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Praetner, Marc (2014): Surface-dependent biodistribution and proinflammatory properties of semiconductor quantum dots. Dissertation, LMU München: Medizinische Fakultät



Methods based on nanotechnologies play a growing role in biomedical research. Quantum dots (QDs) are a group of engineered fluorescent nanoparticles suited for advanced imaging applications. The substitution of the particle’s surface with defined molecular structures could enable the adoption as targeted contrast agents or therapeutic devices for a variety of clinical approaches. However, important aspects such as the basic surfacedependent behavior of non-targeted QDs in the organism and arising health effects upon systemic administration remain incompletely understood. Acute inflammatory effects for instance are often initiated on the microcirculatory level and are probably relevant for cardiovascular pathologies observed in epidemiologic and experimental studies of certain nanoparticles. Most in vitro studies show that the surface structures of QDs and other nanoparticles seem to be predominantly accountable for different cytotoxic effects and a variable potential to liberate proinflammatory cytokines. Currently, no systematic in vivo studies have addressed surface-dependent interactions of QDs on the level of the microcirculation and assessed the resulting impact on biokinetics as well as on proinflammatory parameters. Thus, this thesis aimed to i) analyze the incidence of QDsurface- dependent acute microvascular interactions and their influence on key biokinetic parameters and ii) investigate acute immunomodulatory effects on the multistep process of leukocyte recruitment in vivo. For this, three types of commercially available QDs with different surface modifications: carboxyl-QDs, amine- and polyethylene glycol-QDs (amine-QDs) and polyethylene glycol-QDs (PEG-QDs) were used. The physicochemical characterization was done by dynamic light scattering (DLS) analysis and microscale thermophoresis. In a first set of experiments, circulating half-lives, tissue distribution in different organs, and hepatic as well as renal clearance were measured. Ex vivo analysis of QD tissue distribution was performed on selected tissue samples via transmission electron microscopy (TEM) and two-photon microscopy. By combining reflected-light oblique transillumination (RLOT) and fluorescence in vivo microscopy of the murine M. cremaster, interactions of QDs with components of the microcirculation as well as leukocyte migration parameters were visualized and quantified. The extreme short circulating half-life of anionic carboxyl-QDs was related to pronounced clearance by the mononuclear phagocyte system. Beyond this, further investigations showed, for the first time, that the continuous capillary endothelium of skeletal and heart muscle tissue has the capacity to directly extract carboxyl-QDs from the circulation by means of caveolaemediated endocytosis. Carboxyl-QDs were also taken up by perivascular macrophages in the surgically exposed but not in the native M. cremaster and led to a significant increase of adherent and (subsequently) transmigrated leukocytes in this model. Further experiments provided evidence for a probable involvement of mast cells in the intercellular adhesion molecule-1 (ICAM-1)- and endothelial (E)-selectinmediated modulation of leukocyte recruitment. This process is most likely initiated by the endocytosis of carboxyl-QDs through activated perivascular macrophages. The primary activation of tissue-resident perivascular macrophages seems to be the consequence of tissue damage related to the surgical preparation of the cremaster muscle. This is supposedly a prerequisite for the endocytosis of carboxyl-QDs whereupon endothelial and mast cells seem to be secondarily activated in a paracrine fashion that then leads to an increase in leukocyte recruitment.