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Development of a liver targeted macromolecular iron chelator for the treatment of iron overload

University of British Columbia

Patients with thalassemia, myelodysplastic syndromes, sickle cell disease and other acquired anemia require life sustaining and often repeated red blood cell transfusions. Since humans lack an iron excretion pathway, excess iron results in systemic iron overload either due to an underlying genetic component or acquired through disease pathogenesis or repeated transfusions. Toxicity arises from the generation of reactive oxygen species and elicits considerable damage. The resulting iron toxicity accounts for a majority of premature deaths, primarily from liver and heart dysfunction and failures. The current standard of care for the treatment of transfusion-dependent iron overload is iron chelation therapy, which effectively reduces the toxicity associated with labile iron by lowering the iron burden. However, the toxicity, shorter circulation time and non-specificity of the current iron FDA approved iron chelators proved challenging and patient compliance are poor for this life-long therapy. Recently, Dr. Kizhakkedathu’s team developed a macromolecular iron chelating system with decreased toxicity, increased half-life and iron excretion profiles compared to the current standard iron chelator, deferoxamine in mice. Further, since the discovery of the asialoglycoprotein receptor and its specificity for N-acetyl galactosamine, there has been significant research pertaining to liver targeting and delivery of various drugs. Thus, we hypothesize that a macromolecular iron chelating system conjugated with liver targeting groups would enhance the iron removal from liver thereby preventing complications due to iron overload. In this thesis, a novel class of liver targeted macromolecular iron chelators were developed for the treatment of iron overload. The macromolecular scaffold was optimized for hepatocyte uptake in vitro and HPG-GalNAc₅₀ and HPG-TAG₂ were selected for iron chelation. The tolerability, biodistribution, and excretion of liver targeted iron chelating systems, HPG-DFO-GalNAc and HPG-DFO-TAG, were investigated in vivo. Remarkably, HPG-DFO-GalNAc and HPG-DFO-TAG exhibited significant hepatocyte accumulation with immediate lysosomal localization and subsequent rapid excretion with over 70% eliminated within 24 h. Liver targeted iron chelating systems with higher DFO units translated into superior systemic iron removal in a mice iron overload model. This thesis demonstrates the utility of liver targeted iron chelator for the removal of excess iron.

Text

2022-11-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/76569

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/