Efficient gene therapy based targeting system for the treatment of inoperable tumors Thomas Wirth 1 * † Jere Tuomas Pikkarainen 1,4† Haritha Dhammika Samaranayake 1,4 Pauliina Lehtolainen-Dalkilic 4 Hanna Pirita Lesch 1,4 Kari Juhani Airenne 1 Varpu Marjomäki 5 Seppo Pasi Antero Ylä-Herttuala 1,2,3 1 AI Virtanen Institute, University of Eastern Finland, Kuopio, Finland 2 Department of Medicine and Gene Therapy Unit, University of Eastern Finland, Kuopio, Finland 3 Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland 4 Ark Therapeutics Oy, Kuopio, Finland 5 Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland *Correspondence to: T. Wirth, A.I. Virtanen Institute, University of Eastern Finland, PO Box 1627 (Neulaniementie 2), FIN-70211 Kuopio, Finland. E-mail: thomas.wirth@uef.fi † Both investigators contributed equally. Abstract Background A considerable percentage of tumors are not amenable to sur- gery. We have designed a simple and powerful targeting system that offers an al- ternative option for the multi-component pre-targeting strategies used clinically. This targeting system can be used for any type of solid tumors independent of the tumor type, thereby omitting the need to engineer unique antibodies for each specific application or tumour type. In the present study, we show the expression of a chimeric fusion protein, which contains the low-density lipoprotein receptor transmembrane domains and avidin, after local gene transfer and its ability to bind biotinylated compounds in vivo. Methods Semliki Forest virus and lentivirus vectors were used to express the fusion protein with a high affinity binding site for biotinylated compounds in the tumor. Three different animal models and imaging modalities were used for the demonstration of the functionality and efficacy of the targeting system in vitro and in vivo. Results We demonstrate targeting of biotinylated compounds after local gene transfer in vivo using two different gene transfer vectors. The findings were confirmed by immunohistochemistry, single-photon emission computed tomography and magnetic resonance imaging. The therapeutic efficacy was tested in a syngeneic rat glioma model by injecting biotinylated- 90 Yttrium into the tail vein of glioma bearing rats. The study demonstrates that animals, which were treated by using the gene therapy based targeting system, lived significantly longer than control animals. Conclusions Our gene therapy based targeting system is a promising tool for the treatment of inoperable tumors and other disease conditions, as well as diagnostic imaging. Copyright © 2012 John Wiley & Sons, Ltd. Keywords brain cancer; drug targeting; gene therapy; molecular imaging; radiotherapy Introduction A significant proportion of cancers are often inoperable. In such cases, chemo- therapy and radiotherapy are the commonly available therapeutic options. How- ever, unwanted toxicities are integral to both therapeutic modalities. By targeting these therapies into the tumors, toxicities maybe avoided and the therapeutic index can be improved. As an example, the most malignant type of brain tumor, glioblastoma multiforme is a tumor that frequently infiltrates diffusely into the surrounding brain parenchyma, making a complete surgical resection virtually impossible [1–3]. These tumors are considered noncurable with a poor prognosis RESEARCH ARTICLE Received: 16 December 2011 Revised: 10 February 2012 Accepted: 5 March 2012 Copyright © 2012 John Wiley & Sons, Ltd. THE JOURNAL OF GENE MEDICINE J Gene Med 2012; 14: 221–230. Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jgm.2619