Abstract
Abstract Background: Short interfering RNA (siRNA) has emerged as a promising molecular therapeutic tool for targeted cancer treatment. However, systemically administered siRNA has demonstrated only limited success, due to limited delivery to cancer cells. Therefore, the lack of a robust and versatile siRNA delivery system is a critical issue in translating this therapeutic tool for cancer treatment. Recent developments in DNA nanotechnology have made programmable DNA nanoparticles (DNPs) a potent drug delivery platform. This study focuses on the development of a novel DNP-based siRNA delivery system to knockdown Bcl2 gene, as a targeted cancer therapeutic. Methods: Structural DNA technology was applied to design a library of DNPs with different sizes and shapes. Flow cytometry, confocal imaging, and electron microscopy were utilized to study the cellular internalization of DNPs. The efficacy of Bcl2 knockdown by DNP-siBcl2 and the resulting influence on cell growth and progression were assessed in cancer cells (in vitro) and in mice bearing corresponding tumor xenografts (in vivo). Results: DNPs of varying sizes (10-120 nm) and shapes (polyhedral or rod) were constructed using DNA origami techniques and successfully verified by agarose gel electrophoresis, atomic force microscopy, and transmission electron microscopy. The cell internalization capabilities of three DNPs including a tetrahedron (TET, diameter: 10 nm), a small rod (SR, 5x5x30 nm), and a large rod (BR, 10x10x120 nm) were examined. BR internalized with relatively higher efficiency and rate compared to TET and SR, and also demonstrated the most efficient knockdown of Bcl2. BR-siBcl2 demonstrated significant cell growth inhibition of DMS53 and H146 small cell lung cancer (SCLC) cell lines after 48hrs of treatment. A pilot study with BR-siBcl2 (1.25 mg/kg, iv) in mice bearing DMS53 tumor xenograft (n=3) slowed tumor growth compared with buffer control and naked siBcl2. Significant differences were observed in tumor volume by pairwise comparison between the two groups: Buffer vs DNP-BR-siBcl2 (p=0.007), and siBcl2 vs DNP-BR-siBcl2 (0.028), respectively. No toxicity was observed in lung, liver, kidney, heart, brain, or spleen. Conclusions: Our novel DNP formulations demonstrated substantial cellular internalization of siBcl2. Targeting Bcl2 and its downstream signaling intermediaries reduced cellular growth. We validated the strategy of silencing of Bcl2 using DNPs in order to inhibit cancer progression in vivo. We believe that the DNPs and methodologies developed in this project will be applicable to knockdown of Bcl2 and other gene targets and may be applicable to future anti-cancer therapy. (This work is supported by NIH grant R21EB022828-01). Citation Format: Mohammad Aminur Rahman, Pengfei Wang, Dongsheng Wang, Selwyn J. Hurwitz, Zhengjia Chen, Zhuo G. Chen, Yonggang Ke, Dong M. Shin. Efficient delivery of Bcl2 siRNA by DNA nanoparticles to inhibit cellular growth and cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 187. doi:10.1158/1538-7445.AM2017-187
Published Version
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