The therapeutic potential of RNA interference (RNAi) has been limited by inefficient delivery of short interfering RNA (siRNA). Tumor-specific recognition can be effectively achieved by antibodies directed against highly expressed cancer cell surface receptors. We investigated the utility of linking an internalizing streptavidinconjugated HER2 antibody to an endosome-disruptive biotinylated polymeric nanocarrier to improve the functional cytoplasmic delivery of siRNA in breast and ovarian cancer cells in vitro and in an intraperitoneal ovarian cancer xenograft model in vivo, yielding an 80% reduction of target mRNA and protein levels with sustained repression for at least 96 hours. RNAi-mediated site specific cleavage of target mRNA was demonstrated using the 5' RLM-RACE (RNA ligase mediated-rapid amplification of cDNA ends) assay. Mice bearing intraperitoneal human ovarian tumor xenografts demonstrated increased tumor accumulation of Cy5.5 fluorescently labeled siRNA and 70% target gene suppression after treatment with HER2 antibody-directed siRNA nanocarriers. Detection of the expected mRNA cleavage product by 5' RLM-RACE assay confirmed that suppression occurs via the expected RNAi pathway. Delivery of siRNA via antibody-directed endosomolytic nanoparticles may be a promising strategy for cancer therapy.
M. C. Palanca-Wessels et al., "Antibody Targeting Facilitates Effective Intratumoral SiRNA Nanoparticle Delivery to HER2-Overexpressing Cancer Cells," Oncotarget, vol. 7, no. 8, pp. 9561-9575, Impact Journals LLC, Jan 2016.
The definitive version is available at https://doi.org/10.18632/oncotarget.7076
Materials Science and Engineering
Keywords and Phrases
Breast cancer; HER2 antibody; Ovarian cancer; siRNA; Targeted antibody delivery
International Standard Serial Number (ISSN)
Article - Journal
© 2016 Impact Journals LLC, All rights reserved.
01 Jan 2016