title: Amphipathic weak acid glucocorticoid prodrugs remote-loaded into sterically stabilized nanoliposomes evaluated in arthritic rats and in a Beagle dog: a novel approach to treating autoimmune arthritis.
abstract: OBJECTIVE
  The use of glucocorticoids (GCs) in rheumatoid arthritis is limited by side effects related to unfavorable pharmacokinetics and biodistribution. Liposomal GC formulations have been studied since the 1970s in an attempt to overcome this obstacle, but none has entered clinical use. We undertook this study to determine whether a novel approach could overcome the limitations that have thus far prevented the clinical use of these formulations: low drug:lipid ratio, low encapsulation efficiency, and lack of controlled release.
  
  
  METHODS
  We used approximately 80-nm sterically stabilized (pegylated) nanoliposomes (NSSLs), which were remote-loaded with an amphipathic weak acid GC (such as methyl prednisolone hemisuccinate) utilizing an intraliposome (aqueous compartment)-high/extraliposome (bulk medium)-low transmembrane calcium acetate gradient. This unique method actually "traps" the GC in the liposomal aqueous phase as a calcium-GC precipitate.
  
  
  RESULTS
  Our liposome formulation exhibited high encapsulation efficiency (94%) and a high drug:lipid mole ratio (0.41) and demonstrated controlled release of the encapsulated GC during systemic circulation and in inflamed paws in rats with adjuvant-induced arthritis. In addition, both in arthritic rats and in a Beagle dog, we showed the pharmacokinetic advantage of using liposomes as GC carriers. Finally, we demonstrated the superior therapeutic efficacy of our liposome formulation over that of free GCs in arthritic rats, both in early and in peak disease stages.
  
  
  CONCLUSIONS
  Amphipathic weak acid GCs remote-loaded into approximately 80-nm NSSLs overcome past limitations of liposomal GC formulations. The unique loading method, which also leads to controlled release, improves the therapeutic effect both systemically and locally. Such a development has great potential for improving GC therapy.
authors.affiliation: The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Avnir
authors.forename: Rina
authors.initials: R
authors.lastname: Ulmansky
authors.forename: Veronica
authors.initials: V
authors.lastname: Wasserman
authors.forename: Simcha
authors.initials: S
authors.lastname: Even-Chen
authors.forename: Maya
authors.initials: M
authors.lastname: Broyer
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Barenholz
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Naparstek
mesh_terms: D000143:Acids; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D003692:Delayed-Action Preparations; D004285:Dogs; D016503:Drug Delivery Systems; D005260:Female; D005938:Glucocorticoids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D008081:Liposomes / Q000494:pharmacology*; D049329:Nanostructures; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011917:Rats, Inbred Lew; D014018:Tissue Distribution
chemical_list: D000143:Acids; D003692:Delayed-Action Preparations; D005938:Glucocorticoids; D008081:Liposomes; D011355:Prodrugs