59 research outputs found

    Gelatin Nanoparticles as Delivery System for Nucleotide-Based Drugs

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    The present thesis deals with the development of nanoparticles based on the proteinaceous macromolecule gelatin as delivery system for various nucleotide-based drugs. Since a method to produce homogenous nanoparticles was already described in principle (Coester et al. 2000), it was the first approach to characterize, optimize, and standardize this manufacturing process. The next goal was to advance these plain gelatin nanoparticles via modification of the surface towards a delivery system for nucleotide-based drugs. Subsequent to this, the newly established carrier system should be evaluated in preclinical trials. In addition to these main projects, it was also an aim of this study to investigate and influence the biodistribution of gelatin nanoparticles. Due to the multitude of independent projects, the present work is divided into five self-contained chapters. In Chapter I, fundamental research data concerning the preparation of gelatin nanoparticles is described. Thereby, the work was focused on process optimization of the existing preparation procedure. Moreover, new analytical tools to characterize gelatin and the gelatin nanoparticles are introduced. Chapter II features the data that were produced in cooperation with the Department of Pharmaceutical Biotechnology at Ludwig-Maximilians-University Munich. In this cooperation, plasmid DNA was bound onto the surface of previously modified gelatin nanoparticles by electrostatic interactions. Subsequent preparation optimization, this simple non-viral gene delivery system was investigated in vitro on murine melanoma cells. The major project of this work, the development and evaluation of gelatin nanoparticles as carrier system for immunogenic so called CpG oligonucleotides is presented in Chapter III and Chapter IV. The data has been generated in cooperation with the Department of Internal Medicine at the Ludwig-Maximilians-University Munich and initially during a 3-month research stay at the Faculty of Pharmacy at the University of Alberta in Edmonton, Canada. Chapter III features extensive in vitro investigations on the respective primary murine and human target cells such as dendritic cells and B cells, whereas in Chapter IV, the results of in vivo experiments are presented. Here, the immunogenic effects of CpG oligonucleotide-loaded nanoparticles alone and their adjuvant activity in combination with the model protein antigen ovalbumin (OVA) were explored. In the final chapter, Chapter V, first PEGylation experiments of gelatin nanoparticles are described, with special emphasis on the establishment of new analytical tools for the quality control of the PEGylation process. In the second part of this chapter, radiolabeling strategies were developed in cooperation with the Department of Nuclear Medicine (TU Munich) to enable real-time in vivo tracking of the gelatin nanoparticles via positron emission tomography (PET)

    Lipopolysaccharide-pretreated plasmacytoid dendritic cells ameliorate experimental chronic kidney disease

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    Plasmacytoid dendritic cells play important roles in inducing immune tolerance, preventing allograft rejection, and regulating immune responses in both autoimmune disease and graft-versus-host disease. In order to evaluate a possible protective effect of plasmacytoid dendritic cells against renal inflammation and injury, we purified these cells from mouse spleens and adoptively transferred lipopolysaccharide (LPS)-treated cells, modified ex vivo, into mice with adriamycin nephropathy. These LPS-treated cells localized to the kidney cortex and the lymph nodes draining the kidney, and protected the kidney from injury during adriamycin nephropathy. Glomerulosclerosis, tubular atrophy, interstitial expansion, proteinuria, and creatinine clearance were significantly reduced in mice with adriamycin nephropathy subsequently treated with LPS-activated plasmacytoid dendritic cells as compared to the kidney injury in mice given naive plasmacytoid dendritic cells. In addition, LPS-pretreated cells, but not naive plasmacytoid dendritic cells, convert CD4+CD25− T cells into Foxp3+ regulatory T cells and suppress the proinflammatory cytokine production of endogenous renal macrophages. This may explain their ability to protect against renal injury in adriamycin nephropathy

    Auswahl eines Dokumentenmanagementsystems bei APRIL

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    Auswahl eines Dokumentenmanagementsystems bei APRIL

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