Surface Functionalisation of Metal-Organic Frameworks for Biomedical Applications
Cancer and antimicrobial resistance (AMR) are two of the most significant healthcare-related challenges worldwide. The shortcomings of current cancer treatment methods, combined with the exponential increase of antimicrobial-resistant bacteria, underscore the need for new drug delivery systems that can overcome these challenges. In this context, nanoparticle-based systems have gained attention, with metal-organic frameworks (MOFs) standing out as promising nanocarriers due to their high porosity, controlled drug release, and easily functionalisable external surface. This thesis describes the use of MOFs for several biomedical applications. First, the synthesis procedures for different nanoMOFs were optimised based on the coordination modulation method by studying the effect of reaction time, amount of modulator, and different metal-tolinker ratios on the particle size and crystallinity of the MOFs. By following this approach, three porous and biocompatible MOFs–PCN-222, Zr-fumarate, and MIL-173–were synthesised with high crystallinity and purity. Additionally, a new crystal structure named Mg(bpgal)2 was discovered, which is based on Mg-gallate MOF but features an extended linker to enhance its pore size and surface area. Among all the MOFs synthesised PCN-222 was deemed as the most promising material for drug delivery applications due to its high pore size, BET surface area, and particle size. PCN-222 was then coated with three different phospholipids—1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)—to enhance its internalisation in cancer cells. The coated MOFs underwent a full physicochemical characterisation using powder X-ray diffraction, various microscopy techniques, dynamic light scattering, and zeta potential, among others. These systems were evaluated in PANC-1 pancreatic cancer cells as a proof-of-concept cell line, demonstrating significant biocompatibility and improved cellular uptake when compared to PEGylated PCN-222. Further studies focused on the encapsulation of two standard-of-care drugs used in mesothelioma treatment: pemetrexed and carboplatin. Pemetrexed and carboplatin were dual-loaded into PCN-222, achieving drug loadings of 0.73 mg of pemetrexed and 0.26 mg of carboplatin per mg of PCN-222. The drug-loaded MOFs were coated with optimised phospholipid combinations—DPPC, DOPE/DOPC, and DOPE/DPPC—and the biocompatibility and cytotoxicity of the materials were tested in vitro in 12T epithelioid mesothelioma cells and 33T biphasic mesothelioma cells, as well as ex ovo using the Hen’s egg test-chorioallantoic membrane (HET-CAM) assay, showing increased biocompatibility, sustained release of the cargo, and enhanced performance compared to the free drugs at high concentration. Finally, a novel targeting mechanism based on lectin, a targeting protein, and a DNA bridge was developed to selectively target MG1655 bacteria. PCN-222 was coated with three different nucleic acid coatings (DNA, DNAPhos, and PNAPhos), which were used to hybridise with the targeting complex. Among these, PNAPhos achieved the highest degree of colocalisation, as observed by structured illumination microscopy. The specificity of the targeting complex was confirmed in a co-culture of BL21 and MG1655 bacteria, where selective binding to MG1655 was observed. This thesis highlights the critical role of external surface functionalisation of nanoparticles in addressing the current challenges posed by antimicrobial resistance and cancer.
antimicrobial resistance, cancer treatment, Metal-organic frameworks, MOFs, nanotechnology, surface functionalisation
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