ICRS 2018

E-selectin-targeted copolymers for inhibiting metastasis and attenuating inflammation in the tumor microenvironment

Marie Ruetter Ayelet David
Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva, Israel

Introduction

Cancer is a widespread disease and one of the major causes of death in industrialized countries. Especially, formation of metastasis can narrow options of effective treatment and reduce the rate of success. E-selectin, an adhesion molecule expressed exclusively on endothelial cells in proximity of inflamed tissue, was found to be associated with mediating metastasis[1]. Previously, we have reported that a novel HPMA (N-(2-hydroxypropyl) methacrylamide) based polymer-peptide conjugate containing the high affinity E-selectin binding peptide (Esbp, primary sequence DITWDQLWDLMK) and doxorubicin (designated P-Esbp-DOX) inhibits the formation of B16-F10 metastasis in a pulmonary metastasis mouse model[2]. Interestingly, we found that pretreating the mice with a drug-free copolymer, only carrying the targeting peptide Esbp (P-Esbp), prevents the formation of melanoma lung metastases[2]. The main aim of the current study is to test whether P-Esbp could affect the in vivo growth breast cancer cells and control metastatic spread to the lungs. Considering the role of E-selectin in mediating leukocyte rolling along the vascular wall[3], we also measured markers of inflammation in the tumor microenvironment.

Results and discussion

P-Esbp was synthesized and characterized as described previously[2]. 4T1-Luc cells (3x106) were injected s.c. to BALB/c female mice, treated with P-(Esbp) (1 mg/mouse) on the 5th, 7th and 9th day and primary tumors were excised 12-14 days post tumor inoculation. The levels of TNFα and IL-6 were measured by ELISA. The tissue levels of TNFα and IL-6 were mildly decreased in tumors of mice treated with P-Esbp, as compared to a polymer with a scrambled Esbp peptide sequence (P-Scrm) or control groups. The inhibition of 4T1 lung metastasis formation is currently under investigation in a spontaneous metastasis model.

References

[1] Kolaczkowska, E. et al., Nat. Rev. Immunol., 13.3 (2013): 159-175.‏

[2] Shamay, Yosi, et al., J Control Release, 217 (2015): 102-112.

[3] McEver, Rodger P., Cardiovasc Res, 107.3 (2015): 331-339.‏









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