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

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.