title: Optimization and characterization of a sphingomyelin/cholesterol liposome formulation of vinorelbine with promising antitumor activity.
abstract: Vinorelbine (VRL) is a particularly lipophilic member of the vinca alkaloids which, as a class of drugs, exhibit improved cytotoxicity and therapeutic activity through increased duration of exposure. Here, we describe and optimize a sphingomyelin/cholesterol (SM/Chol) liposome formulation of VRL to maximize in vivo drug retention, plasma circulation time, and therapeutic activity. VRL was efficiently encapsulated (>90%) into 100 nm liposomes using an ionophore-mediated loading method. VRL retention in SM/Chol liposomes after intravenous injection in mice was dependent on drug-to-lipid ratio (D/L), with higher D/L ratios exhibiting increased drug retention (0.3 > 0.2 > 0.1, wt/wt) and improved pharmacokinetics. Cryo-electron microscopic examination of a high D/L ratio formulation indicated that the intravesicular regions of these liposomes were electron dense compared with empty liposomes. The optimized, high D/L ratio SM/Chol VRL formulation showed promising activity against subcutaneous B16 melanoma tumors compared with VRL or SM/Chol formulations of vincristine or vinblastine. Finally, the stability of the formulation was excellent (<5% drug leakage, >99% intact VRL, no changes in liposome size after 1 year at 2-8 degrees C). The optimized drug retention properties of the SM/Chol formulation of VRL, combined with its promising antitumor activity and pharmaceutical stability, make this formulation an excellent candidate for future clinical development.
authors.affiliation: Inex Pharmaceuticals Corporation, 200-8900 Glenlyon Parkway, Glenlyon Business Park, Burnaby, British Columbia, Canada V5J 5J8. ssemple@inexpharm.com
authors.forename: Sean C
authors.initials: SC
authors.lastname: Semple
authors.forename: Robert
authors.initials: R
authors.lastname: Leone
authors.forename: Jinfang
authors.initials: J
authors.lastname: Wang
authors.forename: Esther C
authors.initials: EC
authors.lastname: Leng
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Klimuk
authors.forename: Merete L
authors.initials: ML
authors.lastname: Eisenhardt
authors.forename: Zuan-Ning
authors.initials: ZN
authors.lastname: Yuan
authors.forename: Katarina
authors.initials: K
authors.lastname: Edwards
authors.forename: Norbert
authors.initials: N
authors.lastname: Maurer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hope
authors.forename: Pieter R
authors.initials: PR
authors.lastname: Cullis
authors.forename: Quet-Fah
authors.initials: QF
authors.lastname: Ahkong
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D000001:Calcimycin / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D002784:Cholesterol / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D020285:Cryoelectron Microscopy; D004355:Drug Stability; D005079:Excipients; D005260:Female; D006863:Hydrogen-Ion Concentration; D007476:Ionophores / Q000737:chemistry; D008081:Liposomes; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D010316:Particle Size; D013109:Sphingomyelins / Q000737:chemistry*; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics; D014748:Vinca Alkaloids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005079:Excipients; D007476:Ionophores; D008081:Liposomes; D013109:Sphingomyelins; D014748:Vinca Alkaloids; D000001:Calcimycin; D014747:Vinblastine; D002784:Cholesterol; D000077235:Vinorelbine