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

• Applicants: Privatdozent Dr. Dietmar Appelhans; Professor Dr. Achim Temme
• Subject Area: Pharmacy ; Molecular and Cellular Neurology and Neuropathology ; Preparatory and Physical Chemistry of Polymers ; Cell Biology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 419035191

The delivery of therapeutic nucleic acids, such as DNAs encoding suicide genes or shRNAs using polycationic carrier macromolecules, such as perfectly-branched poly(propyleneimine) dendrimers (PPI), is a promising therapeutic option to treat cancer. However, systemic delivery of carrier-complexed nucleic acids requires huge amounts of DNA which often results in unwanted unspecific off-tissue and off-target effects. This is particularly so since the transient expression of DNA also imply that repeated systemic administration is mandatory for treatment. Yet, the risk of cumulative toxicity is expected to increase. One approach to avoid unwanted off-target effects and to provide stable expression of DNA is the introduction of targeting moieties (ligands, antibodies) that specifically bind to target cells and deliver the therapeutic gene, using the concept of targeted delivery.In our project we plan to investigate a novel targeted transposon-minicircle DNA-delivery approach using functionalized PPIs enabling selective uptake and endosomal release in target cells displaying a surface expression of the cognate cellular receptor. More specifically, functionalized PPIs, coupled to tumor-selective targeting moieties such as single chain fragment variables (scFv) and peptide ligands, will be employed to selectively target glioma and prostate carcinoma tumor cells. The stable expression of the therapeutic genes is provided by co-delivery of a sleeping beauty transposase. In this proof-of-concept study the selective PPI-based transposon-nanocarrier platform will be investigated in vitro using gene transfer of reporter genes (EGFP, Luciferase), a suicide gene (Pseudomonas aeruginosa exotoxin PE38) and DNAs encoding for therapeutic shRNAs. The objective of this project therefore is to establish a biocompatible PPI-based -transposon carriers as a platform for the selective delivery of genes into target cells.

• DFG Programme: Research Grants