Structural and functional characterisation of lipoplexes for tumour vaccination
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Abstract
The formulation and structural characterisation of messenger ribonucleic acid (mRNA)-lipoplexes for tumour vaccination as a new strategy for cancer therapy was the main objective of this thesis. Lipid-based systems were chosen as drug delivery particles due to their high biocompatibility together with a low immunogenicity and toxicity.
Embedded in a highly concentrated matrix of neutral lipids like Egg-Phosphatidylcholine (EPC) or 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), the cationic lipid DOTAP as a classical and well-known transfection reagent served as an anchor for the mRNA. Using various physiochemical methods, a detailed model of the molecular structure could be developed. In first cellular experiments, the biological functionality of the lipoplexes was proven.
Unfortunately, cationic lipids are associated with toxic effects, but the cationic charge is essential for cellular uptake and endosomal release. Hence, ionizable lipids with a pH-dependent charge are used to reduce this toxicity and avoid aggregation after administration. 1,2-Dioleoyl-N,N-dimethyl-3-aminopropane (DODMA) as an ionizable lipid was embedded again in a highly concentration matrix of EPC or DOPC. The structural organization was measured in neutral and acidic pH. With the further addition of heparin, cellular contact and endosomal release should be mimicked.