Antitumor activities of Liver-targeting peptide modified Recombinant human Endostatin in BALB/c-nu mice with Hepatocellular carcinoma

Ma Yan,Zhang Jingjing,Zhu Jiayong,Wang Yan,Bao Dongmei,Jin Xiaobao,Wang Jie

doi:10.1038/s41598-017-14320-0

Abstract

In our previous study, a liver-targeting peptide CSP I-plus modified recombinant human Endostatin (rEndostatin, endostar) (rES-CSP) was constructed and showed potent antiangiogenic capability and could specifically bind to human hepatocellular carcinoma cells to make a direct inhibition in vitro. In this study, the biological activities of rES-CSP in vivo were evaluated by subcutaneous and orthotopic xenograft nude mice model of human hepatocellular carcinoma cells HepG2. We found that rES-CSP significantly decreased tumor volume to 54.9% in the nude mice with subcutaneous xenograft compared with the control. In orthotopic xenograft model, rES-CSP not only decreased tumor volume (to 39.6% compared with the control) and tumor weight, it also increased its biodistribution in the liver tissue and hepatoma tissue. Moreover, lower microvessel density (MVD) and higher apoptotic index (AI) were also observed in the tumor tissues. It had no significant side-effects on the heart, liver, spleen, lung and kidney of mice. Results indicated CSP I-plus modified Endostar may be a potential candidate for a targeting therapy on hepatocellular carcinoma.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed cancer worldwide, and it is the second and sixth leading cause of cancer death in men and women, respectively[1,2]
Subcutaneous xenograft tumors of HepG2 human hepatocellular carcinoma were treated in the vicinity for four weeks, the tumor growth curve and tumor weight as shown in Fig. 1, tumors treated with rES-Circumsporozoite protein (CSP) grew very slowly, the tumor volume and tumor weight of the rES-CSP group was significantly different from that of the control group
Hepatocellular carcinoma (HCC) has a fairly high morbidity and is notoriously difficult to treat due to long latent period before detection, multidrug resistance and severe drug-related adverse effects from chemotherapy

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed cancer worldwide, and it is the second and sixth leading cause of cancer death in men and women, respectively[1,2]. Monoclonal antibodies have shown clinical potential as tumor targeting agents, they are limited by their large molecular size and poor tumor penetration[19]. These limitations can be overcome by using peptide ligands, which are smaller, less immunogenic molecules, and easier to produce and manipulate[20]. The biological activity tests showed that CSP I-plus modified Endostar (rES-CSP) inhibited the proliferation and migration of human umbilical vein endothelial cells (HUVECs) and showed potent antiangiogenic capability on HUVECs tube formation assay and chick embryo chorioallantoic membrane(CAM) assay[25]. RES-CSP could bind to the hepatocellular carcinoma cells HepG2 and made a direct inhibition on tumor cells in vitro[26]. The biological activities of rES-CSP on homing to hepatocellular carcinoma tissue and anti-HCC in vivo have unknown

Methods

Results

Conclusion