Investigation of metallacarboranes as unexpected therapeutics against triple-negative breast cancer cells
Murphy, Neville
Murphy, Neville
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Publication Date
2023-10-03
Type
Thesis
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Abstract
Metallacarboranes have been shown to have very promising properties for biomedical applications, with some derivatives having already shown good results in a number of cancer subtypes. The ability to self-aggregate, and the unique biological interactions made possible by the dihydrogen bonding typical of these cage compounds, make them an especially attractive subject of anticancer studies. The following work aims to unravel the effects of the metal centre of bis-dicarbollide metallacarboranes, focusing primarily on cobalt, iron, chromium and nickel. Factors such as overall stability, toxicity, selectivity and the ability of the compounds to internalise within human breast cancer cell lines will be discussed. Following the determination of potent species of metallacarboranes, drug delivery systems which have favourable physiological properties in terms of stability, release and biocompatibility will be developed. Overall, we show that availability of reactive B-H vertices is critical for the toxicity of the compounds, and the charge density provided by the metal centre greatly affects the capacity of the metallacarborane cage to interact with neighbouring molecules. The first chapter provides a general introduction to boron clusters and their use in biomedical applications, in particular focusing on breast cancer therapy. Boron clusters in general has been a burgeoning field since their conception in the 1950s, with a plethora of potential applications coming to the fore in radionuclide recovery, catalysis and as superacids. In recent times, great strides have been made in medicinal applications such as antimicrobial and anticancer agents. One of the flagships in medicinal boron chemistry has been the use of clusters of borane and carborane in Boron Neutron Capture Therapy (BNCT), an alternative to photodynamic therapy that has seen a borane compound in clinical trials. This chapter addresses the examples of boron clusters applied to the field of breast cancer. Carboranes have been used as pharmacophores, being added to known therapeutics to improve their toxicity and selectivity to good effect. Metallacarboranes, the subject of this work, have been tested less against breast cancer cell lines but some useful correlations can be brought together when looking at metallacarborane-protein interactions. Chapter 2 provides the aim, objectives and inspiration of the work as well as the main research questions that we have aimed to answer throughout the thesis. The third chapter provides evidence on the metallacarborane synthetic, stability and cytotoxicity versus human breast cancer cell lines MDA-MB-231 and HCC-1954, as well as normal human dermal fibroblasts used as an example of healthy cells. Stability is assessed through UV-Vis and NMR over 72 h in PBS to mimic physiological conditions. Cytotoxicity is measured through cell viability assay MTS, and the mechanism of action partly investigated with reactive oxygen species assays. The toxicity of the compounds has been tested using an in vivo zebrafish model. Within chapter four a study comparing SRS intensities of the B–H stretch characteristic of boron clusters within breast cancer MDA-MB-231 and HCC-1954 cell lines is described. The metallacarboranes are incubated with cells at uniform exposure time and concentrations to compare the uptake between metal centres. The unmixing of B–H, C–D and C≡C signals is detected within HeLa cells using SRS microscopy, with the methodology of spectral phasor analysis, providing 9 discrete SRS regions of interest within the cellular environment. These experiments have been carried out with metallacarboranes 4, 5 and 6 to demonstrate the wide range of applications possible with each species. In a first attempt to incorporate metallacarborane in a drug delivery system, chapter five shows preliminary results and attempts using an aliphatic polycarbonate as a biocompatible polymer, and the thiol-ene click chemistry used for the coupling of organic thiols is tested. Thiol-terminated synthon of CoSAN 15 is loaded to the polymer, to ascertain the effects on their physiological properties. With the complications encountered using a polycarbonate backbone, the sixth chapter demonstrates the incorporation of metallacarboranes into hyaluronic acid materials using two methods of linkage, encompassing non-covalent and covalent tethering. The connotations on the release and cytotoxicity properties of the materials is assessed on the same breast cancer cell lines, and their internalisation visualised using SRS.
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NUI Galway