Antibody targeting facilitates effective intratumoral siRNA nanoparticle delivery to HER2-overexpressing cancer cells
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Maria C. Palanca-Wessels1,2,*, Garrett C. Booth1, Anthony J. Convertine3, Brittany B. Lundy3, Geoffrey Y. Berguig3, Michael F. Press4, Patrick S. Stayton3, Oliver W. Press1,3
1Clinical Research Division and Center for Intracellular Delivery of Biologics, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
2Department of Medicine, Hematology Division, University of Washington, Seattle, WA, USA
3Department of Bioengineering and Center for Intracellular Delivery of Biologics, University of Washington, Seattle, WA, USA
4Department of Pathology, University of Southern California, Los Angeles, CA, USA
*This work was performed in Seattle, WA, USA. M.C.P.W. performed this work while at the Fred Hutchinson Cancer Research Center, but is now employed by Seattle Genetics
Oliver W. Press, e-mail: [email protected]
Keywords: HER2 antibody, siRNA, targeted antibody delivery, ovarian cancer, breast cancer
Received: August 28, 2015 Accepted: January 19, 2016 Published: January 30, 2016
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 streptavidin-conjugated 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.
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