Abstract
Abstract Successful siRNA based therapy has the potential to revolutionize cancer therapy by mediating the silencing of any gene deemed important for disease progression. However, unprotected siRNA has a short half-life in blood and lacks the ability to selectively identify target cells. Our group is developing an effective siRNA based nanoparticle platform that overcomes these shortcomings by utilizing a mesoporous silica nanoparticle electrostatically loaded with siRNA and conjugated with an antibody for target homing. The human epidermal growth receptor type 2 (HER2) is a highly validated therapeutic target in breast cancer due to its prognostic role in cancer aggressiveness and drug resistance when overexpressed in tumors. Suppression of HER2 with siRNA based therapy (siHER2) offers a new treatment modality and provides a testable system for the development of our nanoparticle platform. Incorporation of Herceptin, a monoclonal antibody which binds to HER2, serves to selectively target HER2-positive cancer cells. In vitro evaluation of the nanoconstruct loaded with a highly optimized siHER2 sequence against a panel of HER2-positive (HCC1954, JIMT-1, BT474) and HER2-negative (MCF-7, MCF-10A, HDFa) cell lines demonstrated efficient knockdown of HER2 gene expression (> 75% reduction of HER2 mRNA and protein). Concomitant cell viability assays showed increased cell death in HER2-positive and no HER2-negative cell lines further highlighting treatment specificity. Importantly, treatment of cells with the siHER2-nanoconstruct effectively inhibited growth in HER2-positive cell lines resistant to Herceptin and Lapatinib. Subsequent in vivo tumor modeling studies using orthotopic transplantation of HCC1954 in the mammary fat pad of SCID mice revealed that i.v. injection of the siHER2-nanocontruct reduced overall tumor burden. HER2 knockdown in the tumors was also significant. These findings provide the foundation for a novel translational platform for facilitating therapeutic siRNA. Citation Format: Shaun M. Goodyear. Development of a nanoparticle platform for the targeted delivery of siRNA to HER2-positive breast cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5416. doi:10.1158/1538-7445.AM2014-5416
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