title: Effect of particle size on the biodistribution of nano- and microparticles following intra-articular injection in mice.
abstract: Intra-articular (IA) injection of extended drug release forms based on biodegradable microparticles holds promise for the treatment of joint diseases. However, the fate of microparticles following intra-articular injection is controversial and has not been thoroughly investigated. The aim of this work was therefore to evaluate the biodistribution of fluorescent poly(lactic acid) particles of different sizes after IA injection in arthritic or healthy mice. Regardless of the inflammatory status of the joint, 300 nm-nanoparticles leaked from the joint. Due to inflammation and related increase of vascular permeability, 3 μm-microparticles that were retained in the non-inflamed synovial membrane leaked from the inflamed joint. Complete retention of 10 μm-microparticles was observed independently of the joint inflammatory status. Embedding particles in a hyaluronic acid gel prolonged the retention of the formulations only in inflamed joints. Depending on particle's size, formulations were preferentially eliminated by blood vessels or lymphatic pathways. Poly(lactic acid) particles of 3 μm were biocompatible and retained in knee joints at least for 6 weeks. This work highlights the need to deliver hyaluronic acid-embedded particles of at least 3 μm to guarantee their retention in inflamed joints. These results will contribute to the rational design of long-lasting formulations to treat acute and chronic joint diseases.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Pradal
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Maudens
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University Hospital and Department of Pathology and Immunology, University of Geneva, School of Medicine, Switzerland.
authors.forename: Cem
authors.initials: C
authors.lastname: Gabay
authors.affiliation: Novartis Pharma AG, Postfach, Basel, Switzerland.
authors.forename: Christian Alexander
authors.initials: CA
authors.lastname: Seemayer
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Jordan
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland. Electronic address: eric.allemann@unige.ch.
authors.forename: Eric
authors.initials: E
authors.lastname: Allémann
mesh_terms: D000368:Aged; D000818:Animals; D006801:Humans; D007270:Injections, Intra-Articular; D007719:Knee Joint / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D010316:Particle Size; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
keywords: Arthritic diseases; Hyaluronic acid; In vivo biodistribution; Intra-articular administration; Microparticles; Synovial membrane