title: Synthesis, characterization, and in vivo delivery of siRNA-squalene nanoparticles targeting fusion oncogene in papillary thyroid carcinoma.
abstract: We report the conjugation of the natural lipid squalene (SQ) with a small interfering RNA (siRNA), against the junction oncogene RET/PTC1, usually found in papillary thyroid carcinoma (PTC). The acyclic isoprenoid chain of squalene has been covalently coupled with siRNA RET/PTC1 at the 3'-terminus of the sense strand via maleimide-sulfhydryl chemistry. Remarkably, the linkage of siRNA RET/PTC1 to squalene led to an amphiphilic molecule that self-organized in H(2)O as siRNA-SQ RET/PTC1 nanoparticles (NPs). The siRNA-SQ RET/PTC1 NPs, stable in H(2)O, were used for biological studies. In vitro, they did not show any cytotoxicity. Interestingly, in vivo, on a mice xenografted RET/PTC1 experimental model, RET/PTC1-SQ NPs were found to inhibit tumor growth and RET/PTC1 oncogene and oncoprotein expression after 2.5 mg/kg cumulative dose intravenous injections. In conclusion, these results showed that the "squalenoylation" offers a new noncationic plate-form for the siRNA delivery.
authors.affiliation: Laboratoire de Physicochimie, Pharmacotechnie et Biopharmacie, Faculté de Pharmacie, UMR CNRS 8612, Université Paris Sud 11, 5 Rue J. B. Clément, 92296 Châtenay-Malabry, France.
authors.forename: Mouna
authors.initials: M
authors.lastname: Raouane
authors.forename: Didier
authors.initials: D
authors.lastname: Desmaele
authors.forename: Marie
authors.initials: M
authors.lastname: Gilbert-Sirieix
authors.forename: Claire
authors.initials: C
authors.lastname: Gueutin
authors.forename: Fatima
authors.initials: F
authors.lastname: Zouhiri
authors.forename: Claudie
authors.initials: C
authors.lastname: Bourgaux
authors.forename: Elise
authors.initials: E
authors.lastname: Lepeltier
authors.forename: Ruxandra
authors.initials: R
authors.lastname: Gref
authors.forename: Ridha
authors.initials: R
authors.lastname: Ben Salah
authors.forename: Gary
authors.initials: G
authors.lastname: Clayman
authors.forename: Liliane
authors.initials: L
authors.lastname: Massaad-Massade
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000818:Animals; D002277:Carcinoma; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002470:Cell Survival; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D009368:Neoplasm Transplantation; D009841:Oligonucleotides / Q000737:chemistry; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D013185:Squalene / Q000737:chemistry*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D014183:Transplantation, Heterologous
chemical_list: D009841:Oligonucleotides; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D013185:Squalene; D011505:Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human