Biocompatibility and Physiological Thiolytic Degradability of Radically-made Thioester-functional Copolymers

Abstract

Being non-degradable, 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(7H)-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 non-cytotoxic, making thioester backbone-functional polymers promising for drug delivery applications.

Degradable Polyisoprene by Radical Ring-Opening Polymerization and Application to Polymer Prodrug Nanoparticles

“…Degradation of the copolymers was then performed to confirm the successful insertion of thioester groups. Different degradation conditions were used (e.g., KOH, TBD and isopropylamine) [39][40][41][42][43][44] to investigate hydrolysis and aminolysis as two distinct degradations modalities (in addition to physiological [48] and oxidative [56] degradations of thioester-containing copolymers). In general, whatever the polymerization methods to generate the copolymers, significant degradation was observed after their treatment with either KOH or TBD for 16 h (Table 1, Figure 4, S6 and S7).…”

“…In order to diversify the range of polymers suitable for biomedical applications, the design (bio)degradable vinyl polymers is currently of great interest. [1] Spurred by the physiological thiolytic degradability of DOT-containing copolymers, [48] we illustrated the potential of the I/DOT copolymerization system for drug delivery purposes by first investigating the formulation of P(I-co-DOT) copolymers into nanoparticles (N0-N4, Table 2). Narrowly dispersed nanoparticles were successfully formed by nanoprecipitation, exhibiting average diameter comprised between 105 and 150 nm (Table 2, Figure S9).…”

“…[43] Very recently, DOT was copolymerized with nBA or S by either conventional emulsion polymerization [44] and polymerization-induced self-assembly, [46] while DOT was also used to impart chemical recyclability to polystyrene. [47] Moreover, it has been shown that DOTcontaining copolymers can be degraded in the presence of physiologically relevant concentrations of cysteine or glutathione, [48] which allows to consider DOT-containing copolymers in nanomedicine.…”