Investigation of anthracycline based topoisomerase II inhibitors in triple negative breast cancer

Triple negative breast cancer (TNBC) constitutes10-20% of all breast cancer (BCa) cases. TNBC remains unresponsive to targeted therapy, and primarily relies on chemotherapy for treatment. Mitoxantrone (MTX), a topoisomerase II inhibitor belonging to the anthracenedione class, is used in BCa therapy. This thesis investigates the potential and mechanism of action of the MTX analogue KP71 and two metal organic frameworks (MOFs), UiO-66 and UiO-66-NH2, loaded with MTX, for TNBC treatment, in comparison to free MTX. KP71 exhibited significant anti-proliferative activity in BCa cell lines (MDA-MB-231, MDA-MB-468, and MCF7) using the 3-[4, 5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide and resazurin assay. The results of KP71 demonstrated DNA damage through Western blotting, inhibition of topoisomerase IIα and IIβ via the decatenation assay, and suppression of tubule formation in angiogenesis using the organotypic co-culture assay, thus elucidating its mechanism of action. Specifically, UiO-66 and UiO-66-NH2 showed potential as MTX carrier for BCa cells. Notably, MOFs exhibited substantial drug loading and sustained drug release without any initial burst release under physiological conditions, making them valuable for further drug delivery investigation. Additionally, both KP71 and UiO-66-NH2-MTX exhibited lower cytotoxicity towards non-neoplastic cell lines, namely MCF10-A, human umbilical cord vascular endothelium cells (HUVEC), and human dermal fibroblast (HFB), compared to free MTX. Meanwhile, UiO-66-MTX exhibited almost similar cytotoxicity as that of free MTX. Although the study emphasizes the potential of KP71 and MOFs as alternative drug delivery platforms for MTX, further work is required to fully validate their effectiveness and revolutionize the field of TNBC therapy.

Grantor dc:publisher.institution

University of Bradford

Author dc:creator

• Singhal, Mitali

Advisors dc:contributor.advisor

• Elies, Jacobo
• Riches-Suman, Kirsten

• Breast cancer
• Triple negative breast cancer
• MTX
• KP71
• Topoisomerase inhibitors
• H2AX
• Metal organic frameworks
• Angiogenesis
• Cardiovascular
• UiO-66

Statement dc:rights

• <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>.

Language dc:language.iso

en

Repository record dc:identifier.uri

https://bradscholars.brad.ac.uk/handle/10454/20355

OAI identifier oai:identifier

oai:bradscholars.brad.ac.uk:10454/20355