranched polyglycerols (PSSGs) with controlled molecular weights (2000− 11 000 g/mol) and relatively low molecular weight distributions (M w /M n < 1.15). In addition, copolymerization with a nondegradable glycerol (G) monomer provided P(G-co-SSG) copolymers, which contained an adjustable fraction of degradable moieties within their polyglycerol backbones. The polymerization was characterized using 1 H and 13 C NMR spectroscopy, GPC, and MALDI-ToF mass spectrometry. The copolymerization process was also evaluated using quantitative in situ 13 C NMR kinetic measurements in bulk, which revealed that the reaction kinetics of G were faster than those of the SSG monomer, leading to a gradient during the copolymerization process. Furthermore, we explored the redox-responsive degradation of the polymers upon treatment with a reducing agent, which resulted in selective degradation of the polymers in small segments. In vitro cytotoxicity studies, such as MTT and CCK-8 assays, revealed the superior biocompatibility of these new polymers even at high concentrations of 500 μg/ mL. We anticipate that these novel redox-degradable and highly biocompatible polyglycerols will find applications in a variety of emerging biomedical fields.

Reduction‐Triggered Self‐Cross‐Linked Hyperbranched Polyglycerol Nanogels for Intracellular Delivery of Drugs and Proteins

“…To provide redox‐degradable hyperbranched polyglycerols, we first prepared the SSG monomer as reported previously . After synthesis of the SSG monomer, we performed the polymerization to PSSG homopolymers and P(G‐ co ‐SSG) copolymers via anionic ring‐opening multibranching polymerization methods.…”

“…Moreover, recent advances in the development of functional epoxide monomers have expanded the toolkit for the synthesis of functional hyperbranched PGs with responsive properties under specific biological cues. For example, a glycerol monomer containing a disulfide bond, that is, 2‐((2‐(oxiran‐2‐ylmethoxy) ethyl)disulfanyl) ethan‐1‐ol (SSG), was recently developed by our group to synthesize redox‐degradable hyperbranched PGs (PSSGs) . These PSSGs can offer new opportunities in smart drug delivery systems by taking advantage of considerable redox concentration gradients between intracellular and extracellular environments.…”

Photoinduced Cross‐Linking of Dynamic Poly(disulfide) Films via Thiol Oxidative Coupling

“…Dithiothreitol forms a very stable six-membered ring in its oxidized state, and is currently the most widely used reducing agent of disulfi de-based proteins. [ 8 ] A gradual solubilization was noted, and a slightly turbid solution was obtained after 12 d under stirring (see images in Figure S9, Supporting Information). The reaction progress was assessed using 13 C NMR.…”

Shell Cleavable Dendritic Polyglycerol Sulfates Show High Anti‐Inflammatory Properties by Inhibiting L‐Selectin Binding and Complement Activation

“…[ 19 ] Son and co-workers recently reported redox-sensitive hyperbranched polyglycerols (hPG) containing disulfi de bonds which can undergo intracellular cleavage into their corresponding thiols due to the cellular reductive environment. [ 20 ] Other approaches use pH sensitive systems such as ketals, acetals, or esters. Shenoi et al incorporated different ketal groups into a hPG backbone that led to polymers with controllable degradation kinetics depending on the pH, structure of the ketal functionality, and temperature.…”