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

Subject Area Pharmacy
Biomaterials
Pharmacology
Term from 2019 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 426524608
 
Final Report Year 2024

Final Report Abstract

For many diseases including tumors and 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. Other RNA species or nucleic acids may be of therapeutic relevance as well. Previously, we have explored nanoparticles based on polymers or polymer/lipid combinations for siRNA delivery in vivo. Initial data from the applicants’ and other groups have shown that poly(ethylene)imines (PEIs) and other polyamines, and specific modifications for defined biodegradability and improved NP stability, may allow for novel siRNA formulations, for injection or inhalation. 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 a major hurdle, and NP systems need to be tested rigorously in vitro (2D cell culture) as well as in more sophisticated 3D models and in vivo. This project aimed at the development of polymeric NPs as a platform technology, mainly for the delivery of oncogene-specific siRNAs. This included the generation of a broader set of very defined, novel modified small polyamine systems, esp. tyrosine-modified derivatives, biodegradable derivatives and combinations thereof. Novel NPs were extensively characterized regarding physical, physicochemical, biological and toxicological properties, and tested in vivo in tumor-bearing mouse models (s.c. tumor xenografts, orthotopic glioma xenografts, patient-derived s.c. xenografts (PDX)) 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) were explored, particularly focusing on the establishment of spray-drying procedures with preservation of NP efficacy and high recovery rates. Beyond siRNA, the systems developed were extended towards plasmid DNA, minicircle DNA and CRISPR-Cas9. Some NPs were found to be particularly efficient for plasmid DNA delivery, rather than siRNA complexation. The various tyrosine-modified PEI- and PPI-derivatives also provided the basis for introducing a second chemical modification. This led to a particular enhancement with regard to mRNA transfection. Beyond 2D cell culture, the different NPs were extensively studied in 3D systems as well. These included Air-Liquid Interface (ALI) cell culture models as well as ALI tissue slice cultures, with both giving further insight into NP penetration and efficacy in a more intact 3D setting of fully preserved tissue architecture. The definition and generation of optimal NPs, their optimal formulation (for inhalative application and beyond) as well as their biological assessment relied on the close collaboration between DE and PL, with PL mainly contributing with regard to biophysical analyses and toxicological studies. This allowed to further characterize the advantageous properties of the chemically modified polymers, now providing the basis for further refinement of polymer modifications, NP generation and usage for optimal payloads.

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