Single-Dose Intra-Cartilage Delivery of Kartogenin Using a Cationic Multi-Arm Avidin Nanocarrier Suppresses Cytokine-Induced Osteoarthritis-Related Catabolism

Abstract

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.

Engineered Platelet Microparticle-Membrane Camouflaged Nanoparticles for Targeting the Golgi Apparatus of Synovial Fibroblasts to Attenuate Rheumatoid Arthritis

“…Moreover, the repeated administration of Gol-PMMNPs induced no obvious cumulative organ accumulation (Figure S11). Previous studies illustrated that positively charged nanoparticles with small size (<60 nm) were advantageous in achieving long retention in joints. − With negative charges and sizes of 150–175 nm, the arthritic joint accumulations of all three types of nanoparticles were significantly decreased within 72 h postinjection (Figure S12). However, PMMNPs and Gol-PMMNPs showed high-level accumulations in inflamed joints even 72 h after intravenous administration, which was mainly attributed to the better inflamed joint-targeting ability of these membrane-coated NPs.…”

“…In addition, Gol-PMMNPs showed a moderate effect on increasing drug distribution in synovial macrophages (Figure S13b). Loading drugs into positively charged nanocarriers with a small size (<60 nm) was crucial for penetrating the full depth of cartilage to reach the chondrocytes. − With negative charge and large size (>60 nm), Gol-PMMNPs may not be able to reach chondrocytes efficiently. These data proved that Gol-PMMNPs could selectively deliver drugs to synovial fibroblasts located in inflamed joints.…”

Analysis of Nanomedicine Efficacy for Osteoarthritis

“…[183] In a subsequent study, He et al developed new formulations based on this cationic delivery system loaded with Kartogenin, the drug that protects and repairs cartilage that is quickly removed by synovial fluid and cannot penetrate cartilage due to its hydrophobicity, providing a targeted therapeutic effect while effectively inhibiting cartilage breakdown with only one dose of intra-articular administration. [184] In addition, it has also been shown that intra-articular injections of MSCs-derived NPs have also demonstrated potential for targeting cartilage therapy due to their powerful immunomodulatory capabilities. [185] In the late stages of OA, the most prominent sensation for patients is joint pain and severe damage to the subchondral bone.…”

Cationic peptide carriers enable long-term delivery of insulin-like growth factor-1 to suppress osteoarthritis-induced matrix degradation

“…Media was collected and changed every 2 days and IL-1α was replenished with each media change. In single-dose conditions, the cartilage explants were exposed to IGF-1 for only the first 2 days of culture, and further media changes did not contain IGF-1 to resemble the case of a single-dose IA injection in vivo [23,27,28]. However, for the continuous dose administration, IGF-1 was replenished in the culture with each media change.…”