free rapamycin with lower systemic diffusion. In vivo, IA administration of 10 μM rapamycin NPs increased its local residency vs. Rapamycin NPs did not induce cytotoxicity on articular cells at 10 μM.
Histology revealed no knee injury.ĭiscussion/Conclusion: In vitro, rapamycin (10 μM) did not induce articular cytotoxicity and reduced IL1β's phlogistic effects. T1/2 and MRT were higher after NPs than free rapamycin injections: 57.8–5.0 h, vs. We observed a difference between AUCIA free and AUCIA NP (373 μg/min/L) concerning synovium. In vivo, we determined (10 μM) an AUC higher for IV free rapamycin than for IA injection (AUCIA free and AUCIA NP), with respectively 4248, 28, and 74 μg/min/L in blood. Rapamycin NPs showed similar dose-dependent toxicity on articular cells. No difference was observed for autophagic genes in the three cellular types, but the IL1β-induced MMP13 level decreased. Results: In vitro, we observed the concentration-dependent toxicity of free rapamycin for chondrocytes, synoviocytes, and MSCs. We finally studied in vivo pharmacokinetic parameters of free (IV & IA) or NPs-loaded rapamycin (IA) (10 μM) injections in blood and synovial tissue in rat knees: AUC, T1/2, and MRT. We also developed rapamycin-loaded nanoparticles (NPs) for IA injection to assess NPs' cytotoxicity vs free rapamycin. We then evaluated autophagic (beclin1 and Atg7) and catabolic (MMP13) genes with 10 μM rapamycin exposure for 24 h. Material and methods: We performed in vitro cytotoxicity on human chondrocytes, synoviocytes, and mesenchymal stem cells (MSCs) after 24 h exposure in hypoxia and normoxia with various rapamycin concentrations (10 nM to 100 μM). It is a candidate (10 μM) for experimental intra-articular (IA) treatment of osteoarthritis (OA), autophagy being defective in OA. Introduction: Rapamycin, an immunosuppressant, is a mTOR inhibitor leading to autophagy restoration. Gambier 1ġ CNRS, Imopa & Laboratoire de Pharmacologie, Toxicologie et Pharmacovigilance, CHRU - Nancy, Université de Lorraine, France 2 Cithefor - Nancy, Université de Lorraine, France Designing dedicated rapamycin nanoparticles for articular vectorization: A holistic pharmacological approachĮ.