Development of Metal-Organic Framework Based Magnetic Nanocomposites for Controlled Drug Delivery to Treat Glioblastoma
The work presented in this dissertation focuses on developing a controlled drug delivery system (DDS) utilizing magnetic metal-organic-frameworks (MOFs) as carriers of glioblastoma drugs. This DDS provides the advantage for on-demand drug release triggered by an alternating magnetic field (AMF). MOF has been selected as a drug carrier owing to its great characteristics, including biocompatibility, large surface area, and tunable pore size. For controlled release of the loaded cargo, magnetic nanoparticles (MNPs) have been selected to conjugate with MOFs and provide the required heat with AMF through the magnetothermal effect. We have successfully synthesized two magnetic nanocomposites: MnFe2O4 MIL-88B-4CH3 and Fe3O4 MIL-88B-NH2 with different MNPs and MOFs. As the size of the magnetic nanocomposites needs to be around 100 nm to cross the blood brain barrier, several parameters of synthesizing the nanocomposites have been explored in order to significantly reduce the particles size while maintaining its crystalline structure. Multiple glioblastoma drugs, such as Carmustine (BCNU) and Mertansine (DM1), have been encapsulated in the nanocarriers. A series of experiments have been conducted to achieve optimized loading of the drugs. In vitro studies have been conducted to explore the cytotoxicity of the fabricated nanocarriers and to quantify the therapeutic effect of the proposed drug delivery systems. Cells treated with the MOFs and the magnetic nanocomposites show high cell viability, which reflects the high biocompatibility of the synthesized materials. The study of cellular uptake kinetics has showed internalization of the magnetic nanocomposites into the cells and helped determine the optimal time window for applying the AMF. The developed drug delivery systems have displayed a high treatment efficiency on killing U251 glioblastoma cells. Furthermore, the application of AMF has provided higher therapeutic efficacy through the enhanced release of glioblastoma drug from the pores of the nanocomposites. These results have demonstrated successful development of the MOF-based magnetic nanocomposites as efficient nanocarriers for glioblastoma drugs with high therapeutic efficacy while minimizing potential side effects of the loaded drugs.
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