Nanoparticle-induced gene-silencing for the suppression of inflammation in mouse models (edema, scleroderma, sepsis)

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A multifunctional nanoparticle-based system for local and/or systemic inhibition of NF-[kappa]B p65-mediated transcription of pro-inflammatory cytokines/chemokines in acute and chronic inflammatory diseases will be synthesized and examined. If it is successful, it will be widely applicable to patients who demonstrate a high risk of inflammation, e.g. during surgical operations. This therapeutic system can also be prophylactically applied in patients, especially with regard to the alarming problem of antibiotic resistance. Moreover, it could be also helpful in patients who are incompatible with conventional therapies. NF-[kappa]B is an intracellular protein that cannot be addressed by conventional antibody therapies, therefore nanoparticulate carriers for siRNA will be developed in this project. For this purpose, multi-shell siRNA-loaded calcium phosphate nanoparticles will be developed. They will be functionalized with appropriate cell-targeting molecules, i.e. antibodies and peptides. After near-infrared dye conjugation, they will also be detectable in vivo. As alternative system, siRNA-loaded calcium phosphate nanoparticles will be incorporated into polylactic acid nanoparticles in order to obtain a higher degree of siRNA protection from nucleases. The efficiency of the multifunctional nanoparticle-based system will be studied first in defined target cells, i.e. T-cells, B-cells, monocytes/macrophages, and endothelial cells, under controlled culture conditions, and second in vivo in living animals. Regarding the in vivo study, the ability of the nanoparticles to treat an acute localized (e.g. edema), an acute systemic (sepsis) and a chronic (scleroderma) inflammation will be studied. In all these cases, NF-[kappa]B plays an important role in the course of the disease.