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Development of copper-flavonoid complexes for treatment of acute myeloid leukemia (AML)

University of British Columbia

For more than 30 years, treatment of acute myeloid leukemia (AML) has remained largely unchanged and reliant on chemotherapeutic drug combinations. Despite the approval of novel targeted therapies, broad-spectrum chemotherapy drugs have been used to address the genetic heterogeneity of AML. One class of broad-spectrum compounds called flavonoids has shown promise in the treatment of AML. Of the flavonoids, quercetin and flavopiridol were selected for further investigations. Both quercetin and flavopiridol are hindered therapeutically by their poor solubility in aqueous solutions and tendency to bind serum proteins. To overcome these limitations, quercetin and flavopiridol were reformulated in copper-containing liposomes using the flavonoids’ metal-binding properties. Both formulations attained significant increases in apparent solubility (>100-fold). When injected intravenously into animals, both formulations exhibited an increased plasma area under the curve (AUC)) with no acute or chronic toxicities at the doses given. Given quercetin’s general lack of therapeutic activity as a single agent (IC50 of >10µM when tested against cancer cell lines), the research focused on the formulation of flavopiridol. In subcutaneous AML models, the flavopiridol formulation exhibited enhanced activity compared to a low pH free flavopiridol formulation. Despite the significant therapeutic potential uncovered in this thesis, liposomal flavorpidol’s potential is likely best achieved as part of a combination treatment. A combination regimen called FLAM (sequential treatment of flavopiridol, cytarabine, and mitoxantrone) inspired the development of a combination product consisting of liposomal flavopiridol and liposomal mitoxantrone. Free flavopiridol and mitoxantrone combined to produce significant synergistic activity in vitro. However, when administered in vivo, the combination of liposomal flavopiridol and liposomal mitoxantrone (referred to as enFlaM) resulted in an unexpected increase in toxicity and limited the dose of the combination that could be used in vivo. Although the enFlaM combination exhibited therapeutic effects at reduced doses, the effects were significantly less than what could be achieved with a well-tolerated dose of the single agent. Despite that further modifications will be necessary to devise an optimal combination scheme for the administration of enFlaM, the liposome-based Metaplex technology demonstrated the abilities to reformulate poorly soluble drugs to overcome limitations that would otherwise hinder their clinical utilities.

Text

2020-06-23

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/74775

Interdisciplinary Oncology

University of British Columbia

UBCV

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