title: Development of a liposomal nanoparticle formulation of 5-fluorouracil for parenteral administration: formulation design, pharmacokinetics and efficacy.
abstract: 5-Fluorouracil (5-FU) is a small, very membrane permeable drug that is poorly retained within the aqueous compartment of liposomal nanoparticles (LNP). To address this problem a novel method relying on formation of a ternary complex comprising copper, low molecular weight polyethylenimine (PEI) and 5-FU has been developed. More specifically, in the presence of entrapped copper and PEI, externally added 5-FU can be efficiently encapsulated (>95%) in DSPC/Chol (1,2-Distearoyl-sn-Glycero-3-Phosphocholine/cholesterol; 55:45 mol%) liposomes (130-170 nm) to achieve drug-to-lipid ratios of 0.1 (mol:mol). Drug release studies completed using this LNP formulation of 5-FU demonstrated significant improvements in drug retention in vitro and in vivo. Plasma concentrations of 5-FU were 7- to 23-fold higher when the drug was administered intravenously to mice as the LNP 5-FU formulation compared to free 5-FU. Further, the therapeutic effects of the LNP 5-FU formulation, as determined in a HT-29 subcutaneous colorectal cancer model where treatment was given QDx5, was greater than that which could be achieved with free 5-FU when compared at equivalent doses. This is the first time an active loading method has been described for 5-FU. The use of ternary metal complexation strategy to encapsulate therapeutic agents may define a unique platform for preparation of LNP drug formulations.
authors.affiliation: Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada. athomas@bccrc.ca
authors.forename: Anitha M
authors.initials: AM
authors.lastname: Thomas
authors.forename: Anita I
authors.initials: AI
authors.lastname: Kapanen
authors.forename: Jennifer I
authors.initials: JI
authors.lastname: Hare
authors.forename: Euan
authors.initials: E
authors.lastname: Ramsay
authors.forename: Katarina
authors.initials: K
authors.lastname: Edwards
authors.forename: Göran
authors.initials: G
authors.lastname: Karlsson
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
mesh_terms: D000818:Animals; D001682:Biological Availability; D001835:Body Weight / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009942:Organometallic Compounds / Q000737:chemistry; D010316:Particle Size; D010713:Phosphatidylcholines / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D055672:Static Electricity; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D008081:Liposomes; D009942:Organometallic Compounds; D010713:Phosphatidylcholines; C499308:Rag2 protein, mouse; C015092:cupric acetate; D011094:Polyethyleneimine; D002784:Cholesterol; C010942:1,2-distearoyllecithin; D005472:Fluorouracil