title: Squalenoylation favorably modifies the in vivo pharmacokinetics and biodistribution of gemcitabine in mice.
abstract: Gemcitabine (2',2'-difluorodeoxyribofuranosylcytosine; dFdC) is an anticancer nucleoside analog active against wide variety of solid tumors. However, this compound is rapidly inactivated by enzymatic deamination and can also induce drug resistance. To overcome the above drawbacks, we recently designed a new squalenoyl nanomedicine of dFdC [4-N-trisnorsqualenoyl-gemcitabine (SQdFdC)] by covalently coupling gemcitabine with the 1,1',2-trisnorsqualenic acid; the resultant nanomedicine displayed impressively greater anticancer activity compared with the parent drug in an experimental murine model. In the present study, we report that SQdFdC nanoassemblies triggered controlled and prolonged release of dFdC and displayed considerably greater t(1/2) (approximately 3.9-fold), mean residence time (approximately 7.5-fold) compared with the dFdC administered as a free drug in mice. It was also observed that the linkage of gemcitabine to the 1,1',2-trisnorsqualenic acid noticeably delayed the metabolism of dFdC into its inactive difluorodeoxyuridine (dFdU) metabolite, compared with dFdC. Additionally, the elimination of SQdFdC nanoassemblies was considerably lower compared with free dFdC, as indicated by lower radioactivity found in urine and kidneys, in accordance with the plasmatic concentrations of dFdU. SQdFdC nanoassemblies also underwent considerably higher distribution to the organs of the reticuloendothelial system, such as spleen and liver (p < 0.05), both after single- or multiple-dose administration schedule. Herein, this paper brings comprehensive pharmacokinetic and biodistribution insights that may explain the previously observed greater efficacy of SQdFdC nanoassemblies against experimental leukemia.
authors.affiliation: Faculté de Pharmacie, Unité Mixte de Recherche Centre National de la Recherche Scientifique 8612, Institut Fédératif de Recherche 141, Université Paris XI, Châtenay-Malabry cedex, France.
authors.forename: L Harivardhan
authors.initials: LH
authors.lastname: Reddy
authors.forename: Hania
authors.initials: H
authors.lastname: Khoury
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
authors.forename: Alain
authors.initials: A
authors.lastname: Deroussent
authors.forename: Humberto
authors.initials: H
authors.lastname: Ferreira
authors.forename: Catherine
authors.initials: C
authors.lastname: Dubernet
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
authors.forename: Madeleine
authors.initials: M
authors.lastname: Besnard
authors.forename: Helène
authors.initials: H
authors.lastname: Chacun
authors.forename: Sinda
authors.initials: S
authors.lastname: Lepêtre-Mouelhi
authors.forename: Didier
authors.initials: D
authors.lastname: Desmaële
authors.forename: Bernard
authors.initials: B
authors.lastname: Rousseau
authors.forename: Christelle
authors.initials: C
authors.lastname: Laugier
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Cintrat
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008811:Mice, Inbred DBA; D013185:Squalene / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D013185:Squalene; D000093542:Gemcitabine