Investigation of metallacarboranes as unexpected therapeutics against triple-negative breast cancer cells
Date
2023-10-03Embargo Date
2024-08-17
Author
Murphy, Neville
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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.