Development of copper-flavonoid complexes for treatment of acute myeloid leukemia (AML)
department or school: Medicine, Faculty of
data provider: DSpace
degree campus: UBCV
creator: Chen, Kent Tsung Jeng
issued: 2020-06-23T21:59:06Z
issued: 2020
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: 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 incr…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/74775
note: Development of copper-flavonoid complexes for treatment of acute myeloid leukemia (AML) by Kent Tsung Jeng Chen M.Sc., The University of British Columbia, 2012 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate and Postdoctoral Studies (Interdisciplinary Oncology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) June 2020 © Kent Tsung Jeng Chen, 2020 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Development of copper-flavonoid complexes for treatment of acute myeloid leukemia (AML) submitted by Kent Tsung-Jeng Chen in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Interdisciplinary Oncology Examining Committee: Dr. Marcel Bally, Pathology and Laboratory Medicine/Interdisciplinary Oncology Supervisor Dr. Howard Lim, Medical Oncology Supervisory Committee Member Dr. Urs Hefali, Pharmaceutical Sciences University Examiner Dr. Xiaoyan Jiang, Interdisciplinary Oncology University Examiner iii Abstract 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-fol…
has type: Thesis/Dissertation
date issued: 2020-11
is shown at: 10.14288/1.0391983
language: eng
degree discipline: Interdisciplinary Oncology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/74775