THE IMPLEMENTATION OF NANOPARTICLE DRUG DELIVERY SYSTEMS FOR THE ENCAPSULATION OF DI-2-PYRIDYLKETONE 4,4-DIMETHYL-3-THIOSEMICARBAZONE

Abstract

Iron is an essential metal that is involved in many crucial biological processes. Hence, cells require iron to function and proliferate. Cancer cells have a great demand for this metal due to their high rate of metabolism and proliferation. This tremendous demand for iron is accomplished by changes in the expression of iron-related proteins. There is also evidence that the regulation of other transition metals is altered during cancer progression. Thus, this makes cancer cells vulnerable to metal depletion. The metal chelator known as di-2-pyridylketone 4,4-dimethyl-3- thiosemicarbazone (Dp44mT), and its analogue, namely, di-2-pyridylketone 4-cyclohexyl-4- methyl-3-thiosemicarbazone (DpC) have been demonstrated to possess potent anti-cancer activity against various cancer types in vitro and in vivo. Apart from iron chelation, the anti-cancer effects of these agents are believed to be due to the generation of reactive oxygen species (ROS) induced by redox active metal-chelator complex that causes oxidative stress. While the efficacy and selectivity of these agents is marked, the use of nanoparticle drug delivery system to improve their bioavailability, half-life, aqueous solubility, pharmacokinetics, specificity, and bio-distribution could be advantageous. For cancer treatment, these systems are designed to: (1) increase the selectivity of anti-cancer agents towards cancer cells; (2) reduce the cytotoxicity of chemotherapeutic agents towards normal tissues leading to lower toxic side effects; (3) improve the solubility of hydrophobic drugs for the ease of administration; and (4) provide a controlled and sustained release of drugs. However, limited research had been undertaken to encapsulate chelators within nanoparticles for cancer treatment, particularly Dp44mT and DpC. The work presented in this thesis investigates the implementation of different types of nanoparticles for the encapsulation of Dp44mT (a model drug) using various preparation techniques.