期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 12, 页码 4067-4076出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm2000272
关键词
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资金
- European Research Council under the European Community [FP7/2007-2013, 249835]
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-SQRET/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-SQNPs 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.
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