title: Intra-articular delivery of kartogenin-conjugated chitosan nano/microparticles for cartilage regeneration.
abstract: We developed an intra-articular (IA) drug delivery system to treat osteoarthritis (OA) that consisted of kartogenin conjugated chitosan (CHI-KGN). Kartogenin, which promotes the selective differentiation of mesenchymal stem cells (MSCs) into chondrocytes, 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. Nanoparticles (NPs, 150 ± 39 nm) or microparticles (MPs, 1.8 ± 0.54 μm) were fabricated from kartogenin conjugated-LMWCS and -MMWCS, respectively, by an ionic gelation using tripolyphosphate (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. The rats treated with CHI-KGN NPs or CHI-KGN MPs by IA injection showed much less degenerative changes than untreated control or rats treated with unconjugated kartogenin. In conclusion, CHI-KGN NPs or CHI-KGN MPs can be useful polymer-drug conjugates as an IA drug delivery system to treat OA.
authors.affiliation: Department of Orthopedics, Dongguk University Ilsan Hospital, Goyang, Republic of Korea.
authors.forename: Mi Lan
authors.initials: ML
authors.lastname: Kang
authors.affiliation: Department of Orthopedics, Dongguk University Ilsan Hospital, Goyang, Republic of Korea.
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Ko
authors.affiliation: Department of Orthopedics, Dongguk University Ilsan Hospital, Goyang, Republic of Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Orthopedics, Dongguk University Ilsan Hospital, Goyang, Republic of Korea. Electronic address: gunil@duih.org.
authors.forename: Gun-Il
authors.initials: GI
authors.lastname: Im
mesh_terms: D000368:Aged; D000813:Anilides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002356:Cartilage / Q000187:drug effects* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D048271:Chitosan / Q000737:chemistry*; D019902:Chondrocytes / Q000166:cytology; D020219:Chondrogenesis / Q000187:drug effects*; D006801:Humans; D007270:Injections, Intra-Articular; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D008875:Middle Aged; D053758:Nanoparticles / Q000737:chemistry*; D010003:Osteoarthritis / Q000188:drug therapy*; D010795:Phthalic Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000187:drug effects
chemical_list: D000813:Anilides; D010795:Phthalic Acids; D048271:Chitosan; C572342:kartogenin
keywords: Chitosan microparticles; Chitosan nanoparticles; Intra-articular injection; Kartogenin; Osteoarthritis; Polymer-drug conjugate