Oxidation-Responsive and “Clickable” Poly(ethylene glycol) via Copolymerization of 2-(Methylthio)ethyl Glycidyl Ether

Abstract

Poly(ethylene glycol) (PEG) is a widely used biocompatible polymer. We describe a novel epoxide monomer with methyl-thioether moiety, 2-(methylthio)ethyl glycidyl ether (MTEGE), which enables the synthesis of well-defined thioether-functional poly(ethylene glycol). Random and block mPEG-b-PMTEGE copolymers (Mw/Mn = 1.05-1.17) were obtained via anionic ring opening polymerization (AROP) with molecular weights ranging from 5 600 to 12 000 g·mol(-1). The statistical copolymerization of MTEGE with ethylene oxide results in a random microstructure (rEO = 0.92 ± 0.02 and rMTEG E = 1.06 ± 0.02), which was confirmed by in situ (1)H NMR kinetic studies. The random copolymers are thermoresponsive in aqueous solution, with a wide range of tunable transition temperatures of 88 to 28 °C. In contrast, mPEG-b-PMTEGE block copolymers formed well-defined micelles (Rh ≈ 9-15 nm) in water, studied by detailed light scattering (DLS and SLS). Intriguingly, the thioether moieties of MTEGE can be selectively oxidized into sulfoxide units, leading to full disassembly of the micelles, as confirmed by detection of pure unimers (DLS and SLS). Oxidation-responsive release of encapsulated Nile Red demonstrates the potential of these micelles as redox-responsive nanocarriers. MTT assays showed only minor effects of the thioethers and their oxidized derivatives on the cellular metabolism of WEHI-164 and HEK-293T cell lines (1-1000 μg·mL(-1)). Further, sulfonium PEG polyelectrolytes can be obtained via alkylation or alkoxylation of MTEGE, providing access to a large variety of functional groups at the charged sulfur atom.

Synchronous Chemoradiation Nanovesicles by X‐Ray Triggered Cascade of Drug Release

“…Subsequently, the in situ oxidation of PPS from hydrophobic thioether to sulfoxide and finally hydrophilic sulfone results in efficient degradation of the Au-LAHP-vDOX and release of cargo drugs. [16] In this manner, drug release is synchronously confined when radiation therapy is applied, which may largely mitigate possible development of resistance to monotherapy and in turn potentiate the maximal synergism in chemoradiation therapy. [17] Meanwhile, this approach may also benefit from the radiation dose enhancement effect by the high atomic number (Z) Au NPs and the ROS mediated mechanisms for improving treatment outcomes.…”

Poly(Ethylene Glycol) Dimethacrylates with Cleavable Ketal Sites: Precursors for Cleavable PEG‐Hydrogels

“…To investigate the degradation kinetics of both PEG‐ketal‐diols and PEG‐ketal‐DMA macromonomers, we measured the in situ 1 H NMR kinetics of the degradation of macromonomers dissolved in deuterated phosphate buffer solutions buffered to different pH values (degradation scheme see Scheme S1 in the Supporting Information). In situ 1 H NMR measurements have been extensively used to monitor polymerization reactions online . It is also possible to use this technique to analyze the cleavage of ketal macromonomers by monitoring the changes of typical NMR signals in situ during the hydrolysis reaction.…”

Tuning the LCST of PNIPAM via Random Oxidation-Sensitive Thioether Functionalities

“…In the case of thioethers, in contrast to regular ethers the nature of sulfur provides the possibility of functionalization, while representing a more stable option than disulfides and thiol groups, which is essential for biomedical applications since a precise targeting requires a structure which remains unchanged until it is required . During the last years the incorporation of thioethers for stimuli‐responsive materials has been a deal of research effort, for instance, Tirelli and co‐workers reported the potential of polythioethers as redox‐responsive nanocarriers for inflammation targeting, remarking that hydrophobic thioethers could be oxidized in the milieu of inflamed tissue, changing the hydrophobic/hydrophilic balance with disassembly of the nanostructure, and Long and co‐workers, who studied sulfone‐functional poly(methyl methacrylate) (PMMA) derivatives, found them to be nonviral nucleic acid delivery agents and confirmed their high potential for biomedical applications.…”