Saudi Cultural Missions Theses & Dissertations
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Item Restricted Melanin Nanoparticles as a Potential Iron Chelation Therapy for Women with Beta Thalassemia during Pregnancy(2022-12-09) Bakhamis, Nahla; Townley, HelenThe main challenges in developing medications that are safe to use during pregnancy is to minimize foetal exposure to the drug, which has become increasingly challenging with the increased prevalence of chronic conditions among young women. In beta thalassemia, patients can now survive beyond puberty and achieve pregnancy. β-TM pregnancies, however, are at high risk of maternal morbidity due to the complication of iron overload. Current chelation medications are withheld during pregnancy as they can cross the placenta causing potential risk to the foetus. This thesis addressed this complicated challenge in which a chelation agent needs to be retained in the maternal circulation and not cross the placenta. Previous experiments in iron-overloaded mice have shown that melanin nanoparticles can effectively chelate iron. Since the interaction between nanoparticles and cells/tissues is determined by particle characteristics and functionalization that can manipulated at synthesis, it was hypothesized that a melanin nanoparticulates with appropriate characteristics could be restricted from movement across the placenta, and safely used to treat the mother. A library of melanin nanoparticles of different sizes was established, and functionalized. This was followed by particle characterization and imaging. Functional analysis confirmed that particles were able to chelate iron more effectively than the iron chelator desferroxamine at the same concentration. Haemocompatibility testing found that the particles did not cause red cell haemolysis or blood clots. Moreover, it was determined that a cut off size of 200 nm can be restricted from passing across the placental barrier in an in vitro model using a human choriocarcinoma cell line and ex vivo human placental perfusion. Finally, physiological changes during pregnancy such as the decrease in plasma albumin concentrations can alter the volume of distribution as well as the transport of drugs. Proteomics analysis was used to identify nanoparticle binding proteins in the serum from pregnant women, non-pregnant women, and women with beta thalassemia. 43 significantly different proteins between the three serum groups were identified, followed by the gene ontology analysis of cellular components that revealed the mediation of biological identity of the bio-inspired melanin in the biological system.22 0