Chalker, SL; (2015) Magnetic Nanoparticle and Liposome Technologies for Multimodal Imaging. Doctoral thesis , UCL (University College London).

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Abstract

The overall aim was to produce a magnetolipopolyplex, a multimodal-imaging agent, for the detection of cancer. Iron oxide nanoparticles, which are used as negative contrast agents in magnetic resonance imaging were encapsulated into biocompatible liposomes alongside plasmid DNA and targeting peptides. The plasmid DNA provides the potential for optical imaging and PET through the inclusion of the red fluorescent protein reporter gene and the human sodium iodide symporter, which can be radiolabelled. The inclusion of targeting peptides in the formulation of the magnetolipopolyplexes allows for its site-specific delivery. Initially, poly(L)lysine (PLL) was bio-conjugated to the surface of commercially available iron oxide nanoparticles (MNPs) coated with dextran, rendering the surface charge of the MNPs positive and thus allowing for the electrostatic binding of negatively charged plasmid DNA (pDNA) to the surface. Two plasmids were produced; one coding for the red fluorescent protein (RFP gene) for optical imaging and the other with both RFP and the human sodium iodide symporter (hNIS) which can be radiolabelled for PET imaging. Once the pDNA was electrostatically bound to the PLL on the surface of the MNP, the functionalised MNP was encapsulated into a cationic liposome in order to produce a biocompatible means of delivering the liposome both in vivo and in vitro. Unfortunately, poor results were obtained for the in vitro transfections, which were attributed to their large size and negative surface charges. To overcome the issues faced by the formulation method and in vitro transfections studies, an alternative method of magnetolipopolyplex formulation was carried out. Here, negatively charged MNPs, coated with either carboxymethyldextran or citric acid, were added to preformulated cationic liposomes. The negative surface charge of the MNP allowed the successful diffusion of the MNPs through the positively charged lipid membrane to form magnetoliposomes. To these magnetoliposomes co-condensed pDNA and K16 peptides was also added, ultimately forming magnetolipopolyplexes. Dynamic light scattering and zetapotential characterisation data confirmed the successful formulation of the magnetolipopolyplexes and subsequent in vitro transfection studies were carried out to establish the transfection efficiency of the magnetolipopolyplexes by measuring the RFP expression of the pDNA. SQUID magnetometry data was obtained to determine the concentration of the MNPs taken up into the cells following the incubation of the cells with the magnetlipopolyplexes. The encapsulation of MNPs, pDNA and peptides into liposomes demonstrates the successful formulation of a multimodal-imaging agent with the potential for optical, PET and MRI imaging modalities.

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