Self-assembly of polyisoprenoyl gemcitabine conjugates: influence of supramolecular organization on their biological activity.
An amphiphilic prodrug of gemcitabine, a cytidine analogue used clinically against various tumors, had been previously synthesized by covalent coupling to squalene, a natural isoprenoid chain. The resulting bioconjugate self-assembled spontaneously in water as nanoparticles, displaying an impressive activity both in vitro and in vivo. The aim of the present study was to determine the influence of the length of the isoprene moiety on the structure of the nanoparticles, in an attempt to establish a relationship between the chemical structure of the prodrug, its supramolecular organization, and its pharmacological activity. Remarkably, gemcitabine-squalene and gemcitabine-5-isoprenes, which differ only in the position of two methyl groups on the hydrophobic chain, displayed different supramolecular organizations and different anticancer activities on some cell lines. This difference in activity was related to the ability of nanoparticles to be internalized by cells.
Institut Galien Paris-Sud, UMR CNRS 8612, Faculté de Pharmacie, l'Université Paris-Sud XI , 92296 Châtenay-Malabry Cedex, France.
Elise
E
Lepeltier
Claudie
C
Bourgaux
Andrey
A
Maksimenko
Florian
F
Meneau
Véronique
V
Rosilio
Eric
E
Sliwinski
Fatima
F
Zouhiri
Didier
D
Desmaële
Patrick
P
Couvreur
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000737:chemistry*; D013185:Squalene / Q000737:chemistry; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D003841:Deoxycytidine; D013185:Squalene; D000093542:Gemcitabine