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Poly(Propyleneimine) Transposon-Nanocarriers for Targeted Delivery of Therapeutic DNAs to Tumor Cells

German Research Foundation

The project focuses on the development and functional analysis of a modular, selective and non-viral transport system for the targeted delivery of therapeutic DNA (Survivin-shRNA, PE38 exotoxin) to tumor cells.
For therapeutic gene transfer, polycationic DNA carrier molecules, such as poly(propyleneimine) and modified variants of these are utilized. Targeting molecules (i.e. single chain fragment variables (scFv), peptide ligands) are coupled to these complexes leading to the formation of nanoparticles. Such nanoparticles specifically bind to tumor cells and induce a receptor-mediated endocytosis of the therapeutic payload. Chemical modifications of polycationic DNA carriers should prevent the undesired uptake into healthy cells. For proof-of-concept study in vitro cultures of prostate carcinoma cells expressing the marker prostate specific membrane antigen (PSMA) and glioblastoma cells expressing the neo-antigen epidermal growth factor receptor variant III (EGFRvIII) are used. To selectively deliver the therapeutic DNA to tumor cells a scFv for EGFRvIII and a peptide binding to PSMA will be employed.
The DNA elements used are designed in such a way that the therapeutic genes contained therein - once they have been delivered into the cell - are stably integrated into the genome by a co-delivered 'sleeping beauty transposase'. The additionally envisioned use of 'minicircle-plasmids', which are devoid of bacterial DNA components, should minimize the risk of an unwanted activation of pattern-recognition receptors. In contrast to immunotoxins, which are known to be neutralized by antibodies of the patient, this approach should allow repetitive applications to treat tumors.

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