title: The role of the transition metal copper and the ionophore A23187 in the development of Irinophore C™.
abstract: OBJECTIVE
  A liposomal irinotecan formulation referred to as Irinophore C relies on the ability of copper to complex irinotecan within the liposome. It is currently being evaluated for critical drug-loading parameters. Studies presented here were designed to determine the optimum copper concentration required for the effective encapsulation and retention of irinotecan into liposomes.
  
  
  METHODS
  Distearoylphosphatidylcholine/cholesterol liposomes were formulated using buffers containing various copper or manganese concentrations, and irinotecan loading was determined in the presence and absence of divalent metal ionophore A23187. The rate and extent of irinotecan encapsulation and the rate of irinotecan release from the liposomes were assessed. The amount of copper retained inside liposomes following irinotecan loading and the effect of copper on membrane permeability were determined.
  
  
  RESULTS
  Efficient (>98%) irinotecan loading was achieved using encapsulated copper concentrations of 50 mM. However, irinotecan release was copper concentration dependent, with a minimum 300 mM concentration required for optimal drug retention. The presence of copper increased liposomal membrane permeability.
  
  
  CONCLUSIONS
  Results explain why irinotecan loading rates are enhanced in the presence of formulations prepared with copper, and we speculate that the Irinophore C formulation exhibits improved drug retention, due to generation of a complex between copper and irinotecan.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada. npatankar@gmail.com
authors.forename: Nilesh
authors.initials: N
authors.lastname: Patankar
authors.forename: Malathi
authors.initials: M
authors.lastname: Anantha
authors.forename: Euan
authors.initials: E
authors.lastname: Ramsay
authors.forename: Dawn
authors.initials: D
authors.lastname: Waterhouse
authors.forename: Marcel
authors.initials: M
authors.lastname: Bally
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry*; D000001:Calcimycin / Q000737:chemistry*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry; D002463:Cell Membrane Permeability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002784:Cholesterol / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000737:chemistry*; D005260:Female; D007476:Ionophores / Q000737:chemistry*; D000077146:Irinotecan; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D010713:Phosphatidylcholines / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D007476:Ionophores; D008081:Liposomes; D010713:Phosphatidylcholines; D000001:Calcimycin; D000077146:Irinotecan; D003300:Copper; D002784:Cholesterol; C010942:1,2-distearoyllecithin; D002166:Camptothecin