title: E-selectin Targeting PEGylated-thioaptamer Prevents Breast Cancer Metastases.
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 CD44highbreast 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 CD44highBCa 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.
authors.affiliation: University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, Oklahoma, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Morita
authors.affiliation: University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, Oklahoma, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Kamal
authors.affiliation: University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, Oklahoma, USA.
authors.forename: Shin-Ae
authors.initials: SA
authors.lastname: Kang
authors.affiliation: Department of Pathology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Ganesh Lr
authors.initials: GL
authors.lastname: Lokesh
authors.affiliation: Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Varatharasa
authors.initials: V
authors.lastname: Thiviyanathan
authors.affiliation: Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Nafis
authors.initials: N
authors.lastname: Hasan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Sukyung
authors.initials: S
authors.lastname: Woo
authors.affiliation: University of Oklahoma Health Sciences Center, College of Public Health, Oklahoma City, Oklahoma, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zhao
authors.affiliation: University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, Oklahoma, USA.
authors.forename: Macall
authors.initials: M
authors.lastname: Leslie
authors.affiliation: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Suh
authors.affiliation: Department of Hematology and Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Wajeeha
authors.initials: W
authors.lastname: Razaq
authors.affiliation: Department of Pathology, Medical College of Wisconsin Cancer Center, Milwaukee, Wisconsin, USA.
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.affiliation: AM Biotechnologies, Houston, Texas, USA.|Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Gorenstein
authors.affiliation: Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.|Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Volk
authors.affiliation: University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, Oklahoma, USA.|Department of Pathology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Takemi
authors.initials: T
authors.lastname: Tanaka