title: Encapsulation of vinorelbine into cholesterol-polyethylene glycol coated vesicles: drug loading and pharmacokinetic studies.
abstract: OBJECTIVE
  Pegylated liposome formulations of vinorelbine with prolonged circulation half-life (t½) are desirable. However, DSPE-PEG could affect vinorelbine loading into vesicles due to electrostatic interactions. To resolve this problem, chol-PEG was used to prepare pegylated liposomal vinorelbine and the factors affecting drug loading and plasma pharmacokinetics were investigated.
  
  
  METHODS
  Vinorelbine was loaded into liposomes using a novel triethylamine 5-sulfosalicylate gradient. The effects of cholesterol and chol-PEG on drug loading were investigated. Pharmacokinetic studies were performed in normal KunMing mice treated with different liposomal vinorelbine formulations. To clarify the effects of chol-PEG on membrane permeability, drug release experiments were performed based on the fluorescence dequenching phenomenon of a fluorescence marker.
  
  
  RESULTS
  In contrast to DSPE-PEG, even at high PEG grafting density (∼ 8.3 mol%), chol-PEG had no effect on vinorelbine loading into HSPC/cholesterol (3 : 1, mass ratio) vesicles. However, for the formulations with low cholesterol content (HSPC/cholesterol 4 : 1), loading efficiency decreased with increasing chol-PEG content. In vivo, the vinorelbine t½ of low cholesterol formulations decreased with increasing chol-PEG content, but for high cholesterol liposomes, the maximum vinorelbine t½ was achieved at ∼ 3 mol% chol-PEG grafting density. The resulting vinorelbine circulation t½ was ∼ 9.47 h, which was greater than that of non-pegylated liposomes (∼ 5.55 h). Drug release experiments revealed that chol-PEG might induce membrane defects and concomitant release of entrapped marker, especially at high chol-PEG density.
  
  
  CONCLUSIONS
  Through the investigation of the effects of chol-PEG and cholesterol, an optimum pegylated liposomal vinorelbine formulation with prolonged t½ was achieved. In plasma, the membrane defect induced by chol-PEG may counteract the long circulation characteristics that chol-PEG afforded. When these two opposite effects reached equilibrium, the maximum vinorelbine t½ was achieved.
authors.affiliation: CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd, Shijiazhuang City, Hebei Province, 050051, China. lcllib@hotmail.com
authors.forename: ChunLei
authors.initials: C
authors.lastname: Li
authors.forename: JingXia
authors.initials: J
authors.lastname: Cui
authors.forename: CaiXia
authors.initials: C
authors.lastname: Wang
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.forename: Xian
authors.initials: X
authors.lastname: Xiu
authors.forename: YongFeng
authors.initials: Y
authors.lastname: Li
authors.forename: Na
authors.initials: N
authors.lastname: Wei
authors.forename: YanHui
authors.initials: Y
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001682:Biological Availability; D002784:Cholesterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D018699:Coated Vesicles / Q000737:chemistry*; D004337:Drug Carriers; D005456:Fluorescent Dyes; D006207:Half-Life; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry*; D051379:Mice; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D005456:Fluorescent Dyes; D008081:Liposomes; C118255:polyethylene glycol-cholesterol; D011092:Polyethylene Glycols; D014747:Vinblastine; D002784:Cholesterol; D000077235:Vinorelbine