title: Optimization of vincristine-topotecan combination--paving the way for improved chemotherapy regimens by nanoliposomes.
abstract: There is an opportunity to improve the therapeutic potential of a combination of two drugs using nanoliposomes. The combination of topotecan (TPT) and vincristine (VCR) was selected. The ratio-dependent synergy between these two drugs was evaluated, in an attempt to improve the therapeutic efficacy of this combination in vivo. The interaction between the drugs was evaluated in tissue culture by the median-effect analysis. Certain ratios of combined drugs were synergistic, whereas, others were antagonistic, implying that the most efficacious combinations should be at a specific fixed drug ratio. For in vivo evaluation, nanoliposomes co-remotely loaded simultaneously with both drugs by transmembrane ammonium sulfate gradient were developed. VCR and TPT were successfully co-encapsulated at therapeutically relevant levels in the same nanoliposome (LipoViTo). The nanoliposomes controlled the drugs' "biofate" and maintained a fixed drug ratio in vivo, allowing one to compare the therapeutic efficacy of various predefined drug ratios. Pharmacokinetics and biodistribution studies showed that LipoViTo delivers the two drugs simultaneously to the tumors, where they are released at a predefined ratio. LipoViTo was more efficacious than the free drugs and liposomes with one agent, singly or in combination, in two tumor models in mice. LipoViTo co-loaded with both drugs corresponding to their maximal tolerated dose (MTD) ratio resulted in the best therapeutic efficacy. To summarize: liposomal co-encapsulation of anticancer drug combinations can profoundly influence therapeutic outcomes. Drug combinations can be optimized preclinically through pharmacokinetic control by remote loading into nanoliposomes.
authors.affiliation: Department of Biochemistry, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zucker
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Barenholz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D002460:Cell Line; D004357:Drug Synergism; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019772:Topotecan / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014750:Vincristine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D059004:Topoisomerase I Inhibitors; D014750:Vincristine; D019772:Topotecan