Studies of titanium-based anti-cancer agents and their effects on cancer cell lines
Publication Date
July 27, 2026
Creator
Allo Anginan, Theresia Brigita Rangga
Abstract
Cancer is a leading cause of mortality worldwide, and there is an urgent need for development of new therapies. Pancreatic ductal adenocarcinoma (PDAC), on the other hand, is the most aggressive types of cancers, with 90% of pancreatic cancer cases worldwide. In most cancers, especially pancreatic cancer, increased cellular iron uptake is observed, mediated by transferrin/(apo)ferritin (iron transport) proteins. Cellular iron uptake is typically via the transferrin receptor 1 (TfR1, also known as CD71). This is overexpressed in cancer cells, as iron is required for cell growth, for regulating ROS production and for mitochondrial respiration. This thesis proposes utilising the enhanced TfR1 expression of cancer cells to deliver anticancer agents. Specifically, we use tripodal ON -O bis-phenolateamine titanium(IV) complexes which have already demonstrated potent in vitro anti-cancer activity towards MCF-7 and HCT-116 cancer cell lines. We proposed testing these complexes` activities against PANC-1 pancreatic cancer cells (including as spheroid clusters) and to investigate encapsulation strategies for them within apoferritin. Discussed in Chapter 2, [Ti{MeN(CH2C6H2-2-O-4-OMe-6-R)2}2 (2.1a R = Me; 2.1b R = allyl, 2.1c R = fluoro) were prepared with overall yields of 21-65%. The activity of 2.1a was tested against 2D PANC-1 pancreatic cell lines using MTT and clonogenic assays. The MTT results show both complexes have GI50 values < 5 µM, which is lower than cisplatin (used as a positive control). Clonogenic assays of 2.1a show that the titanium complex also disrupts PANC-1 colony formation by 90% at 10 µM concentrations. Preparation of PANC-1 3D spheroid models (spherical collections of ca. 2500 cells) was optimised to mimic small pancreatic tumours in the human body. Spheroid volume measurement concurred to reveal that treatment with 2.1 (10 M) resulted decreased volume of the spheroid 82% relative to control after 72 hours of treatment.
Initial attempts to encapsulate complex 2.1a into horse spleen apoferritin using a standard pH dependent re-assembly method,[2] led to no detectable titanium species (by ICPMS) within the apoferritin cage. We propose that 2.1a undergoes decomposition by hydrolysis more rapidly when it is entrapped in apoferritin. We studied the related hydrolysis behaviour of 2.1b by UV-vis spectroscopy. Solutions of 76 μM 2.1b in either: (i) DMSO/deionised water (20:80), (ii) DMSO/8 M aqueous urea (20:80), (iii) DMSO/pH 5, 0.1 M acetate buffer (20:80) or (iv) DMSO/ pH 7.4, 0.1 M phosphate buffer (20:80) were compared. We found that the hydrolysis intermediate (resulting from ligand loss from 2.1b) is especially stable in the presence of DMSO/8 M aqueous urea (20:80), suggesting that 8 M urea-based encapsulation might form the basis of a better strategy for apoferritin encapsulated titanium agents.
In Chapter 3 we describe activity of alternative experimental anti-cancer agents: 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (2-ATA) and 2-arylthiazol-5-amine (4-AAP) derivatives as comparators for our titanium work. Preliminary MTT spot tests (at agent concentrations of 10 nM and 100 M) in HCT 116 colon and MCF 7 breast cancer cell lines
revealed only modest activity with greater growth-inhibitory effects apparent in the MCF-7 cell line for most of the tested agents. The activity of three of the more potent compounds (3.1, 3.6, 3.7) were further tested against both cell lines using dose-response MTT and clonogenic assays. The MTT results show compound 3.1 (N1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-N4-phenylsuccinamide) gave the highest GI50 values: 1.73±0.6 M
and 0.752±0.1 M against HCT 116 and MCF 7 cells respectively. These results are comparable to the cisplatin positive control (GI50 values 1.27±0.3 M and 0.69±0.1 MM) against HCT-116 and MCF-7 respectively.
Item Type
ethesis
Thesis Type
MRes
Supervisors
University of Nottingham
Bradshaw, Tracey
University of Nottingham
University of Nottingham
Subjects (LC)
Associated Schools / Departments
UoN Repository URI
Except where otherwise noted, this item's license is described as
File(s)![Thumbnail Image]()
Name
Theresia_Thesis_Final Version.pdf
Size
5.12 MB
Format
Adobe PDF
Checksum (MD5)
b748d185ec5c34d4788aee1397f57b7e