Rapamycin-loaded Poly(lactic-co-glycolic) acid nanoparticles: Preparation, characterization, and in vitro toxicity study for potential intra-articular injection

Elise Pape (1, 2) , Marianne Parent (3) , Astrid Pinzano (1) , Anne Sapin-Minet (3) , Christel Henrionnet (1) , Pierre Gillet (1, 2) , Julien Scala-Bertola (1, 2) , Nicolas Gambier (1, 2)

1 IMoPA - Ingénierie Moléculaire et Physiopathologie Articulaire
2 Service de Pharmacologie Clinique et Toxicologie [CHRU Nancy]
3 CITHEFOR - Cibles thérapeutiques, formulation et expertise pré-clinique du médicament

Osteoarthritis (OA) is the most common degenerative joint disease. Rapamycin is a potential candidate for OA treatment by increasing the autophagy process implicated in its physiopathology. To optimize Rapamycin profit and avoid systemic side effects, intra-articular (i.a.) administration appeared helpful. However, Rapamycin's highly hydrophobic nature and low bioavailability made it challenging to develop purpose-made drug delivery systems to overcome these limitations. We developed Rapamycin-loaded nanoparticles (NPs) using poly (lactic-co-glycolic acid) by emulsion/evaporation method. We evaluated these NPs' cytocompatibility towards cartilage (chondrocytes) and synovial membrane cells (synoviocytes) for a potential i.a. administration. The in vitro characterization of Rapamycin-loaded NPs had shown a suitable profile for an i.a. administration. In vitro biocompatibility of NPs was highlighted to 10 µM of Rapamycin for both synoviocytes and chondrocytes, but significant toxicity was observed with higher concentrations. Besides, synoviocytes are more sensitive to Rapamycin-loaded NPs than chondrocytes. Finally, we observed in vitro that an adapted formulated Rapamycin-loaded NPs could be safe at suitable i.a. injection concentrations. The toxic effect of Rapamycin encapsulated in these NPs on both articular cells was dose-dependent. After Rapamycin-loaded NPs i.a. administration, local retention, in situ safety, and systemic release should be evaluated with experimental in vivo models

Mots clés: Rapamycin; Intra-articular injection; Nanoparticles

Domaines: Polymères; Pharmacie galénique; Pharmacologie; Rhumatologie et système ostéo-articulaire

Elise Pape, Marianne Parent, Astrid Pinzano, Anne Sapin-Minet, Christel Henrionnet, et al.. Rapamycin-loaded Poly(lactic-co-glycolic) acid nanoparticles: Preparation, characterization, and in vitro toxicity study for potential intra-articular injection. International Journal of Pharmaceutics, 2021, 609, pp.121198. ⟨10.1016/j.ijpharm.2021.121198⟩. ⟨hal-03395646⟩