Biocompatibility and Physiological Thiolytic Degradability of Radically Made Thioester-Functional Copolymers: Opportunities for Drug Release
Nathaniel M. Bingham, Qamar un Nisa, Priyanka Gupta, Neil P. Young, Eirini Velliou, Peter J. Roth
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(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 noncytotoxic, making thioester backbone-functional polymers promising for drug delivery applications.