PURPOSE: 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. CONCLUSION: 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.
PURPOSE: 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. CONCLUSION: 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: G Batist; G Ramakrishnan; C S Rao; A Chandrasekharan; J Gutheil; T Guthrie; P Shah; A Khojasteh; M K Nair; K Hoelzer; K Tkaczuk; Y C Park; L W Lee Journal: J Clin Oncol Date: 2001-03-01 Impact factor: 44.544
Authors: Euan C Ramsay; Malathi Anantha; Jason Zastre; Marieke Meijs; Jet Zonderhuis; Dita Strutt; Murray S Webb; Dawn Waterhouse; Marcel B Bally Journal: Clin Cancer Res Date: 2008-02-15 Impact factor: 12.531
Authors: Jennifer I Hare; Robert W Neijzen; Malathi Anantha; Nancy Dos Santos; Natashia Harasym; Murray S Webb; Theresa M Allen; Marcel B Bally; Dawn N Waterhouse Journal: PLoS One Date: 2013-04-23 Impact factor: 3.240
Authors: Lina Chernov; Rebecca J Deyell; Malathi Anantha; Nancy Dos Santos; Roger Gilabert-Oriol; Marcel B Bally Journal: Cancer Med Date: 2017-05-23 Impact factor: 4.452