Nanoparticle platform for therapeutic siRNA delivery to HER2 positive breast cancer

W. Ngamcherdtrakul, J. Morry, T. Sangvanich, R. Lee, Z. Hu, S. Gu, J. Gray, W. Yantasee
Oregon Health and Science University, US

Keywords: nanoparticle, mesoporous silica, siRNA, breast cancer

Summary:

Human epidermal growth receptor type 2 (HER2) is commonly found in breast and stomach cancer. Patients with HER2 positive breast cancer (accounting for 20-30% of all breast cancer patients) have poor clinical prognosis. Many are resistant or become resistant to HER2 targeted drugs such as Trastuzumab (Herceptin) and Lapatinib. We have developed siRNA against HER2 (siHER2) that show excellent growth inhibition in cell lines that are resistant to Herceptin and Lapatinib. Despite its great potential, siRNA based therapy has not been widely used clinically, mainly due to the lack of enabling delivery platform. In this regard, we have developed nanoparticle platform that consists of PEG-PEI co-copolymer coated on mesoporous silica nanoparticle core, HER2 antibody, and pore forming peptide for siRNA loading. The nano-constructs (carrier + siRNA) could successfully silence HER2 in HER2 positive breast cancer cell line (HCC1954), leading to growth inhibition of the cells at 5 days post transfection. The nano-constructs were evaluated in mice bearing breast cancer cells stably transfected with HER2 and luciferase. Silencing of luciferase within the tumor was achieved within 24 hrs and lasted for at least 4 days post injection of the siRNA-nano-constructs. The nano-constructs have good safety profile.