Physicochemical Characteristics and Preliminary in Vivo Biological Evaluation of Nanocapsules Loaded with siRNA Targeting Estrogen Receptor Alpha

被引:33
作者
Bouclier, Celine [1 ,2 ]
Moine, Laurence [1 ,2 ]
Hillaireau, Herve [1 ,2 ]
Marsaud, Veronique [1 ,2 ]
Connault, Elisabeth
Opolon, Paule [3 ]
Couvreur, Patrick [1 ,2 ]
Fattal, Elias [1 ,2 ]
Renoir, Jack-Michel [1 ,2 ]
机构
[1] Univ Paris Sud, CNRS UMR 8612, F-92296 Chatenay Malabry, France
[2] IFR 141, F-92296 Chatenay Malabry, France
[3] Inst Gustave Roussy, CNRS UNR 8121, Villejuif, France
关键词
D O I
10.1021/bm800664c
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Specific siRNAs that target estrogen receptor alpha (ER alpha) were encapsulated in nanocapsules (NCs). We produced small (similar to 100-200 nm) ER alpha-siRNA NCs with a water core by incorporating two mixed duplexes of specific ER alpha-siRNAs (ER alpha-mix-siRNA) into NCs. The encapsulation yield that was obtained with poly(isobutylcyanoacrylate) (PIBCA) NCs was low, whereas no release of trapped siRNA was observed for poly(ethylene)glycol-poly(D,L-lactide-co-glycolide) (PEG-PLGA) NCs. High levels of ER alpha-siRNA incorporation into PEG-epsilon-caprolactone-malic acid (PEG-PCL/MA) NCs (3.3 mu M in a polymer solution at 16 mg/mL) were observed (72% yield). No difference in size or zeta potential was observed between siRNA NCs that were based on PEG-PCL/MA and empty NCs. Fluorescence quenching assays confirmed the incorporation of siRNA into the NC core. A persistent loss of ER alpha (90% over 5 days) was observed in MCF-7 human breast cancer cells that were exposed to PEG-PCL/MA NCs that were loaded with ER alpha-siRNA. The intravenous injection of these NCs into estradiol-stimulated MCF-7 cell xenografts led to a significant decrease in tumor growth and a decrease in ER alpha expression in tumor cells. These data indicate that a novel strategy, based on ER alpha-siRNA delivery, could be developed for the treatment of hormone-dependent breast cancers.
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收藏
页码:2881 / 2890
页数:10
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