Development of Novel Cupric- Tirapazamine Liposomes for Hypoxia Selective Therapy

Silva, Vera (2018) Development of Novel Cupric- Tirapazamine Liposomes for Hypoxia Selective Therapy. Doctoral thesis, University of East Anglia.

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Abstract

Hypoxia prodrugs have become an emerging topic in cancer therapeutics. Tirapazamine (TPZ) is the most advanced and potent hypoxia prodrug to date, but its clinical outcome has been controversial, due to poor cellular uptake, rapid metabolic reduction and limited tumour diffusion. The reassessment of this drug may offer alternative strategies to overcome its current biological limitations, maintaining its strong selective cytotoxicity. Previous studies have shown that the development of metal-complexes can efficiently modulate the physicochemical properties of its ligand, possibly enhancing their cellular activity.

Herein, TPZ cupric-complexes [Cu(TPZ)2] were synthetised and characterised with the aim of redefining TPZ. Cu(TPZ)2 showed good stability over a wide range of conditions and its fluorescent properties provided an invaluable tool to monitor cellular uptake and localization. In addition, Cu(TPZ)2 exhibited higher lipophilicity and more electronegative redox-potential, compared to TPZ, which conferred potent hypoxia selectivity against a range of prostate cancer cells. More promisingly, the complex showed higher potency in three-dimensional tumour spheroids, and induced S-phase cell cycle arrest, followed by marked cell apoptosis.

This work also focused on the development of Cu(TPZ)2-loaded liposomes, aiming to improve on TPZ retention. The effect of pH, temperature, PEGylation, lipid composition, and lipid:complex ratio on drug loading was systemically studied. Likewise, increased complex loading formed small precipitate aggregates, within the liposomal core, which provided better TPZ retention. The liposomes exhibited good stability over time and sustained release. Furthermore, they displayed potent in vitro activity that was formulation-dependant, in both 2D and 3D environments. Cu(TPZ)2-loaded liposomes maintained hypoxia selectivity in 2D models and provided improved cytotoxicity against tumour spheroids, probably due to slower reduction and penetrative capacity, compared to Cu(TPZ)2 alone. In conclusion, these novel Cu(TPZ)2-loaded liposomes could offer a promising approach to overcome TPZ’s biological shortcomings, offering a versatile delivery system for hypoxia targeted therapy.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Jennifer Whitaker
Date Deposited: 21 Jun 2019 09:39
Last Modified: 04 Dec 2022 01:38
URI: https://ueaeprints.uea.ac.uk/id/eprint/71509
DOI:

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