Nanotheranostics 2019; 3(2):212-222. doi:10.7150/ntno.31827

Research Paper

Ultrasound-mediated delivery of siESE complexed with microbubbles attenuates HER2+/- cell line proliferation and tumor growth in rodent models of breast cancer

Kang-Ho Song1, Tammy Trudeau2, Adwitiya Kar2, Mark A. Borden1✉, Arthur Gutierrez-Hartmann2✉

1. Department of Mechanical Engineering, University of Colorado, Boulder, CO 80309, USA
2. Departments of Medicine and of Biochemistry & Molecular Genetics, University of Colorado Anschutz Medical Center, Aurora, CO 80045, USA

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Citation:
Song KH, Trudeau T, Kar A, Borden MA, Gutierrez-Hartmann A. Ultrasound-mediated delivery of siESE complexed with microbubbles attenuates HER2+/- cell line proliferation and tumor growth in rodent models of breast cancer. Nanotheranostics 2019; 3(2):212-222. doi:10.7150/ntno.31827. Available from http://www.ntno.org/v03p0212.htm

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Abstract

The highly tunable, noninvasive and spatially targeted nature of microbubble-enhanced, ultrasound-guided (MB+US) drug delivery makes it desirable for a wide variety of therapies. In breast cancer, both HER2+ and HER2- type neoplasms pose significant challenges to conventional therapeutics in greater than 40% of breast cancer patients, even with the widespread application of biologics such as trastuzumab. To address this therapeutic challenge, we examined the novel combination of tumor-injected microbubble-bound siRNA complexes and monodisperse size-isolated microbubbles (4-µm diameter) to attenuate tumor growth in vivo, as well as MB+US-facilitated shRNA and siRNA knockdown of ESE-1, an effector linked to dysregulated HER2 expression in HER2+/- cell line propagation. We first screened six variants of siESE and shESE for efficient knockdown of ESE in breast cancer cell lines. We demonstrated efficient reduction of BT-474 (PR+, ER+, HER2+; luminal B) and MDA-MB-468 (PR-, ER-, HER2-; triple-negative) clonogenicity and non-adherent growth after knockdown of ESE-1. A significant reduction in proliferative potential was seen for both cell lines using MB+US to deliver shESE and siESE. We then demonstrated significant attenuation of BT-474 xenograft tumor growth in Nod/SCID female mice using direct injection of microbubble-adsorbed siESE to the tumor and subsequent sonication. Our results suggest a positive effect on drug delivery from MB+US, and highlights the feasibility of using RNAi and MB+US for breast cancer pathologies. RNAi coupled with MB+US may also be an effective theranostic approach to treat other acoustically accessible tumors, such as melanoma, thyroid, parotid and skin cancer.

Keywords: ESE-1, microbubbles, ultrasound contrast agent, theranostics, gene therapy