Biocompatibility and Physiological Thiolytic Degradability of Radically Made Thioester-Functional Copolymers: Opportunities for Drug Release

Abstract

Being nondegradable, vinyl polymers have limited biomedical applicability. Unfortunately, backbone esters incorporated through conventional radical ring-opening methods do not undergo appreciable abiotic hydrolysis under physiologically relevant conditions. Here, PEG acrylate and di(ethylene glycol) acrylamide-based copolymers containing backbone thioesters were prepared through the radical ring-opening copolymerization of the thionolactone dibenzo[c,e]oxepin-5(7 H )-thione. The thioesters degraded fully in the presence of 10 mM cysteine at pH 7.4, with the mechanism presumed to involve an irreversible S–N switch. Degradations with N -acetylcysteine and glutathione were reversible through the thiol–thioester exchange polycondensation of R–SC(=O)–polymer–SH fragments with full degradation relying on an increased thiolate/thioester ratio. Treatment with 10 mM glutathione at pH 7.2 (mimicking intracellular conditions) triggered an insoluble–soluble switch of a temperature-responsive copolymer at 37 °C and the release of encapsulated Nile Red (as a drug model) from core-degradable diblock copolymer micelles. Copolymers and their cysteinolytic degradation products were found to be noncytotoxic, making thioester backbone-functional polymers promising for drug delivery applications.

Degradable Vinyl Polymer Nanoparticles/Latexes by Aqueous Nitroxide-Mediated Polymerization-Induced Self-Assembly

“…Thioester-containing copolymers can be cleaved by hydrolysis, 23 aminolysis, 19,[21][22][23] methanolysis 21 and even thiolysis. 24 More recently, they have also been shown to degrade under physiological conditions in presence of cysteine or glutathione at concentrations mimicking extra-and intracellular conditions, 32 respectively. Herein, we used isopropylamine to perform aminolysis, as well as TBD as a strong base.…”

Thiocarbonyl chemistry in polymer science

“…Note that the specific rates may differ from this guide based on the basicity of the nucleophile and nucleofuge, the nature of group R, and the solvent polarity. 67,80,[84][85][86][87]…”

“…66 The degradation was shown to cause insolublesoluble transitions (including of thermally responsive polymers with LCST or UCST behaviour) 66 in water, which was exploited to release an encapsulated dye (as a drug model) from core-degradable PEG-based diblock copolymer micelles. 67 As the thioester linkages were shown not to contribute to cytotoxicity, the TARO method is promising for intracellular drug delivery applications with glutathione-triggered degradation and release. 67 TARO monomers have also found a use in producing degradable cross-linked materials through uncontrolled radical polymerization.…”

“…67 As the thioester linkages were shown not to contribute to cytotoxicity, the TARO method is promising for intracellular drug delivery applications with glutathione-triggered degradation and release. 67 TARO monomers have also found a use in producing degradable cross-linked materials through uncontrolled radical polymerization. 68,71 Incorporation of only 4 mol% of DOT into acrylate-based networks led to the ability to completely degrade the insoluble materials.…”

Degradable linear and bottlebrush thioester-functional copolymers through atom transfer radical ring-opening copolymerization of a thionolactone

“…Recently, thionolactones were shown to undergo radical ring-opening via thiocarbonyl additionring-opening (TARO) [6][7][8][9][10][11][12][13][14] which provides backbone thioester functionality. These thioesters can be selectively cleaved through aminolysis, thiolysis (including under biologically relevant conditions) 7 and, very rapidly, through persulfate oxidation. 6 RDRP of thionolactones has been achieved exclusively through RAFT polymerization with which TARO radical polymerization appears to be fully compatible.…”