LAUSR

Objective Kartogenin (KGN) has proven as a both chondrogenic and chondroprotective drug for osteoarthritis (OA) therapy. However, being a small hydrophobic molecule, KGN suffers from rapid joint clearance and inability to penetrate cartilage to reach chondrocytes following intra-articular administration. As such multiple high doses are needed that can lead to off-target effects including stimulation and tissue outgrowth. Here we design charge-based cartilage targeting formulation of KGN by using a multi-arm cationic nano-construct of Avidin (mAv) that can rapidly penetrate into cartilage in high concentrations owing to weak-reversible electrostatic binding interactions with negatively charged aggrecan-glycosaminoglycans (GAGs) and form an extended-release drug depot such that its therapeutic benefit can be reaped in just a single dose. Design We synthesized 2 novel formulations, one with a releasable ester linker (mAv-OH-KGN, release half-life ~58 h) that enables sustained KGN release over 2 weeks and another with a non-releasable amide linker (mAv-NH-KGN) that relies on mAv’s ability to be uptaken and endocytosed by chondrocytes for drug delivery. Their effectiveness in suppressing cytokine-induced catabolism was evaluated in vitro using cartilage explant culture model. Results A single 100 μM dose of cartilage homing mAv-KGN was significantly more effective in suppressing cytokine-induced GAG loss, cell death, inflammatory response and in rescuing cell metabolism than a single dose of free KGN; multiple doses of free KGN were needed to match this therapeutic response. Conclusion mAv mediated delivery of KGN is promising and can facilitate clinical translation of KGN for OA treatment with only a single dose.