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Development of a cardiac-targeted macromolecular chelator for the treatment of iron overload

University of British Columbia

Disorders of hemoglobin, such as sickle cell anemia and thalassemia, are an increasing global health concern for which patients must regularly receive blood transfusions. Unfortunately, chronic blood transfusion can lead to a condition known as transfusion-associated iron overload wherein iron becomes available for catalytic reactions that cause oxidative damage to cells. Further, because the human body lacks an iron excretion pathway, excess iron accumulates in vital organs such as the liver, heart and endocrine organs leading to organ damage and failure. The current standard of care is chelation therapy using small molecule Fe³⁺ chelators such as deferoxamine (DFO), deferiprone (L1) and deferasirox (DFX) which suffer from short circulation time, low iron excretion efficiency, and adverse side effects. To date, no methods are available to remove iron from specific organs to prevent organ toxicity; consequently, iron overload remains associated with significant morbidity and mortality. Recently, the Kizhakkedathu group demonstrated conjugation of DFO onto hyperbranched polyglycerol (HPG) improves the circulation profile of the drug (Hamilton, 2017). In addition, EP4 receptors, which prostaglandin E₂ (PGE₂) has high affinity for, has been shown to be abundant in the heart tissue of several species including humans (Regan, 1994; Castleberry, 2001; Sugimoto, 2007). Thus, I hypothesize that the use of PGE₂ as a cardiomyocyte targeting moiety in a macromolecular chelation approach would greatly enhance iron chelation efficacy of DFO in cardiomyocytes and protect heart from iron mediated injury. In this thesis, a novel macromolecular cardiac-targeted macromolecular iron chelator, termed CTMC, has been developed and assessment of its targeting ability, circulation and biodistribution, toxicity and iron removal efficiency have been conducted. CTMC was selectively taken up by cardiomyocytes in an in vitro co-culture model. CTMC was taken up 11.5-fold higher than non-targeted controls in the hearts of female C57BL/6 mice and shows long circulation. Studies conducted in an in vitro iron overload model of HL-1 murine cardiomyocytes demonstrated that after 2 days of treatment, CTMC was able to reduce intracellular iron levels and reactive oxygen species generation to those of baseline. Overall, the presented work suggests that CTMC is a promising candidate for organ-specific iron removal.

Text

2022-02-28

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/73777

Pathology and Laboratory Medicine

University of British Columbia

UBCV

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