Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 7, 2016; 22(21): 5042-5049
Published online Jun 7, 2016. doi: 10.3748/wjg.v22.i21.5042
Transarterial administration of integrin inhibitor loaded nanoparticles combined with transarterial chemoembolization for treating hepatocellular carcinoma in a rat model
Jun Qian, Elsie Oppermann, Andreas Tran, Ulli Imlau, Kun Qian, Thomas Josef Vogl
Jun Qian, Kun Qian, Department of Radiology, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
Elsie Oppermann, Andreas Tran, Ulli Imlau, Thomas Josef Vogl, Institute for Diagnostic and Interventional Radiology, Johann Wolfgang Goethe University, D-60590 Frankfurt am Main, Germany
Author contributions: Qian J designed the study and wrote the paper; Qian J, Oppermann E and Tran A performed the majority of experiments and analyzed the data; Qian K performed the nanoparticles preparation; Imlau U performed the molecular investigations; Vogl TJ coordinated the research and reviewed the paper.
Supported by the National Natural Science Foundation of China, No. 81071241.
Institutional review board statement: The study design was approved by Ethics Committee of Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
Institutional animal care and use committee statement: All of the experiments on animals were approved by the German government and the institutional animal research review board, and Jun Qian's license number is Aktenzeichen F86/03.
Conflict-of-interest statement: All authors have seen and agree with the contents of the manuscript and there is no financial interest to report.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Thomas Josef Vogl, PhD, Institute for Diagnostic and Interventional Radiology, Johann Wolfgang Goethe University, D-60590 Frankfurt am Main, Germany. t.vogl@em.uni-frankfurt.de
Telephone: +49-69-63017277 Fax: +49-69-63017258
Received: December 3, 2015
Peer-review started: December 4, 2015
First decision: February 18, 2016
Revised: February 24, 2016
Accepted: March 14, 2016
Article in press: March 14, 2016
Published online: June 7, 2016
Abstract

AIM: To compare the effect of transarterial chemoembolization (TACE) plus GRGDSP (Gly-Arg-Gly-Asp-Ser-Pro, integrin-inhibitor) loaded nanoparticles with TACE alone or TACE + GRGDSP in a rat model of liver tumor.

METHODS: Morris hepatoma 3924A tumors were implanted in the livers of 30 ACI rats. The ACI rats were divided randomly into three groups (10 animals each). Tumor volume before treatment (V1) was examined by magnetic resonance imaging (MRI), and then, after laparotomy and placement of a PE-10 catheter into the hepatic artery, the following interventional protocols were performed: TACE (mitomycin C + lipiodol + degradable starch microspheres) + GRGDSP loaded nanoparticles for group A; TACE + GRGDSP for group B (control group 1); TACE alone for group C (control group 2). Tumor volume (V2) was assessed by MRI and the mean ratio of the post-treatment to pretreatment tumor volumes (V2/V1) was calculated. Immunohistochemical analysis was performed to assess the quantification of matrix metalloprotein 9 (MMP-9) and vascular endothelial growth factor (VEGF) positive tumor cells in each treatment group.

RESULTS: The mean tumor growth ratios (V2/V1) were 1.3649 ± 0.1194 in group A, 2.0770 ± 0.1595 in group B, and 3.2148 ± 0.1075 in group C. Compared with groups B and C, group A showed a significant reduction in tumor volume. Lower expression of MMP-9 and VEGF in hepatocellular carcinoma was observed in group A than in groups B and C. The angiogenesis of tumor was evaluated using anti-VEGF antibodies, and the metastasis of tumor was assessed using anti-MMP-9 antibody. MMP-9 and VEGF were expressed in all specimens. The immunoexpression of these proteins was confirmed by the presence of red cytoplasmic staining in tumor cells. Lower expression of MMP-9 and VEGF in hepatocellular carcinoma was observed in group A than in groups B and C.

CONCLUSION: Transarterial administration of integrin inhibitor loaded nanoparticles combined with TACE evidently retards tumor growth and intrahepatic metastases compared with TACE alone or TACE plus integrin inhibitor in an animal model of hepatocellular carcinoma.

Keywords: Hepatocellular carcinoma, Transarterial chemoembolization, Integrin inhibitor, Nanoparticles, Matrix metalloprotein 9, Vascular endothelial growth factor, ACI rats

Core tip: Our experimental study was designed to reduce tumor progression and recurrence through a combination of transarterial administration of GRGDSP (integrin-inhibitor) loaded nanoparticles plus transarterial chemoembolization (TACE) in an animal model of liver tumor. Our data showed that the combined biological and interventional treatment is a safe and effective therapy compared with TACE alone or TACE plus GRGDSP. The combined multimodal targeting therapies exhibit tremendous advantages over conventional interventional therapy alone.