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Abstract
Hemochromatosis can be described as a medical condition with excessive iron accumulation in the body. There are two types of hemochromatosis, which include hereditary and
acquired. Acquired hemochromatosis, as seen in patients with β-thalassemia and sickle cell
disease, is due to transfusion-induced during the management of anaemia. When there is iron
++overload in the body, this can lead to the generation of reactive oxygen species, which can affect
the heart, brain, liver, pancreas, joints, etc. One of the most established treatment strategies for
hemochromatosis is iron chelation therapy, with deferoxamine being described clinically as the
most successful in removing excess iron from the body. Deferoxamine is a clinically approved
iron chelator and is a standard treatment in the management of hemochromatosis, but suffers from
poor oral bioavailability, clinical toxicity, poor patient adherence, and suboptimal
pharmacokinetics, necessitating prolonged intravenous infusion regimens. To address these issues,
we developed two distinct: oral delivery strategies and which include:(1) self-assembled polymeric
nanoparticles based on hyaluronic acid (HA, MW 15 kDa) conjugated with bile acids—
deoxycholic acid (DOCA) or taurocholic acid (TCA)—and DFO, and (2) deferoxamine-loaded
nanostructured lipid carriers (DFO-NLCs) engineered using glyceryl monooleate and oleic acid,
with poloxamer 188 as surfactant and a chitosan-alginate coating to enhance stability in gastric
environments and gastrointestinal permeation.
In this dissertation, HA-BA-DFO conjugates were synthesized and formulated into self
assembled nanoparticles. The structural integrity was investigated with NMR, FTIR, and UV-Vis
spectroscopy. It was observed that TCA9-HA-DFO displayed superior in vitro permeability and
lower cytotoxicity compared to free DFO, while maintaining effective iron-chelating activity. For
the second strategy, a Quality by Design (QbD) framework with Design of Experiments (DOE)
was applied to optimize DFO-NLC formulations. Physicochemical characterization showed that
formulations (F2, F3, and F5) demonstrated desirable particle size, encapsulation efficiency, DFO
loading, and controlled release profiles, with F2 exhibiting the most sustained DFO release. With
these two approaches, it was observed that both highlighted promising strategies that can be
exploited to overcome the limitations of current DFO therapy. This offers huge potential for the
development of safe, effective, and patient-friendly oral formulations that enhance therapeutic
outcomes in iron-overload disorders.