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

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.

Thionolactone as Resin Additive to Prepare (bio)degradable 3D Objects via VAT Photopolymerization

3D printing and especially VAT photopolymerization leads to cross-linked materials with high thermal, chemical and mechanical properties. Nevertheless, such stability is incompatible with degradability and re/upcyclability. We showed here that thionolactone and especially dibenzo[c,e]-oxepane-5-thione (DOT) could be used as an additive (2 wt%) to acrylate-based resins to introduce weak bonds into the network via a radical ring-opening polymerization process. The low amount of additive allows to only slightly modify the printability of the resin, keep intact its resolution and maintain the mechanical properties of the 3D object. The resin with additive was used in UV microfabrication and 2-photon stereolithography setup and commercial 3D printers. The fabricated objects were shown to degrade in basic solvent as well in a home-made compost. The rate of degradation is nonetheless dependent of the size of the object. This feature was used to prepare 3D objects with support structures that could be easily solubilized.

A Simple Route to Aqueous Suspensions of Degradable Copolymer Nanoparticles from Radical Ring-Opening Polymerization-Induced Self-Assembly (rROPISA)

Degradable polymer nanoparticles are almost exclusively obtained by formulation of preformed degradable polymers, such as aliphatic polyesters, thus resulting is very low nanoparticle concentrations and limited structural diversity. On the other hand, many different vinyl polymers can be obtained by polymerization in aqueous dispersed media, but their non-degradability limits their use especially in the biomedical field. Herein, we combined the best of both worlds by developing a two-step radical ring-opening copolymerization-induced self-assembly (rROPISA) process, allowing to generate aqueous suspensions of narrowly dispersed, degradable vinyl copolymer nanoparticles at 15 wt.% solid contents, containing cyclic ketene acetal (CKA) units in the nanoparticle core. This strategy relied on rROPISA in DMF, followed by a simple transfer step to water. It was successfully applied to the three main CKAs used in rROP and yielded nanoparticles of ~80–215 nm in diameter with tunable amount of CKA up to 21 mol.%. Successful incorporation of ester groups in the copolymers was demonstrated by hydrolytic degradation of both the copolymers and the nanoparticles. The nanoparticles’ cytocompatibility was then established by cell viability assays and cell morphology observation with three representative healthy cell lines. Not only this synthetic strategy could be of great potential for drug delivery applications, but it can also be beneficial to other research fields to yield more environmentally friendly materials involving the use of latexes, such as paints or coatings.

Truly Random Degradable Vinyl Copolymers via Photocontrolled Radical Ring-Opening Cascade Copolymerization

Degradable vinyl polymers by radical ring-opening polymerization have become a promising solution to the challenges caused by the widespread use of non-degradable vinyl plastics. However, achieving even distribution of labile functional groups in the backbone of degradable vinyl polymers remains challenging. Herein, we report a photocatalytic approach to truly random degradable vinyl copolymers with tunable main-chain composition via radical ring-opening cascade copolymerization (rROCCP). The rROCCP of the macrocyclic allylic sulfone and acrylates or acrylamides mediated by visible light at ambient temperature achieved near-unity reactivity ratios of both comonomers over the entire range of the comonomer compositions and afforded truly random vinyl copolymers with degradable units evenly distributed in the polymer backbone. Experimental and computational evidence revealed an unusual reversible inhibition of chain propagation by in situ generated sulfur dioxide, which was successfully overcome by reducing the solubility of sulfur dioxide in the reaction mixture. This study provided a powerful approach to truly random degradable vinyl copolymers with tunable main-chain labile functionalities and comparable thermal and mechanical properties to traditional non-degradable vinyl polymers.