title: Use of a passive equilibration methodology to encapsulate cisplatin into preformed thermosensitive liposomes.
abstract: A conventional, cholesterol-containing liposome formulation of cisplatin has demonstrated insignificant activity in clinical trials, due in part, to insufficient release of encapsulated content following localization within solid tumors. For this reason, the development of a triggered release liposome formulation is desirable. In this report, cisplatin was encapsulated into lysolipid-containing thermosensitive liposomes (LTSL) using a novel technique, which relies on the equilibration of cisplatin across the liposomal membrane at temperatures above the gel-to-liquid crystalline phase transition temperature (TC) of the bulk phospholipid. Mild heating and drug loading into LTSL did not induce morphological changes of the liposomes. In vitro data demonstrated that >95% of encapsulated cisplatin was released from LTSL within 5 min following mild heating at 42 degrees C, while <5% was released at 37 degrees C. Under similar conditions, lysolipid-free thermosensitive liposomes exhibited 70% release of cisplatin at 42 degrees C, and cholesterol-containing liposomes exhibited negligible drug release at 42 degrees C. The pharmacokinetic profiles of LTSL- and TSL-cisplatin indicated that these formulations were rapidly eliminated from circulation (terminal t(1/2) of 1.09 and 2.83 h, respectively). The therapeutic utility of LTSL-cisplatin formulation will be based on strategies where hyperthermia is applied prior to the administration of the liposomal drug-a strategy similar to that used in the clinical assessment of LTSL-doxorubicin formulation.
authors.affiliation: Department of Advanced Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC, Canada V5Z 1L3.
authors.forename: Janet
authors.initials: J
authors.lastname: Woo
authors.forename: Gigi N C
authors.initials: GN
authors.lastname: Chiu
authors.forename: Göran
authors.initials: G
authors.lastname: Karlsson
authors.forename: Ellen
authors.initials: E
authors.lastname: Wasan
authors.forename: Ludger
authors.initials: L
authors.lastname: Ickenstein
authors.forename: Katarina
authors.initials: K
authors.lastname: Edwards
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D020285:Cryoelectron Microscopy; D004337:Drug Carriers; D004339:Drug Compounding; D006358:Hot Temperature; D008081:Liposomes; D008567:Membranes, Artificial; D051379:Mice; D046529:Microscopy, Electron, Transmission; D010316:Particle Size; D010539:Permeability; D012995:Solubility; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D008567:Membranes, Artificial; D002945:Cisplatin