Synthesis and functionalisation of metal and metal oxide nanoparticles for theranostics

Metal and metal oxide nanoparticles including calcium oxide, gold, and superparamagnetic iron oxide nanoparticles (SPIOs) were synthesised using a range of techniques including reduction, co-precipitation and spinning disc technology. SPIOs were primarily synthesised via a co-precipitation method using iron (II) chloride, iron (III) chloride and ammonia; a spinning disc reactor and gaseous ammonia were trialled successfully for scale up, producing spherical particles of 10-40 nm in diameter as analysed by TEM. Nanoparticles were coated via a novel solvent-free grinding process which was successful for drug molecules, immunogenic peptides and amino acids; the mode of binding theorised to be taking place via an electrostatic interaction between the SPIO and the carboxyl, amine or hydroxyl groups on the coating materials. Recrystallisation of the coating materials to form HCl salts, was found to increase the binding efficiency with no detrimental effects to the particles. These coated SPIOs were found to be stable in a range of buffered solutions as well as blood and cell culture media. Separation of particles by size exclusion chromatography (SEC), dialysis and magnetic separation was only effective for a small range of coatings, with high speed centrifugation at a speed of 60 000 rpm being confirmed as the only universally successful method. Imaging of citrate capped gold nanoparticles using a CT phantom revealed that gold concentrations of 3700 mg.l-1 were required for in vivo use and so this was not continued. Coated SPIOs however produced relaxation times comparable with Endorem®, as well as being non-toxic. SPIOs coated in this way were more stable than Endorem® and stayed in solution retaining their superparamagnetic properties for periods in excess of 72 days with only a negligible degree of degradation. Various peptides were synthesised using an optimised microwave assisted solid-phase peptide synthesis (SPPS) method using double the suggested coupling times, all of which were analysed for purity and structure using MALDI-TOF MS and HPLC. A cell-penetrating peptide (CPP) synthesised via this method was coated onto SPIOs and mixed into a gel for transdermal delivery using porcine skin. An NMR profile of the skin using a 0.25T NMR MOUSE® before and after application of the gel showed that after an incubation period of 2 hrs the CPP-SPIOs had penetrated the skin leading to a reduction in signal. This has potential applications for subcutaneous drug delivery and hyperthermia. Cell studies using U937 and BMDCs indicated by both ICP and fluorescence microscopy that SPIOs coated with fluorescently labelled peptides were successfully taken up into cells. SPIOs were further investigated as vectors for delivery of immunogenic peptides, namely p53(105) using female C57BL/6 mice. Results indicated that mice immunised with SPIO as a vector showed similar levels of immune response to the p53(105) following immunisation as when incomplete Freund’s adjuvant (IFA) was used. However, SPIO immunisations produced a significantly increased specific response compared to the condition using IFA. Results indicate that SPIO could be successful as a vector for cancer vaccines.

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