Biodistribution and anticancer activity of a new Vinca alkaloid encapsulated into long-circulating liposomes.
S12363 is a potent therapeutic agent with a strong in vitro activity against a variety of tumor types but also a high in vivo toxicity. Loading of this drug into long-circulating liposomes is expected to enhance its therapeutic index. Pharmacokinetics of liposomal S12363 showed that circulating S12363 was entrapped into liposomes until 24 hours after intravenous injection in mice. The liposomal formulation significantly increased the plasma concentration, half-life, and AUC and decreased the plasma clearance rates and volume of distribution of S12363. Liposome extravasation was evaluated with two tumor models by both microscopic analysis and liposome radiolabeling. Liposome accumulation was much more important in the case of B16 melanoma, compared to H460 tumor, with both inoculated subcutaneously and with comparable size. H460 tumor was also inoculated into the lung. The tumor localization did not influence liposome accumulation into the tissue. The liposomal formulation injected into mice bearing B16 melanoma allowed a 10-fold accumulation of S12363 into the tumor interstitium, as compared to the solution. Bioluminescence data, supported by the survival curves of the animals, showed that S12363-liposomes were able to significantly restrict B16 melanoma progression and increase mice survival.
Chemin
Caroline
C
Université Paris-Sud 11, CNRS UMR 8612, Châtenay-Malabry, France. caroline.chemin@fr.netgrs.com
Péan
Jean-Manuel
JM
Le Pape
Alain
A
Delbos
Jean-Marie
JM
German-Fattal
Michèle
M
Wüthrich
Patrick
P
Couvreur
Patrick
P
D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D005260:Female; D006207:Half-Life; D008081:Liposomes / Q000493:pharmacokinetics*; D008297:Male; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D020849:Raloxifene Hydrochloride; D014018:Tissue Distribution; D014748:Vinca Alkaloids
D008081:Liposomes; D014748:Vinca Alkaloids; D020849:Raloxifene Hydrochloride