THU0462 Intra-Articular Delivery of Kartogenin-Conjugated Chitosan Nano/Microparticles for Cartilage Regeneration

BackgroundOsteoarthritis (OA), also known as degenerative arthritis or degenerative joint disease, affects millions of people around the world. Intra-articular (IA) drug delivery can be a useful modality in OA treatment, delivering a drug directly to the main focus of the disease. The therapeutic effect of IA drug depends mostly on the efficacy of the drug delivery system, due to the short retention time and rapid clearance of soluble drugs from the joint. Kartogenin is a recently characterized material that promotes the selective differentiation of mesenchymal stem cells (MSCs) into chondrocytes, thus stimulating cartilage regeneration [1].ObjectivesWe developed an intra-articular (IA) drug delivery system to treat osteoarthritis (OA) that consisted of kartogenin conjugated chitosan (CHI-KGN). The aim of this study was to (1) characterize the CHI-KGN particles for sustained release and chondrogenic activity in vitro, (2) evaluate the CHI-KGN particles as novel IA drug delivery systems for IA retention and regeneration of OA joint in vivo.MethodsKartogenin was conjugated with low-molecular-weight chitosan (LMWCS) and medium-molecular-weight chitosan (MMWCS) by covalent coupling of kartogenin to each chitosan using an ethyl (dimethylaminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS) catalyst. The particular drug delivery systems were prepared by an ionic gelation of the CHI-KGN conjugate with tripolyphosphate (TPP) anion that can interact with cationic chitosan by electrostatic forces.ResultsNanoparticles (NPs, 150±39 nm) or microparticles (MPs, 1.8±0.54 μm) were successfully fabricated from kartogenin conjugated-LMWCS and –MMWCS, respectively, by an ionic gelation using TPP. The in vitro release profiles of kartogenin from the particles showed sustained release for 7 weeks. When the effects of the CHI-KGN NPs or CHI-KGN MPs were evaluated on the in vitro chondrogenic differentiation of human bone marrow MSCs (hBMMSCs), the CHI-KGN NPs and CHI-KGN MPs induced higher expression of chondrogenic markers from cultured hBMMSCs than unconjugated kartogenin. In particular, hBMMSCs treated with CHI-KGN NPs exhibited more distinct chondrogenic properties in the long-term pellet cultures than those treated with CHI-KGN MPs. The in vivo therapeutic effects of CHI-KGN NPs or CHI-KGN MPs were investigated using a surgically-induced OA model in rats. The CHI-KGN MPs showed longer retention time in the knee joint than the CHI-KGN NPs after IA injection in OA rats.