Design and synthesis of biocompatible metal-organic frameworks for anti-cancer, anti-tubercular and MRI application
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Date
2023-07-11Embargo Date
2025-07-07
Author
Ahmed, Ahmed
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Abstract
Metal-organic frameworks (MOFs) are relatively new porous materials that have attracted significant
attention in recent decades. Potential applications in gas storage and separation have been at the
forefront of this research. Their biomedical applications have also received attention; however,
significant work is needed to expand the field. Therefore, the aim of this thesis is to expand our
understanding on the biomedical applications of novel MOFs. Chapter 1 provides an introduction into
metal-organic frameworks, their properties and applications. It also provides a literature review on
the biomedical applications of MOFs, with a particular focus on their drug delivery and MRI
applications.
Chapter 2 is a published review on the synthesis and biomedical applications of highly porous MOFs.
The review defines a highly porous MOF as any MOF with a surface area above 4000 m2 g-1
. Synthetic
approaches to highly porous MOFs are classified and discussed in detail. Challenges such as
interpenetration and methods of overcoming them are also discussed. The biomedical applications of
highly porous MOFs are classified. Highly porous MOFs are unique as their high pore volume allows
for the encapsulation of large guest biomolecules such as protein, enzymes, genetic material etc. The
ability of the frameworks to load such biomolecules lends to applications in protein crystallisation,
biocatalysis and gene therapy. This work has been published in Molecules. 2022; 27(19):6585.
Chapter 3 discusses the synthesis of a novel Zn2+ MOF, NUIG4. NUIG4 is a rare example of four-fold
interpenetrated pcu MOF. The framework is composed of an octahedral [Zn4O(COO)6] secondary
building unit and a linear ditopic 4-((4-carboxybenzylidene)amino)benzoic acid (CBABH2) linker. The
structure of the framework was determine by single crystal X-ray diffraction. NUIG4 shows an
exceptionally high loading of the anticancer drug doxorubicin (DOX) 1955 mg DOX g-1
. A combination
of DFT calculations and solid-state NMR studies indicated the loading is driven by aromatic π–π
stacking interactions between DOX and the framework. DOX release from the framework is pH
controlled, with substantially more DOX release under acidic conditions. Cytocompatibility studies on
human dermal fibroblast cells indicated the framework and linker are both biocompatible. The gas
separation potential of the framework was evaluated using individual component adsorption
isotherms. NUIG4 displays a rare “inverse selectivity” for C2H2 over CO2. This work was published in J.
Mater. Chem. B, 2022,10, 1378-1385.
Chapter 4 Discusses the synthesis and characterisation of multivariate (MTV) NUIG4 MOFs. Attempts
were made to synthesise nitrated, fluorinated, pyridyl, naphthyl, methylated and hydroxylated
analogues of NUIG4. Of these functional groups, only methyl and hydroxyl functionality could be introduced into the framework, at various different ratios, when used in combination with the original
CBABH2 linker. Frameworks were also isolated with the CBABH2-OH and CBABH2-CH3 linkers
exclusively. The methylated framework and the MTV-NUIG4 frameworks shared the same structure
with the parent MOF. There was an observed decrease in framework crystallinity as the degree of
functionality increased. The Dox uptake and release of the MTV-NUIG4 MOFs was studied, providing
an insight into the effects of functionality on uptake capacity and release.
Chapter 5 discusses the synthesis of a family of Ln3+ (Ln = Gd, Tb, Dy) MOFs based on the biocompatible
CBABH2 linker. The frameworks are isostructural, featuring rhombic channel-type pores. The Gd
analogue (NUIG5-Gd) was loaded with the anti-epilepsy drug carbazmazepine (CBZ) at a loading of
11.6 wt%. The loading occurred in two steps, indicative of the breathing effect. CBZ release takes three
days in water and twelve hours in PBS solution. As NUIG5-Gd contains a large number of Gd3+ ions, its
potential as a magnetic resonance imaging (MRI) contrast agent was explored. Firstly, the framework
was nanosized by treatment with polyvinylpyrrolidone, followed by ultrasonication. Dynamic Light
Scattering (DLS) measurements indicated a mean particle size of 229 nm. The relaxivity of the
nanoparticles (nano-NUIG5-Gd) was calculated from concentration dependent proton relaxation
rates. Nano-NUIG5-Gd displays a longitudinal relaxivity of 9.7 mM-1 s-1 per Gd3+, marginally greater
than those of commercial Gd3+ MRI contrast agents. Cytotoxicity studies on nano-NUIG5-Gd indicate
the framework is biocompatible, with a cell viability >70% at a concentrations as high as 1 mg mL-1
.
Chapter 6 discusses the design and synthesis of novel MOFs for the treatment of tuberculosis. A
prodrug linker 4,4’-azodisalicylic acid (AZDH4) was synthesised and combined with divalent metal ions
(Mg2+, Zn2+, Cu2+, Co2+) yielding a family of isostructural MOFs (M2(AZD)). The AZDH4 linker is a prodrug,
whose metabolic product is para-aminosalicylic acid (ASA), an antitubercular drug. The M2(AZD)
frameworks share a topology with the well-studied IRMOF-74 family, featuring 1-dimensional
hexagonal channel-type pores. The rate of linker release was studied in water and PBS solution. The
frameworks show differing rates of AZD4- in deionised water and PBS solution. The rate of AZD4-
release was correlated with metal hardness, with Mg2(AZD) showing a faster release rate than the
other frameworks. In order to investigate their dual drug delivery potential, we attempted to load the
frameworks with the antitubercular antibiotic isoniazid (INH). Zn2(AZD) and Mg2(AZD) loaded INH at
loadings of 4 and 22 wt% respectively. Minimum inhibitory concentration (MIC) assays were carried
out to determine the antibacterial activity of the frameworks. This was carried out on Pseudomonas
aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus). The frameworks showed no
inhibitory effects, this may be due specificity of INH and ASA, as they are used almost exclusively to
treat tuberculosis. Interestingly the only framework to show an inhibitory effect is Co2(AZD) likely due
to the high toxicity of Co2+ ions towards bacteria.