Reason: Access restricted by the author. A copy can be requested for private research and study by contacting your institution's library service. This copy cannot be republished
Design of functionalized nanoparticles as imaging agents for cancer
thesisposted on 06.02.2017, 02:05 authored by Barreto Solano, José Alejandro
This thesis describes the synthesis and characterization of three different generations of iron oxide magnetic nanoparticles derivatized with macrocyclic ligands for application as bi-modal imaging agents in the detection of cancer tumors by Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET). The nanoparticles have been modified with polyethyleneglycol (PEG) in order to avoid uptake by the Reticuloendothelial System (RES), whilst the macrocyclic ligands have been introduced for chelation of the radionuclide 64Cu2+, which is detectable by PET. Apart from being a platform for the transport of the radionuclide complexes, the magnetic nanoparticles themselves act as MRI contrast agents and can be used for hyperthermia treatment of cancer due to their superparamagnetic nature. Synthesis of the first generation nanoparticles involved coprecipitation of the core nanoparticles from a solution of iron(II) and iron(III) salts through addition of base. The macrocycles 1,4-bis(2-pyridylmethyl)-1,4,7-triazacyclononane (dmptacn), 1,4,7,10- tetraazacyclododecane (cyclen) and 1,4,8,11-tetraazacyclotetradecane (cyclam) were reacted with glycidyloxypropyltriethoxysilane (GPTES) to form the corresponding siloxane derivatives, which were then hydrolyzed over the surface of the nanoparticles to form a stable coating. Macrocycle loadings of the order of 0.2 mmol/g were achieved using this methodology, and the mean diameter of the nanoparticles was found to be ca. 7 nm, irrespective of the ligand used. Light scattering measurements showed that the particles form aggregates in solution, with a hydrodynamic size of 150–200 nm. The nanoparticles could be rapidly radiolabeled with 64Cu2+. Challenge experiments performed with an excess of cyclam indicated that the nanoparticles derivatized with dmptacn were the most resistant to 64Cu2+ leaching. These particles were also found to be the most stable in rat plasma. A second generation of nanoparticles was synthesized in order to diminish the aggregation of the nanoparticles. This involved synthesis of the core nanoparticles by coprecipitation, followed by surface coating with oleic acid, which provided enhanced stability (reduced aggregation) in organic media. Displacement of the oleic acid chains with polyethyleneglycol silane (PEG-silane) derivatives was used to produce a stable coating on the nanoparticles and to render them water soluble. Two different PEG-silane molecules, with different PEG chain lengths (Mn 250 and 600), were used to modified the nanoparticles. It was found that the nanoparticles coated with the longer PEG chains (PEG 600) were less susceptible to aggregation in aqueous media. The nanoparticles were also functionalized with different macrocycles through amide coupling to the terminal carboxylic acid groups of the PEG chains. The nanoparticles were found to bind 64Cu2+ both specifically (via the macrocycles) and nonspecifically, however the weakly bound ions could be removed by addition of cyclam. In addition to MRI and PET, these second generation nanoparticles would be suitable for use in hyperthermia treatment as they possess a good specific absorption rate. The third generation nanoparticles consisted of iron oxide particles synthesized by thermal decomposition of iron oleate in the presence of oleic acid. Substitution of the surface oleate molecules by ligand exchange reaction with a PEG 600-silane derivative produced water dispersible nanoparticles with narrower size distribution and smaller hydrodynamic size than the first two generations of nanoparticles. The nanoparticles were found to accumulate in the liver after injection, as revealed by in vivo imaging studies performed on rats. The particles were further functionalized with the 64Cu2+ complex of a new dmptacn derivative, via the free carboxyl groups of the PEG chains, to produce an agent suitable for dual modal MRI-PET imaging.