title: Dose effect activity of ferrocifen-loaded lipid nanocapsules on a 9L-glioma model.
abstract: Ferrociphenol (Fc-diOH) is a new molecule belonging to the fast-growing family of organometallic anti-cancer drugs. In a previous study, we showed promising in vivo results obtained after the intratumoural subcutaneous administration of the new drug-carrier system Fc-diOH-LNCs on a 9L-glioma model. To further increase the dose of this lipophilic entity, we have created a series of prodrugs of Fc-diOH. The phenol groups were protected by either an acetyl (Fc-diAc) or by the long fatty-acid chain of a palmitate (Fc-diPal). LNCs loaded with Fc-diOH prodrugs have to be activated in situ by enzymatic hydrolysis. We show here that the protection of diphenol groups with palmitoyl results in the loss of Fc-diOH in vitro activity, probably due to a lack of in situ hydrolysis. On the contrary, protection with an acetate group does not affect the strong, in vitro, antiproliferative effect of ferrocifen-loaded-LNCs neither the reduction of tumour volume observed on an ectopic model, confirming that acetate is easily cleaved by cell hydrolases. Moreover, the cytostatic activity of Fc-diOH-LNCs is confirmed on an orthotopic glioma model since the difference in survival time between the infusion of 0.36 mg/rat Fc-diOH-LNCs and blank LNCs is statistically significant. By using LNCs or Labrafac to carry the drug, a dose-effect ranging from 0.005 to 2.5mg of Fc-diOH per animal can be evidenced.
authors.affiliation: INSERM, U646, Angers, F-49100 France.
authors.forename: E
authors.initials: E
authors.lastname: Allard
authors.forename: N T
authors.initials: NT
authors.lastname: Huynh
authors.forename: A
authors.initials: A
authors.lastname: Vessières
authors.forename: P
authors.initials: P
authors.lastname: Pigeon
authors.forename: G
authors.initials: G
authors.lastname: Jaouen
authors.forename: J-P
authors.initials: JP
authors.lastname: Benoit
authors.forename: C
authors.initials: C
authors.lastname: Passirani
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage; D005260:Female; D005296:Ferrous Compounds / Q000008:administration & dosage*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D008055:Lipids / Q000008:administration & dosage*; D053769:Nanocapsules / Q000008:administration & dosage*; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D004337:Drug Carriers; D005296:Ferrous Compounds; D008055:Lipids; D053769:Nanocapsules; C514120:ferrocifen; C533771:ferrociphenol