Background and Objective:
Kartogenin (KGN), a chondrogenic and chondroprotective small molecule, suffers from rapid clearance after intra-articular administration. Repeated injection of high doses can lead to off-target effects, including stimulation of the overgrowth of normal tissues at non-target sites. Therefore, in this study, we aimed to synthesize a nanoparticle hydrogel system to improve the release profile of KGN and increase its retention time in the joint cavity.Materials and Methods: The oxidation of hyaluronic acid (HA) by sodium periodate (NaIO۴) was performed to create aldehyde functional groups and investigated by FTIR spectrometry and TNBS assay. Then, oxidized hyaluronic acid (oxi-HA) was cross-linked with adipic acid dihydrazide (ADH) to form the oxi-HA/ADH hydrogel. The KGN-loaded nanoparticles were prepared by the ionic gel method and embedded in the oxi-HA/ADH hydrogel. The in vitro release of KGN from drug-loaded nanoparticles and hydrogel was evaluated at ۳۷ °C in PBS for two weeks. The cytotoxicity and hemocompatibility of both hydrogel and KGN-loaded nanoparticles were investigated by MTT and hemolysis assays, respectively. The water absorption capacity and the degradation behavior of oxi-HA/ADH hydrogel with or without nanoparticles were investigated by a swelling test and degradation test, respectively.Findings: The FTIR spectrum confirmed the formation of aldehyde groups in the oxi-HA, nanoparticle synthesis, and hydrogel formation. The results of the degradation test showed that the hydrogel with nanoparticles was able to maintain its gel matrix for a longer time in PBS than without nanoparticles. Also, the oxi-HA/ADH hydrogel with KGN-loaded nanoparticles improved KGN release compared with pure oxi-HA/ADH hydrogel. The hemolysis results showed that both hydrogel and nanoparticles did not damage RBCs and had proper hemocompatibility. The cell viability of both hydrogel and nanoparticles was confirmed using chondrocyte cells.Conclusions: The results suggest that the composite hydrogel-mediated delivery of KGN can be a promising technique and can facilitate the clinical translatability of KGN for endogenous cartilage repair with only a single dose.