Ovarian cancer treatment with a tumor-targeting and gene expression-controllable lipoplex.

Zhi-Yao He,Cui-Cui Ma,Li Liu,Xiao Liang,Ya-Li Shen,Xiao-Ning Zhang,Yu-Quan Wei,Min Luo,Zhi-Yong Qian,Ya-Xiong Sang,Ting Liu,Yan-Jun Wen,Ping Zhang,Wei Wang,Yan-Tong Liu,Feng Deng,Xia-Wei Wei,Han-Xiao Qin,Xia Zhao

doi:10.1038/srep23764

Abstract

Overexpression of folate receptor alpha (FRα) and high telomerase activity are considered to be the characteristics of ovarian cancers. In this study, we developed FRα-targeted lipoplexes loaded with an hTERT promoter-regulated plasmid that encodes a matrix protein (MP) of the vesicular stomatitis virus, F-LP/pMP(2.5), for application in ovarian cancer treatment. We first characterized the pharmaceutical properties of F-LP/pMP(2.5). The efficient expression of the MP-driven hTERT promoter in SKOV-3 cells was determined after an in-vitro transfection assay, which was significantly increased compared with a non-modified LP/pMP(2.5) group. F-LP/pMP(2.5) treatment significantly inhibited the growth of tumors and extended the survival of mice in a SKOV-3 tumor model compared with other groups. Such an anti-tumor effect was due to the increased expression of MP in tumor tissue, which led to the induction of tumor cell apoptosis, inhibition of tumor cell proliferation and suppression of tumor angiogenesis. Furthermore, a preliminary safety evaluation demonstrated a good safety profile of F-LP/pMP(2.5) as a gene therapy agent. Therefore, FRα-targeted lipoplexes with therapeutic gene expression regulated by an hTERT promoter might be a promising gene therapy agent and a potential translational candidate for the clinical treatment of ovarian cancer.

Highlights

Overexpression of folate receptor alpha (FRα) and high telomerase activity are considered to be the characteristics of ovarian cancers
We developed a tumor-targeting gene delivery system based upon FRα -targeted lipoplexes and that includes a vector with a tumor-specific promoter to encode a gene for ovarian cancer treatment
The results indicated that mice treated with FRα -targeted liposomes (F-LP)/plasmid containing the therapeutic agent (pMP)(2.5) showed a significant increase in apoptosis within tumor cell populations compared with other groups as determined by transferase-mediated dUTP nick end-labeling DeadEnd Fluorometric (TUNEL) assay

Summary

Introduction

Overexpression of folate receptor alpha (FRα) and high telomerase activity are considered to be the characteristics of ovarian cancers. We developed FRα-targeted lipoplexes loaded with an hTERT promoter-regulated plasmid that encodes a matrix protein (MP) of the vesicular stomatitis virus, F-LP/pMP(2.5), for application in ovarian cancer treatment. FRα-targeted lipoplexes with therapeutic gene expression regulated by an hTERT promoter might be a promising gene therapy agent and a potential translational candidate for the clinical treatment of ovarian cancer. We developed a tumor-targeting gene delivery system based upon FRα -targeted lipoplexes and that includes a vector with a tumor-specific promoter (hTERT) to encode a gene (pMP) for ovarian cancer treatment. It is hypothesized that the FRα -targeted lipoplexes would deliver the pMP gene to the tumor site in an active fashion and drive the specific expression of the pMP gene by the hTERT promoter in ovarian cancer cells. The pharmaceutical properties, in-vitro biological activities, in-vivo antitumor effects, antitumor mechanisms, and preliminary toxicity evaluation of FRα -targeted lipoplexes loaded with pMP are presented in this report

Methods

Results

Conclusion