A novel capsid-modified oncolytic recombinant adenovirus type 5 for tumor-targeting gene therapy by intravenous route
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Zhen Wang1,*, Bin Yu1,*, Baoming Wang1, Jingyi Yan1, Xiao Feng1, Zixuan Wang1, Lizheng Wang1, Haihong Zhang1, Hui Wu1, Jiaxin Wu1, Wei Kong1,2, Xianghui Yu1,2
1National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, 130012, China
2Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, Jilin University, Changchun, 130012, China
*These authors contributed equally to this work
Xianghui Yu, email: [email protected]
Wei Kong, email: [email protected]
Keywords: oncolytic adenovirus, gene therapy, capsid protein IX, TRAIL
Received: January 17, 2016 Accepted: June 04, 2016 Published: June 15, 2016
Oncolytic adenovirus (Ad)-vectored gene therapy is a promising strategy for cancer treatment. However, the lack of cancer cell selectivity or tumor tissue specificity of Ads limits their clinical application by intravenous (IV) injection. In this paper, a novel recombinant Ad5 vector was constructed carrying the capsid protein IX modified by the tumor necrosis factor related apoptosis-inducing ligand (TRAIL), which targets tumor cells bearing high levels of its receptor far above those of normal cells. Specific association of the Ad virion with TRAIL was achieved using synthetic leucine zipper-like dimerization domains (zippers). Analysis of the chemical properties of the modified recombinant Ad (rAd5pz-zTRAIL-RFP) showed that the TRAIL protein was present on the surface of purified virus particles, and it could induce apoptosis of infected cancer cells prior to expression of foreign genes. We also constructed a novel modified recombinant oncolytic Ad (rAd5pz-zTRAIL-RFP-SΔ24E1a) which showed significantly enhanced anti-tumor effects both in vitro and in vivo by linkage of TRAIL to the viral capsid. Moreover, rAd5pz-zTRAIL-RFP-SΔ24E1a showed significantly improved tumor tissue targeting and reduced liver tropism when IV injected in vivo. Thus, we successfully obtained new oncolytic Ad5 gene therapy vectors with enhanced targeting and efficacy, providing a platform for further clinical application of Ad vectors for cancer treatment.
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