title: Characterization of the drug retention and pharmacokinetic properties of liposomal nanoparticles containing dihydrosphingomyelin.
abstract: The drug retention and circulation lifetime properties of liposomal nanoparticles (LN) containing dihydrosphingomyelin (DHSM) have been investigated. It is shown that replacement of egg sphingomyelin (ESM) by DHSM in sphingomyelin/cholesterol (Chol) (55/45; mol/mol) LN results in substantially improved drug retention properties both in vitro and in vivo. In the case of liposomal formulations of vincristine, for example, the half-times for drug release (T(1/2)) were approximately 3-fold longer for DHSM/Chol LN as compared to ESM/Chol LN, both in vitro and in vivo. Further increases in T(1/2) could be achieved by increasing the drug-to-lipid ratio of the liposomal vincristine formulations. In addition, DHSM/Chol LN also exhibit improved circulation lifetimes in vivo as compared to ESM/Chol LN. For example, the half-time for LN clearance (Tc(1/2)) at a low lipid dose (15 micromol lipid/kg, corresponding to 8 mg lipid/kg body weight) in mice was 3.8 h for ESM/Chol LN compared to 6 h for DHSM/Chol LN. In addition, it is also shown that DHSM/Chol LN exhibit much longer half-times for vincristine release as compared to LN with the "Stealth" lipid composition. It is anticipated that DHSM/Chol LN will prove useful as drug delivery vehicles due to their excellent drug retention and circulation lifetime properties.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, 2146 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Michael J W
authors.initials: MJ
authors.lastname: Johnston
authors.forename: Sean C
authors.initials: SC
authors.lastname: Semple
authors.forename: Sandy K
authors.initials: SK
authors.lastname: Klimuk
authors.forename: Steve
authors.initials: S
authors.lastname: Ansell
authors.forename: Norbert
authors.initials: N
authors.lastname: Maurer
authors.forename: Pieter R
authors.initials: PR
authors.lastname: Cullis
mesh_terms: D000818:Animals; D002417:Cattle; D002784:Cholesterol; D004337:Drug Carriers; D005260:Female; D006207:Half-Life; D008081:Liposomes / Q000493:pharmacokinetics*; D051379:Mice; D053758:Nanoparticles; D044367:Phase Transition; D013109:Sphingomyelins / Q000493:pharmacokinetics*; D013696:Temperature; D014750:Vincristine / Q000493:pharmacokinetics*
chemical_list: C091181:4,5-dihydrosphingomyelin; D004337:Drug Carriers; D008081:Liposomes; D013109:Sphingomyelins; D014750:Vincristine; D002784:Cholesterol