Cationic emulsions improves the delivery of oligonucleotides to leukemic P388/ADR cells in ascite.
The aim of this study was to investigate the in vivo ability of O/W cationic emulsions to deliver oligonucleotides (ON) in leukemic P388/ADR cells in ascite, after intraperitoneal (IP) administration in mice. Cationic emulsions were prepared by microfluidization as previously described by Teixeira et al. [Pharm. Res 16 (1999) 30]. The formulations consisted mainly of medium chain triglycerides, phosphatidylcholine (PC), poloxamer, and either a monocationic lipid stearylamine (PC/SA-emulsion) or a polycationic lipid RPRC(18) (PC/RPRC(18)-emulsion). A model ON (33P-pdT(16)) was associated with cationic emulsions by single addition at the end of the manufacturing process. Seven days after P388/ADR inoculation IP to mice, ON free or associated with PC/SA or PC/RPRC(18) emulsions was injected IP at a dose of 0.5 mg/kg. At different interval times, ascite including cells, blood and the main organs were collected and the radioactivity counted by liquid scintillation. The overall results showed significantly high amounts of ON in the leukemic cell pellet, 24 h after administration of ON associated to either PC/SA (AUC(0-24 h)=13634, %injected dose/min) or PC/RPRC(18) (AUC(0-24 h)=22592, % injected dose/min), contrary to the free ON solution (AUC(0-24 h)=3095, %injected dose/min), which displayed only reduced capture by cancer cells. In conclusion, complexation of ON with cationic emulsions had a beneficial effect in increasing tumor cells uptake in vivo (up to sevenfold for PC/RPRC(18)-emulsion) after IP administration. This could open interesting prospects for the treatment of ovarian cancers.
Laboratoire de Physico-chimie, Pharmacotechnie et Biopharmacie, UMR 8612, Université Paris XI, Centre d'Etudes Pharmaceutiques 5, Rue J B Clément 92296, Châtenay-Malabry, France.
H
H
Teixeira
C
C
Dubernet
H
H
Chacun
L
L
Rabinovich
V
V
Boutet
J R
JR
Deverre
S
S
Benita
P
P
Couvreur
D000818:Animals; D001202:Ascitic Fluid / Q000188:drug therapy / Q000378:metabolism*; D002412:Cations; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D004655:Emulsions; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000627:therapeutic use*
D002412:Cations; D004655:Emulsions; D009841:Oligonucleotides