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Dynamic Polysaccharide-based Nanoparticles for Advanced Drug Delivery Applications

Mainz: Univ. 2020 0 S.

Erscheinungsjahr: 2020

Publikationstyp: Buch (Dissertation)

Sprache: Englisch

Doi/URN: urn:nbn:de:hebis:77-diss-1000032337

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Inhaltszusammenfassung


Nanoparticles gained great importance in the medical field since their first discovery 50 years ago. Based on the ability to select from a repertoire of materials, shapes, and sizes, nanocarrier can be designed to deliver a wide range of high potent drugs. They can protect and significantly improve the bioavailability of sensitive and pharmaceutically active cargo, that otherwise would not be applicable in biological systems and thereby enabling a broad field of medical applications. This t...Nanoparticles gained great importance in the medical field since their first discovery 50 years ago. Based on the ability to select from a repertoire of materials, shapes, and sizes, nanocarrier can be designed to deliver a wide range of high potent drugs. They can protect and significantly improve the bioavailability of sensitive and pharmaceutically active cargo, that otherwise would not be applicable in biological systems and thereby enabling a broad field of medical applications. This thesis presents the further development of a biocompatible and biodegradable acid-sensitive polysaccharide-based nanocarrier system for the simultaneous delivery of hydrophilic and hydrophobic drugs. L-Asparaginase and etoposide were dual encapsulated in dextran-based nanoparticles by a double emulsion technique. Studies revealed a controlled pH-sensitive release of both drugs and a high synergistic toxicity in K562 cells in vitro. For immunotherapy applications, a biocompatible and targeted transport of active agents is required to enhance the therapeutic effect and limit the undesired side effects. Therefore, the dextran-based nanoparticle system was further advanced in the second project. The introduction of a hydrophilic polyethylene glycol (PEG) layer on the surface of these particles prevents unspecific cellular uptake and prolongs circulation time. Furthermore, specific antibodies as active targeting ligands for dendritic cells were attached on PEG. In vitro and in vivo studies showed that the modified particles were preferred taken up by receptor-mediated endocytosis in dendritic cells, which enables a potential anti-tumor CD8+ cytotoxic T-lymphocytes activation. In addition, based on the pH-responsive modified dextran, an advanced biocompatible horseradish peroxidase-polysaccharide conjugate was developed through formation of a disulfide bridge. The obtained double stimuli-responsive biodegradable hybrid material self assembles in water into spherical nanoparticles. During this process the structure integrity and enzymatic activity of the enzyme conjugate was retained. Nanoparticle degradation behavior was studied in detail with a focus on triggered drug released. The highly potent, indole-3 acetic acid (IAA) prodrug was encapsulated and successfully delivered into the cytosol of HeLa cells. Hereby the released prodrug was oxidized by the horseradish peroxidase particle material, which leads to cellular apoptosis. Both developed dextran-based particle systems represent promising candidates for successful applications in the delivery of therapeutics.» weiterlesen» einklappen

Autoren


Konhäuser, Matthias (Autor)

Klassifikation


DDC Sachgruppe:
Chemie