E-selectin Targeting PEGylated-thioaptamer Prevents Breast Cancer Metastases

Yoshihiro Morita; Mohamed Kamal; Shin-Ae Kang; Roy Zhang; Ganesh Lr Lokesh; Varatharasa Thiviyanathan; Nafis Hasan; Sukyung Woo; Daniel Zhao; Macall Leslie; Stephen Suh; Wajeeha Razaq; Hallgeir Rui; David G Gorenstein; David E Volk; Takemi Tanaka

doi:10.1038/mtna.2016.103

E-selectin Targeting PEGylated-thioaptamer Prevents Breast Cancer Metastases

Mol Ther Nucleic Acids. 2016 Dec 13;5(12):e399. doi: 10.1038/mtna.2016.103.

Authors

Yoshihiro Morita¹, Mohamed Kamal¹, Shin-Ae Kang¹, Roy Zhang², Ganesh Lr Lokesh³, Varatharasa Thiviyanathan³, Nafis Hasan⁴, Sukyung Woo⁵, Daniel Zhao⁶, Macall Leslie¹, Stephen Suh⁷, Wajeeha Razaq⁸, Hallgeir Rui⁹, David G Gorenstein^{10

11}, David E Volk^{3

11}, Takemi Tanaka^{1

2}

Affiliations

¹ University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, Oklahoma, USA.
² Department of Pathology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
³ Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
⁴ Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
⁵ Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
⁶ University of Oklahoma Health Sciences Center, College of Public Health, Oklahoma City, Oklahoma, USA.
⁷ John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey, USA.
⁸ Department of Hematology and Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
⁹ Department of Pathology, Medical College of Wisconsin Cancer Center, Milwaukee, Wisconsin, USA.
¹⁰ AM Biotechnologies, Houston, Texas, USA.
¹¹ Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Houston, Texas, USA.

PMID: 27959340
DOI: 10.1038/mtna.2016.103

Abstract

E-selectin is an adhesion molecule expressed on the luminal surface of inflamed blood vessels that mediates hematogenous metastasis by assisting shear-resistant adhesion of circulating tumor cells to the vessel surface under dynamic blood flow. Previously, we developed an E-selectin antagonistic thioaptamer (ESTA) for the prevention of hematogenous metastasis through the blockade of CD44^high breast cancer cells (BCa) adhesion to E-selectin-expressing premetastatic endothelial niche. The current study focuses on developing a PEGylated E-selectin targeting thioaptamer with improved pharmaceutical properties. A serial deletion of stem-loops reveled that loop-1 and -2 (ESTA7) are the minimally effective backbone structure necessary to obtain inhibition of the E-selectin/CD44 interaction and shear resistant adhesion of CD44^high BCa to E-selectin-expressing human endothelial cells (HMVECs) at a level equal to ESTA. Chemical conjugation of methoxy-polyethylene-glycol (PEG) at the sizes of 5 and 10 kDa did not interfere with ESTA7-mediated shear-resistant adhesion. However, in vivo study demonstrated that only 10 kDa PEG-conjugated ESTA7 (ESTA7-p10) retains the activity to inhibit metastases at a level equal to parental ESTA. Additionally, a single intravenous injection of ESTA7-p10 inhibited the development of lung, brain, and bone metastases of MDA-MB-231, through the blockade of E-selectin. Moreover, PEGylation led to an extension of elimination half-life and increase of AUC, resulting in superior inhibition of metastasis development compared to parental ESTA with a longer interval between dosing in a spontaneous metastasis model. Lastly, repeated intravenous administration of ESTA7-p10 was tolerated in mice, highlighting the potential prophylactic application of ESTA7-p10 for metastasis prevention.

Abstract

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