Synthesis, Characterization, and in Vivo Delivery of siRNA-Squalene Nanoparticles Targeting Fusion Oncogene in Papillary Thyroid Carcinoma

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 o...

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Veröffentlicht in:Journal of medicinal chemistry 2011-06, Vol.54 (12), p.4067-4076
Hauptverfasser: Raouane, Mouna, Desmaele, Didier, Gilbert-Sirieix, Marie, Gueutin, Claire, Zouhiri, Fatima, Bourgaux, Claudie, Lepeltier, Elise, Gref, Ruxandra, Ben Salah, Ridha, Clayman, Gary, Massaad-Massade, Liliane, Couvreur, Patrick
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Sprache:eng
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Zusammenfassung: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 H2O as siRNA-SQ RET/PTC1 nanoparticles (NPs). The siRNA-SQ RET/PTC1 NPs, stable in H2O, 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm2000272