title: Sulfosalicylate mediates improved vinorelbine loading into LUVs and antineoplastic effects.
abstract: Liposomal vinorelbine formulation is desirable, as it might improve the therapeutic activity of vinorelbine. However, because of its lipophilic and membrane-permeable properties, vinorelbine is hard to be formulated into liposomes using conventional drug-loading technologies. To improve vinorelbine retention, ammonium salts of several anionic agents were employed to prepare liposomal vinorelbine formulations. It was found that 5-sulfosalicylate (5ssa) could form stable complexes with vinorelbine and stabilize entrapped vinorelbine. The resultant vesicles had an in vitro release t(1/2) of ~12.49 hours in NH(3)-containing media, which is longer than those of sulfate and phytate vesicles (~0.57 hours). The circulation half-life of vinorelbine after the injection of 5ssa vesicles into normal mice was ~13.01 hours, accounting for ~2-fold increase relative to that of sulfate vesicles. Improved drug retention correlated with enhanced antitumor efficacy. In the RM-1/c57 model, 5ssa vesicles were more efficacious than sulfate vesicles (P < 0.05). In RM-1/BDF1 and Lewis lung cancer/c57 models, antitumor efficacy was also considerably improved after vinorelbine encapsulation into 5ssa vesicles. For instance, in the RM/BDF1 model, liposomal vinorelbine was at least 4-fold more therapeutically active than free vinorelbine. Our results demonstrated that 5ssa could stabilize vinorelbine relative to other anions, resulting in the formulation with improved drug retention and efficacy. Improved vinorelbine retention might be associated with the formation of insoluble precipitate, which could be proved by precipitation study and decreased drug-release rate at a high D/L ratio.
authors.affiliation: CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd., Shijiazhuang, 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: Jinna
authors.initials: J
authors.lastname: Cao
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Liang
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: Chenxin
authors.initials: C
authors.lastname: Deng
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D008081:Liposomes / Q000138:chemical synthesis / Q000737:chemistry*; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D010713:Phosphatidylcholines / Q000737:chemistry*; D012459:Salicylates / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D016588:Anticarcinogenic Agents; D001557:Benzenesulfonates; D008081:Liposomes; D010713:Phosphatidylcholines; D012459:Salicylates; D014747:Vinblastine; D002784:Cholesterol; C003366:sulfosalicylic acid; D000077235:Vinorelbine