title: Nanoparticles for improved local retention after intra-articular injection into the knee joint.
abstract: OBJECTIVE
  To evaluate using cationic polymeric nanoparticles that interact with hyaluronate to form ionically cross-linked hydrogels to increase the intra-articular retention time of osteoarthritis drugs in the synovial cavity.
  
  
  METHODS
  In vitro tests included nanoparticle release from cross-linked hydrogels using syringe and membrane dissolution tests, viscosity measurement of synovial fluid containing hydrogels, and release-rate measurement for a model active conjugated to a cationically substituted dextran using a hydrolyzable ester linkage in a sink dissolution test. Nanoparticle retention after intra-articular injection into rat knees was measured in vivo using fluorescence molecular tomography.
  
  
  RESULTS
  Diffusional and convective transport of cationic nanoparticles from ionically cross-linked hydrogels formed in synovial fluid was slower in vitro than for uncharged nanoparticles. Hydrogels formed after the nanoparticles were mixed with synovial fluid did not appreciably alter the viscosity of the synovial fluid in vitro. In vitro release of a conjugated peptide from the cationic nanoparticles was approximately 20% per week. After intra-articular injection in rat knees, 70% of the nanoparticles were retained in the joint for 1 week.
  
  
  CONCLUSIONS
  This study demonstrates the feasibility of using cationic polymeric nanoparticles to increase the retention of therapeutic agents in articular joints for indications such as osteoarthritis.
authors.affiliation: Bend Research Inc, 64550 Research Road, Bend, Oregon 97701, USA. mike.morgen@bendresearch.com
authors.forename: Michael
authors.initials: M
authors.lastname: Morgen
authors.forename: David
authors.initials: D
authors.lastname: Tung
authors.forename: Britton
authors.initials: B
authors.lastname: Boras
authors.forename: Warren
authors.initials: W
authors.lastname: Miller
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Malfait
authors.forename: Micky
authors.initials: M
authors.lastname: Tortorella
mesh_terms: D000818:Animals; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D020100:Hydrogels / Q000737:chemistry; D007270:Injections, Intra-Articular; D007719:Knee Joint / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010003:Osteoarthritis / Q000188:drug therapy; D010455:Peptides / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013582:Synovial Fluid / Q000737:chemistry / Q000378:metabolism; D014783:Viscosity
chemical_list: D004337:Drug Carriers; D020100:Hydrogels; D010455:Peptides; D006820:Hyaluronic Acid