MOF-mediated destruction of cancer using Fenton reaction

© 2018 Dr. Hadi RanjiburachalooCancer which is the second greatest cause of death worldwide has reached critical levels. In the past various therapies including photodynamic, photothermal and chemo-therapy are utilized for selective tumor treatment. Unfortunately, these methods suffer from various problems which limit their efficiency and performance. For this reason, novel strategies are being explored which improve the efficiency of these traditional therapeutic methods or treat the tumor cells directly. One such strategy utilizing the Fenton reaction has been investigated by many groups for the possible treatment of cancer cells. This therapy involves the utilisation of existing high levels of H2O2 in cancer cells to react with iron nanoparticles following the Fenton reaction to produce hydroxyl radicals capable of killing the cells. However, studies which attempted to use classical Fenton reaction alone to destroy the tumor cells, requires high concentrations of nanoparticles in order to be toxic to cancer cells. For this reason, there has not seen a successful nanoparticle which can treat cancer cells using the Fenton reaction without the need for external H2O2 sources. The aim of my work was to synthesize and develop novel metal organic frameworks (MOFs) for cancer treatment using the Fenton reaction. These specific nanoparticles can be utilized directly to destroy the cancer cells via the Fenton reaction or indirectly to deliver the Fenton reagent into cancer cells. In the first approach, a novel reduced iron metal-organic framework nanoparticle with cytotoxicity specific to cancer cells was fabricated. Iron present on the MOF can react with high levels of hydrogen peroxide found specifically in cancer cells to increase the hydroxyl radical concentration. The hydroxyl radicals oxidize proteins, lipids and/or DNA within the biological system to decrease cell viability. In vitro experiments demonstrate that this novel nanoparticle is cytotoxic to cancer cells through generation of hydroxyl radical using the cell’s own hydrogen peroxide. However, this emerging method is largely restricted due to the poor selectivity of reported nanoparticles. Subsequent improvements in nanoparticle size were facilitated by PEGylation on the particles through surface-initiated atom transfer radical polymerization, thus improving the stability, reducing the size and increasing the selectivity. In vitro experiments show that the selectivity index increased from 2.45 to 4.48 for HeLa cells, which is significantly higher than those reported in the literature for similar strategies. Finally, in an alternative approach, pH-responsive MOFs have been utilized for hemoglobin (Fenton reagent) and glucose oxidase (starvation reagent) delivery into the cancer cells. In a slightly acidic environment of cancer cells, GOx is released and consumes glucose and molecular oxygen that are essential survival nutrients in cancer cells and produces gluconic acid and hydrogen peroxide, respectively. The produced gluconic acid increases the acidity of the tumor microenvironment so completes MOFs destruction and enhances hemoglobin and GOx release. Fe ion from the heme groups of hemoglobin also releases in the presence of both endogenous and produced H2O2 and generate hydroxyl radical. In vitro experiments demonstrate that this novel nanoparticle is cytotoxic to both cancer (HeLa and MCF-7) cells at very low concentration (>2 µg/mL). Due to the great potential of the reported metal-organic frameworks in this thesis, these interesting particles may function as a new type of agents for controlled delivery and hydroxyl radical generation to treat cancer cell