Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Gruber, M.
Nanoparticle and Macromolecular Transfer across the Human Placental Barrier
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2021. pp. 155
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Wadsack Christian
- Windpassinger Christian
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- Abstract:
- Macromolecular transfer and transfer of nanoparticles (NP) across the placenta are gaining importance due to increasing exposure of NP to humans. On the one hand, this importance is based on the targeted therapeutic application of NP-based drugs and biopharmaceuticals such as immunoglobulins gamma (IgG). On the other hand, the increased general use of nanoparticles and biopharmaceuticals poses unknown hazards to the foetus during pregnancy. The ability of NPs to cross the placenta was shown for a limited number of investigated NPs. However, whether this transfer occurs in the presence of physiologically relevant macromolecules has not yet been investigated. Knowledge on placental IgG transfer is better established than for NPs. It is known that IgG, mediated by the neonatal Fc receptor (FcRn), can cross the placental barrier. Whether and to what extent specific therapeutic IgGs cross the placenta or act directly on the placenta was only investigated for few antibodies. In the first part of the thesis, the placental transfer of 80 nm polystyrene (PS) and 100 nm polylactide-co-glycolide (PLGA) NP was demonstrated in a human ex-vivo perfusion model. Perfusion data showed that antipyrine (AP) decreased 500 nm PS NP concentration in the maternal circulation. For 80 nm PS NP, an influence of plasma proteins on NP transfer was demonstrated. Albumin was found to mediate transfer of 80 nm PS NP across the placenta. The second part of the thesis used the perfusion model to investigate the placental transfer of two therapeutic antibodies, anti-HER2 IgG1 and anti-RANKL IgG2. The expression of HER2 was confirmed, and expression of RANKL was shown in the term placenta. ELISA could not detect a placental transfer of IgG1, but a close relationship of IgG with FcRn and lysosome-associated membrane protein 1 (LAMP1) after perfusion could be detected. Specific peptides of IgG2 were detected by proteomics in foetal circulation, whereas intact therapeutic antibody was not detected. A functional approach detecting free RANKL showed that the term placenta releases RANKL into the foetal circulation. Generated data suggest an influence of AP on properties and placental uptake of PS NP at the placental barrier. The relevance of a biocorona on PS NP during perfusion and its ability to increase the placental transfer of NP was evident. A hypothesis-generating estimate of how the placenta processes PS NP was made, but this should be examined in detail in the future. PLGA as a biodegradable material showed potential to deliver drugs across the placenta. Since the anti-HER2 IgG1 could not cross the placenta but was detected together with FcRn and LAMP 1, it is assumable that antibodies whose epitope are present on or in the placenta do not cross the tissue. The negative consequences described for the foetus could be directly related to an IgG placenta interaction. For anti-RANKL IgG2, a negative effect on the placenta after short exposures with therapeutic concentrations can neither be confirmed nor denied. Data suggests further studies to investigate the relevance of RANKL in the placenta.