Development of a nanoparticle based anti-tumor gene therapy for treatment of breast cancer

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Breast cancer is one of the most common cancers worldwide and the most common cause of cancer related death in women. Because theonly currently available therapy for triple-negative breast cancer ischemotherapy, targeted therapies are needed to improve prognosis and reduce side effects. The project, which represents a Middle East cooperation between Germany (UKER-SEON) and Israel (TAU), aims to develop a nanoparticle-based anti-tumor gene therapy for the treatment of breast cancer. Gene therapy by toxins is based on the specific expression of a toxin gene in the cancer cells, e.g. Diphteria toxin A (DTA), which blocks the translation machinery of the cell. To limit the expression of DTA on tumor cells, a binary system of two plasmids has been developed (TAU). Plasmid 1 carries the DTA gene, which is separated from its tumor-specific promoter hTERT by atranscription terminator. The transcriptional terminator is flanked by attR and attL recombination sites. A second plasmid encodes thegene for a site-specific recombinase (SSR) under the control of a hTERT promoter. Once the recombinase is expressed in tumor cells, it cuts out the recombination terminator from plasmid 1 and DTA is expressed. In mice with lung carcinomas, the binary system has already been shown to be superior to the system with only one plasmid in terms of efficiency and side effects. A problem so far is to bring the plasmids in sufficient amount to the tumor, because many plasmids are already lost after the application in the blood circulation.The intratumoral concentration of the plasmids will be enhanced bymagnetically controlled transport using superparamagnetic iron oxide nanoparticles (SPIONs). The principle of magnetic drug targeting has already been successfully applied to the transport of thechemotherapeutic agent mitoxantrone in tumor-bearing rabbits (UKER-SEON). In the proposed project SPIONs carrying DTA andrecombinase plasmids will be developed. The SPIONs will be comprehensively characterized physico-chemically and toxicologically and tested for their anti-tumor efficacy in vitro on breast cancer cell lines. Finally, the efficacy in various breast cancer mouse models will be investigated. Here it is possible to enrich the SPIONs either passively via the Enhanced Permeation and Retention Effect (EPR) or actively by means of magnetic control in the tumor. Both options are compared in terms of pharmacokinetics, biodistribution and anti-tumor efficacy. At each stage of the project, feedback loops will take place between the two project partners, so that particle synthesis will be optimized in the course of the project and adapted to the respective question. By nanoparticle-based targeting of expression plasmids we expect an improved anti-tumor effect with simultaneous reduction oftoxic side effects.