Novel polymeric nanoparticles for pulmonary nucleic acid therapy - synthesis, toxicological analysis and biological / therapeutic assessment

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For many pulmonary diseases including lung tumors / metastases, novel treatment strategies are needed. Therapeutics based on RNA interference (RNAi) are advantageous but require efficient delivery of small interfering RNAs (siRNAs). Inhalative siRNA application offers direct contact, immediate availability, limited systemic spread and thus higher doses in the lung, but meets major challenges.Nanoparticles based on polymers or polymer/lipid combinations have been explored for siRNA delivery in vivo. Initial data from the applicants’ and other groups indicate that poly(ethylene) imines (PEIs) and other polyamines, and specific modifications for defined biodegradability and improved NP stability, may allow for novel inhalable siRNA formulations. Beyond efficacy, the assessment of toxicity will critically determine optimal NPs for lung delivery. Additionally, the development of inhalable formulations, e.g. based on nebulizers or dry powder inhalers, is crucial for clinical applications. This project will develop polymeric NPs as a platform for the delivery of oncogene-specific siRNAs, for direct application via inhalation. This includes generating a library of very defined, novel modified small polyamine systems, esp. tyrosine-modified derivatives, biodegradable derivatives and combinations thereof. Novel NPs will be extensively characterized regarding physical, physicochemical, biological and toxicological properties, and tested in vivo in lung metastasis mouse models regarding siRNA delivery, biodistribution and therapeutic efficacy. Different nebulization strategies (NPs from aqueous solution or dry powder, lyophilized or spray-dried upon NP embedding into hydrogels) will be explored. Beyond siRNA, the systems developed will be extended towards minicircle plasmid DNA and CRISPR-Cas9 (i.e., sgRNA + Cas9 plasmid).The definition and generation of optimal NPs, their optimal formulation for inhalative application and their biological assessment rely on the high degree of interaction between DE and PL, with both sides contributing their core competences. In an iterative process, results on biological efficacy (DE, PL) and biocompatibility/toxicity (PL) of NPs based on novel polymers (DE) influence further refinement of polymer modifications (DE) and NP generation (DE, PL).