E-selectin Targeting PEGylated-thioaptamer Prevents Breast Cancer Metastases

• Main Authors: Yoshihiro Morita (Author), Mohamed Kamal (Author), Shin-Ae Kang (Author), Roy Zhang (Author), Ganesh LR Lokesh (Author), Varatharasa Thiviyanathan (Author), Nafis Hasan (Author), Sukyung Woo (Author), Daniel Zhao (Author), Macall Leslie (Author), Stephen Suh (Author), Wajeeha Razaq (Author), Hallgeir Rui (Author), David G Gorenstein (Author), David E Volk (Author), Takemi Tanaka (Author)
• Format: Book
• Published: Elsevier, 2016-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 CD44high 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 CD44high 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.

Item Description

2162-2531
10.1038/mtna.2016.103