Effect of residue structure on the thermal and thermoresponsive properties of γ-substituted poly(N-acryloyl-2-pyrrolidones)

Abstract

We discuss the results of an investigation into the structure/property correlations of γ-substituted poly(N-acryloyl-2-pyrrolidone)s, a recently reported class of pyrrolidone-based polymers prepared from pyroglutamic acid, a bio-derived resource. Monomers bearing alkoxy and thiolate substituents were polymerized by reversible addition–fragmentation chain-transfer (RAFT) polymerization with polymer molecular weights and dispersities (Đ_M) estimated by gel-permeation chromatography (GPC). Single-crystal X-ray diffraction studies reveal a large degree of steric congestion about the monomer acryl-imide functionality, a topological feature that has residual effects on polymer physicochemical properties when variations to γ-substituent structure are applied. Indeed, glass transition temperature T_g is significantly influenced by both substituent structure (e.g., saturated linear aliphatic vs. cyclic aliphatic vs. aromatic) and chemical class with the more thermally stable thiolated polymers possessing lower T_g values than their alkoxy congeners of comparable molecular weight. Regarding solubility, all polymers dissolve in common organic solvents including chloroform, dichloromethane, and tetrahydrofuran while only those bearing methoxyethoxy (poly(MeOEthONP)) and tetrahydrofurfuryloxy (poly(FurONP)) substituents are soluble in water, a medium where they also exhibit thermoresponsive behavior. Despite the structural similarities among these polymers, a remarkable difference of ca. 32 °C is observed between their cloud point (CP) temperatures (poly(MeOEthONP), CP = 47 °C, poly(FurONP), CP = 15 °C) measured during a phase transition that is sensitive to polymer concentration (0.1–1.0 g L⁻¹) and chemical environment (e.g. deionized water vs. phosphate buffered saline (PBS)). Given that both the methoxyethyl thiolate-substituted (poly(MeOEthSNP) and substituent-free (poly(NP)) polymers are insoluble in aqueous media, we conclude that the observed thermoresponsivity arises from both the topology of the hydrophilic ether-based moiety and identity of the atom (i.e. O vs. S) that tethers the substituent to the lactam scaffold. Finally, cytotoxicity assays were performed on poly(MeOEthONP) as its lower critical solution temperature (LCST) is close to that of the human body, an attribute that is desirable for hydrophilic materials used in thermoresponsive drug-delivery platforms. The results of this investigation show that over a concentration range of ca. 0.1–100 μg mL⁻¹, poly(MeOEthONP) formulations are primarily noncytotoxic to both MCF-7 breast cancer cells and human dermal fibroblasts.