A photocrosslinkable and anti-inflammatory hydrogel of loxoprofen-conjugated chitosan methacrylate†

Abstract

Polymer–drug conjugates are widely used for drug delivery. Herein, we report an injectable hydrogel for local delivery of nonsteroidal anti-inflammatory drugs (NSAIDs) using chitosan (CS) as a carrier polymer. Loxoprofen (LOX) was conjugated to the backbone of CS via carbodiimide chemistry to obtain the LOX–CS conjugate. This conjugation transformed the water-insoluble unmodified CS into the water-soluble LOX–CS conjugate. In particular, the LOX–CS conjugate did not precipitate at pH 7, allowing smooth subsequent chemical modification with methacrylic anhydride (MA) to synthesize LOX–CS methacrylate (LOX–CS–MA) with significantly higher methacrylation substitution. The LOX–CS–MA was capable of in situ gel formation under visible light irradiation in the presence of a benzoin-2,4,6-trimethylbenzoylphosphinate lithium (LAP) photoinitiator. Our results show that the LOX–CS–MA hydrogel exhibited good cytocompatibility and blood compatibility. It promoted M2 polarization, inhibited pro-inflammatory gene expression, and upregulated anti-inflammatory gene expression of macrophages. Furthermore, the LOX–CS–MA hydrogel significantly reduced reactive oxygen species (ROS) and nitric oxide (NO) produced by lipopolysaccharide (LPS)-stimulated macrophages. A subcutaneous implanted LOX–CS–MA hydrogel in a rat model revealed significantly reduced inflammatory cell density, decreased cell infiltration, and a much thinner fibrous capsule compared to the CS methacrylate (CS–MA) hydrogel, thus markedly alleviating the inflammatory response. This study highlights the feasibility of CS–drug conjugates in preparing CS-based methacrylate hydrogels for sustained drug release.