title: Nanoemulsion formulation of fisetin improves bioavailability and antitumour activity in mice.
abstract: The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) has shown antitumour activity but its administration is complicated by its low water solubility. Our aim was to incorporate fisetin into a nanoemulsion to improve its pharmacokinetics and therapeutic efficacy. Solubility and emulsification tests allowed to develop an optimal nanoemulsion composed of Miglyol 812N/Labrasol/Tween 80/Lipoid E80/water (10%/10%/2.5%/1.2%/76.3%). The nanoemulsion had an oil droplet diameter of 153 ± 2 nm, a negative zeta potential (-28.4 ± 0.6 mV) and a polydispersity index of 0.129. The nanoemulsion was stable at 4 °C for 30 days, but phase separation occurred at 20 °C. Pharmacokinetic studies in mice revealed that the fisetin nanoemulsion injected intravenously (13 mg/kg) showed no significant difference in systemic exposure compared to free fisetin. However, when the fisetin nanoemulsion was administered intraperitoneally, a 24-fold increase in fisetin relative bioavailability was noted, compared to free fisetin. Additionally, the antitumour activity of the fisetin nanoemulsion in Lewis lung carcinoma bearing mice occurred at lower doses (36.6 mg/kg) compared to free fisetin (223 mg/kg). In conclusion, we have developed a stable nanoemulsion of fisetin and have shown that it could improve its relative bioavailability and antitumour activity.
authors.affiliation: Paris Descartes University, Faculty of Pharmacy, INSERM U1022, CNRS UMR8151, Chimie ParisTech, Sorbonne Paris Cité, Chemical, Genetic and Imaging Pharmacology Laboratory, F-75006 Paris, France.
authors.forename: Héloïse
authors.initials: H
authors.lastname: Ragelle
authors.forename: Sylvie
authors.initials: S
authors.lastname: Crauste-Manciet
authors.forename: Johanne
authors.initials: J
authors.lastname: Seguin
authors.forename: Denis
authors.initials: D
authors.lastname: Brossard
authors.forename: Daniel
authors.initials: D
authors.lastname: Scherman
authors.forename: Philippe
authors.initials: P
authors.lastname: Arnaud
authors.forename: Guy G
authors.initials: GG
authors.lastname: Chabot
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D004655:Emulsions; D042783:Endothelial Cells / Q000187:drug effects; D005079:Excipients; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D044948:Flavonols; D006207:Half-Life; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D010316:Particle Size; D012995:Solubility; D012997:Solvents; D013501:Surface-Active Agents
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004655:Emulsions; D005079:Excipients; D005419:Flavonoids; D044948:Flavonols; D012997:Solvents; D013501:Surface-Active Agents; C017875:fisetin