Project Details
Projekt
Development of novel nanoparticle formulations for therapeutic in vivo lncRNA knockdown and circRNA-mediated oncomiR inhibition
Applicant
Professor Dr. Achim Aigner
Subject Area
Hematology, Oncology
Pharmacy
Pharmacy
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 468534282
Besides protein-encoding mRNAs, various non-coding RNAs (small microRNAs (miRNAs) or long non-coding RNAs (lncRNAs)) exist. In cancer, their levels can be aberrantly high or low. Pathologically upregulated, oncogenic lncRNAs are very interesting candidates for therapeutic inhibition. Their druggability through lncRNA knockdown will be explored in colorectal and gastric carcinoma cells. Upregulated oncogenic miRNAs (oncomiRs) may be targets for inhibition as well. So-called circular RNAs (circRNAs) represent attractive drug candidates in this regard, because as so-called oncomiR decoys, they bind and thus inhibit oncomiRs. Both strategies heavily rely on the efficient delivery of RNAs as drugs. Based on polymeric nanoparticle platform technologies for RNA delivery available in the Aigner group, this project will develop new modified nanoparticles. This aims at further enhancement of efficacy and biocompatibility, biodegradability and refinement for siRNA and oncomiR decoy delivery. More specifically, based on available polyethylenimine (PEI) polymers and derivatives, this project will generate a larger set of defined novel chemical modifications, also aiming at the development of biodegradable polymers. Furthermore, the combination of optimal polymeric systems from the above with lipid nanoparticles (liposomes) will be explored as well. These lipopolyplexes aim at the combination of favorable properties of both systems. For this, various established lipid formulations will be tested. Lipopolyplexes will be directly compared with the corresponding liposomes and polymers to identify which combinations would show improved properties in comparison to the single components. The novel nanoparticles will be analyzed regarding their physical/physicochemical, biological, pharmacological and toxicological properties. They will be extensively studied in various 2-dimensional and 3-dimensional cell and tissue culture models. The major focus of this project is thus on the development, characterization and testing of optimized nanoparticles as basis of potential RNA therapeutics, especially for the knockdown of onco-lncRNAs and the delivery of circular oncomiR decoys. Most promising polymers and RNA drugs will proceed towards pre-clinical in vivo therapy studies in mice bearing colorectal carcinomas or gastric carcinomas from tumor cells or from patients’ tumors (so-called “xenopatient” (AVATAR) models). Nanoparticles and delivery technologies will also be provided to other projects within the consortium for research and pre-clinical development of novel therapeutic strategies.
DFG Programme
Research Units
