title: A unique squalenoylated and nonpegylated doxorubicin nanomedicine with systemic long-circulating properties and anticancer activity.
abstract: We identified that the chemical linkage of the anticancer drug doxorubicin onto squalene, a natural lipid precursor of the cholesterol's biosynthesis, led to the formation of squalenoyl doxorubicin (SQ-Dox) nanoassemblies of 130-nm mean diameter, with an original "loop-train" structure. This unique nanomedicine demonstrates: (i) high drug payload, (ii) decreased toxicity of the coupled anticancer compound, (iii) improved therapeutic response, (iv) use of biocompatible transporter material, and (v) ease of preparation, all criteria that are not combined in the currently available nanodrugs. Cell culture viability tests and apoptosis assays showed that SQ-Dox nanoassemblies displayed comparable antiproliferative and cytotoxic effects than the native doxorubicin because of the high activity of apoptotic mediators, such as caspase-3 and poly(ADP-ribose) polymerase. In vivo experiments have shown that the SQ-Dox nanomedicine dramatically improved the anticancer efficacy, compared with free doxorubicin. Particularly, the M109 lung tumors that did not respond to doxorubicin treatment were found inhibited by 90% when treated with SQ-Dox nanoassemblies. SQ-Dox nanoassembly-treated MiaPaCa-2 pancreatic tumor xenografts in mice decreased by 95% compared with the tumors in the saline-treated mice, which was significantly higher than the 29% reduction achieved by native doxorubicin. Concerning toxicity, SQ-Dox nanoassemblies showed a fivefold higher maximum-tolerated dose than the free drug, and moreover, the cardiotoxicity study has evidenced that SQ-Dox nanoassemblies did not cause any myocardial lesions, such as those induced by the free doxorubicin treatment. Taken together, these findings demonstrate that SQ-Dox nanoassemblies make tumor cells more sensitive to doxorubicin and reduce the cardiac toxicity, thus providing a remarkable improvement in the drug's therapeutic index.
authors.affiliation: Faculté de Pharmacie, Institut Galien Paris Sud, Université Paris Sud, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 8612, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Andrei
authors.initials: A
authors.lastname: Maksimenko
authors.forename: Franco
authors.initials: F
authors.lastname: Dosio
authors.forename: Julie
authors.initials: J
authors.lastname: Mougin
authors.forename: Annalisa
authors.initials: A
authors.lastname: Ferrero
authors.forename: Severine
authors.initials: S
authors.lastname: Wack
authors.forename: L Harivardhan
authors.initials: LH
authors.lastname: Reddy
authors.forename: Andrée-Anne
authors.initials: AA
authors.lastname: Weyn
authors.forename: Elise
authors.initials: E
authors.lastname: Lepeltier
authors.forename: Claudie
authors.initials: C
authors.lastname: Bourgaux
authors.forename: Barbara
authors.initials: B
authors.lastname: Stella
authors.forename: Luigi
authors.initials: L
authors.lastname: Cattel
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D020285:Cryoelectron Microscopy; D004317:Doxorubicin / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D005453:Fluorescence; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D008968:Molecular Conformation; D015394:Molecular Structure; D050997:Nanomedicine / Q000379:methods*; D051381:Rats; D013185:Squalene / Q000737:chemistry* / Q000378:metabolism; D020107:Troponin T / Q000097:blood
chemical_list: D020107:Troponin T; D013185:Squalene; D004317:Doxorubicin
keywords: lung cancer; pancreatic cancer; squalene-doxorubicin bioconjugate