Rat synovial tissue and blood rapamycin pharmacokinetics after intra-articular injection of free solution or nanoparticles vs free rapamycin intravenous shot.

Intra-articular (IA) injection of a chondroprotective candidate may delay the osteoarthritis (OA) course, but its rapid absorption into systemic circulation may limit efficacy and produce untoward effects. We compared the pharmacokinetics (PK) of IA rapamycin injected as sustained release in nanoparticles (NPs) versus a free rapamycin suspension in the rat knee compared to an intravenous (IV) free rapamycin shot taken as a reference. Rats received either a single IV injection of free rapamycin (10 µM) or an IA of free or NPs-loaded rapamycin. After sequential exsanguination (15, 30, 60, 180, 360 min, D1, and D7), knee synovial tissue (ST) and cartilage histology were performed. Blood and ST concentrations (LC-MS/MS), PK parameters (area under the curve: AUC; mean residence time: MRT; elimination half-life: T), and IA biocompatibility were assessed. AUC was significantly higher for IV than for both IA injections (AUC and AUC), with 4248 vs 28 and 74 µg.min.L. For ST parameters, we observed a significant difference between AUC and AUC with 3735 and 10513 µg.min.L correspondingly. Articular T and MRT were higher after NPs than after free rapamycin injection: 57.8 and 5.0 h for T and 80.6 and 5.5 h for MRT, respectively. Histological analysis revealed no chondral injuries and slight transient synovitis only 3 h after the administration of NPs. In the rat knee, rapamycin-loaded NPs delivery via a single IA injection is biocompatible and prolongs synovium joint residency, diminishes blood levels, and reduces detrimental systemic exposure.