Coadministration of nanosystems of short silencing RNAs targeting oestrogen receptor alpha and anti-oestrogen synergistically induces tumour growth inhibition in human breast cancer xenografts.

The suppression of oestrogen receptor alpha (ERalpha) functions by silencing RNAs in association with or not with anti-oestrogens (AEs) both in vitro and in breast cancer cell xenografts was assessed. In vitro, a prolonged decrease in ERalpha protein expression and an enhanced AE-induced inhibition of ERalpha-mediated transcription, together with antiproliferative activity, were observed. Incorporation of ERalpha-siRNAs in pegylated nanocapsules (NC) was achieved; and their intravenous injections in MCF-7 xenografts, in contrast to scramble siRNA containing NCs, lead to decrease in ERalpha protein content and Ki67 labelling in tumour cells. The pure AE RU58668 (RU) both free and entrapped in stealth nanospheres (NS) at very low concentration (8 microg/kg/week) had no effect on tumour growth evolution. However, coinjection of the two nanocarriers potentiated the decrease in ERalpha protein, concomitantly with decreasing tumour vasculature and glucose transporter-1. These data support that the targeted delivery of ERalpha-siRNA in breast tumours potentiates the inhibition of E(2)-induced proliferative activity by encapsulated AE through enhanced anti-vascular activity. In the hormone-independent MDA-MB-231 xenograft model, RU-NS at 4 mg/kg/week induce also a strong tumour vascular normalisation. Together, these findings suggest that the anti-oestrogen activity of RU as well as that of targeted ERalpha-siRNA leads to anti-angiogenic activity. Their delivery in stealth nanocarriers may constitute a new anti-cancer therapeutic strategy in solid tumours.