A new class of stable azlactone-functionalized thermoresponsive nanoparticles have been synthesized and characterized. Such particles are based on well-defined copolymers of poly(N-isopropylacrylamide) (PNIPAM), poly(N,N-dimethylacrylamide) (PDMA) and poly(2-vinyl-4,4-dimethylazlactone) (PVDM) copolymers synthesized using reversible addition–fragmentation chain transfer (RAFT) polymerization. A well-defined PNIPAM macromolecular RAFT agent and a PDMA macromolecular RAFT agent of low polydispersities (PDIs = 1.04–1.12) were used to mediate the copolymerizations of DMA/VDM and of NIPAM/VDM, respectively, resulting in copolymers of M_n ranging from 19 500 g mol⁻¹ to 64 600 g mol⁻¹ and PDIs ranging from 1.04 to 1.20. Depending on the number-average polymerization degrees of NIPAM, DMA and VDM, lower critical solution temperatures (LCSTs) ranging from 36 °C to 44 °C were measured. Two block copolymers PNIPAM₄₆-b-P(VDM₆-co-DMA₆₅) and PDMA₂₃-b-P(VDM₁₀-co-NIPAM₄₆) have a LCST that occurs at the physiological temperature. Above the LCST, the resulting nanoparticles were covalently stabilized by reacting a diamine with azlactone rings. The size exclusion chromatography (SEC) analyses revealed that all unimers are incorporated into the core-crosslinked structures and into the shell-crosslinked structures. This new strategy of crosslinking nanoparticles based on thermoresponsive copolymers is of particular interest as it is highly efficient. The azlactone groups remaining in core-crosslinked nanoparticles are suitable to react with dansylhydrazine as shown by SEC analysis using UV detection.

Polymers containing the highly reactive azlactone group have emerged as a powerful platform useful in various application areas. This Highlight summarizes recent developments in the field of azlactone-derived polymers made in our group using controlled radical polymerizations (ATRP and RAFT) and ‘click’ chemistry methodology (thiol-Michael addition), leading to well defined reactive polymers.

Thermoresponsive block copolymers based on poly(ethylene oxide) (PEO) and poly(N-isopropyl acrylamide) (PNIPAM) containing azlactone groups along the backbone and at the chain-end of the macromolecular chain were synthesized by statistically reversible addition–fragmentation chain transfer (RAFT) copolymerization and by using a combination of RAFT polymerization and thiol–ene Michael addition. Well-defined poly(ethylene oxide)-b-poly(2-vinyl-4,4-dimethylazlactone-co-N-isopropyl acrylamide) (PEO-b-P(VDM-co-NIPAM)) block copolymers and azlactone-terminated poly(ethylene oxide)-b-poly(N-isopropyl acrylamide) (PEO-b-PNIPAM-VDM) diblock copolymers with low polydispersity indices (PDIs ≤ 1.10) were prepared and fully characterized by ¹H NMR spectroscopy, FT-IR spectroscopy, and SEC. Such PEO-b-P(VDM-co-NIPAM) block copolymers and azlactone-terminated PEO-b-PNIPAM block copolymers present tunable lower critical solution temperature (LCST) depending on PEO, PNIPAM, and PVDM molar ratios. The reactivity of the PEO₄₄-b-P(VDM₂₀-co-NIPAM₈₀) copolymer (M_n,NMR = 14 200 g mol⁻¹, PDI = 1.08) and of the PEO₄₄-b-PNIPAM₁₀₁-VDM copolymer (M_n,NMR = 13 700 g mol⁻¹, PDI = 1.08) was studied with lysozyme as a model protein. A bioconjugate with a higher apparent molecular weight was obtained with the PEO₄₄-b-P(VDM₂₀-co-NIPAM₈₀) copolymer in comparison with the one obtained using the PEO₄₄-b-PNIPAM₁₀₁-VDM copolymer as shown by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The results suggest promising applications of azlactone-functionalized polymers within the field of bioconjugation.

Well-defined poly(N-isopropylacrylamide) (PNIPAM) polymers with an oxazolone ring at the chain end have been synthesized by combining controlled radical polymerization and thiol-Michael addition “click” chemistry. First, PNIPAM was synthesized using reversible addition–fragmentation chain transfer (RAFT) polymerization to afford polymers of controlled molecular weight and molecular weight distribution (M_{n ( 1H NMR )} = 3200 g mol⁻¹; PDI_SEC = 1.05). The chain end was quantitatively converted to a thiol by aminolysis. Then, the functional monomer vinyl azlactone (VDM) was quantitatively “clicked” onto the chain end using a thiol-Michael addition reaction. The polymers were reacted with a model amine in order to demonstrate the potential of these polymers for bioconjugation.

New azlactone-based heterobifunctional linkers that proceed in orthogonal click-like reactions for chemical ligations in biologically relevant medium without releasing any byproduct.