This thesis describes the experimental studies to improve the treatment of malignant pleural mesothelioma, an incurable cancer with a survival time of only one year after diagnosis. Mesothelioma is mainly caused by exposure to mining asbestos, a natural fibre widely used in building constructions. This untreatable cancer is histologically classified into three subtypes: epithelioid (60% of all mesothelioma cases), sarcomatoid (20%) and biphasic (20%), consisting of both epithelioid and sarcomatoid histology. Current treatment using carboplatin and pemetrexed induces severe side effects and has limited improvement in the survival of mesothelioma patients (3 months). Here, we proposed a new drug delivery system (DDS) based on metal-organic frameworks (MOFs) for mesothelioma therapy.

MOFs are crystalline and porous materials formed by the self-assembling of metal ions and organic ligands. Zirconium (Zr)-based MOFs have emerged as promising candidates in biomedical applications owing to their excellent stability and bioavailability. First, NU-901 Zr-MOF was synthesised and a bilayer coating method using phospholipid and biosurfactant was developed to protect the NU-901 from aggregating and degrading in the cellular media. An approved chemotherapeutic drug for mesothelioma, pemetrexed, was then encapsulated into NU-901, followed by the bilayer coating, to achieve a more sustained drug release and improve uptake by A549 lung cancer cells. Live confocal imaging confirmed the colocalisation of bilayer-coated MOFs with 3T patient-derived epithelioid mesothelioma cells and A549 cells with less lysosomal uptake.

Next, two more Zr-MOFs with larger porosities, PCN-128 and PCN-222, were synthesised to co-encapsulate the first-line treatments for mesothelioma, carboplatin and pemetrexed. The surface functionalisation process was then simplified from two steps (bilayer coating) to one step using a phosphate anchored polyethylene glycol (PEG) to improve the stability of MOF in three types of cellular media. The number of cell line was also expanded from one to four, including both epithelioid and biphasic subtypes. Compared to the same concentration of pure carboplatin and pemetrexed, dual PCN-222 DDS showed greater toxicity in three mesothelioma cell lines, while PCN-128 DDS was more toxic in one mesothelioma cell line. Furthermore, PCN-128 DDS required shorter time to kill biphasic mesothelioma cells compared to pure drugs.

After exploring the role of Zr-MOF in mesothelioma, we realised that introducing toxic solvents and metal ions in the synthesis of Zr-based MOFs was potentially carcinogenic and harmful to the environment. Inspired by the Zr-MOFs syntheses, the PCN-128 linker was functionalised with aldehyde groups and PCN-222 linker with amine groups to develop a new room temperature synthesis protocol of covalent organic frameworks (COF) without adding any metal ions. The COF showed high surface area and crystallinity, but its large size in both dried and suspension states hindered its application in nanoparticle-based drug delivery. Thus, the potential of COF in dye capture for environmental protection was explored. The COF performed as an excellent absorber for dye solution, showing its high affinity to cationic dyes such as rhodamine B and brilliant blue due to its negative surface charge.

In summary, Zr-based MOFs have shown great promise in mesothelioma therapy due to their functionalisable surface (bilayer and PEG), dual drug loading (carboplatin and pemetrexed), and improved cytotoxicity to mesothelioma cells. This thesis presented the first milestone in using MOF for mesothelioma therapy, which offers new insights into their applications in animal studies and clinical trials.