Synthesis, Characterization, and Biomedical Application of Iron Nanoparticles

Abstract

Magnetic nanoparticles (NPs) are actively investigated for their capabilities in biomedical research. Due to their unique magnetic characteristics, novel possibilities as theranostic (therapy & diagnostic) agents and/or drug delivery vehicles arise. Iron-based NPs are of particular interest due to their inherent low toxicity.

Magnetic fluid hyperthermia therapy uses NPs to treat cancer. The NPs are delivered to the cancer site and an alternating magnetic field is used to generate heat from the NPs. The resulting localized temperature elevation destroys cancer tissue while ideally leaving healthy tissue unaffected. One of the main challenges in hyperthermia is the sufficient heat generation by magnetic NPs. Since currently mainly iron oxide NPs are used, the challenge is addressed by novel NP heating agents. The work presented in this thesis explores iron/iron-oxide (Fe/FeOx) core/shell NP system to be used as a novel heat generator in magnetic fluid hyperthermia therapy.

Calculations of the theoretically achievable heating in hyperthermia with iron-based NPs, based on the linear response theory, show that the Fe/FeOx core/shell NPs with their increased saturation magnetization should be able to increase the heat generation compared to FeOx NPs currently widely used. Also, the hyperthermia hardware is discussed and calibration measurements with FeOx NPs determine the experimental conditions required to conduct reliable hyperthermia studies. It is found that the NP size is of crucial importance to the success of efficient heat generation.

Furthermore, the synthesis of the Fe/FeOx core/shell NPs is discussed. Results of modifying the synthetic protocol to specifically increase the size of the NPs for hyperthermia experiments are presented. It is found that a synthetic protocol to achieve pure Fe/FeOx core/shell NPs is challenging and that other iron phases, such as iron-carbide, are also present for NP synthesis experiments aimed to produce Fe/FeOx core/shell NPs. A novel synthesis strategy employing hexadecylamine hydrochloride is presented to avoid the formation of such oxide species.

The magnetic and structural properties of the Fe/FeOx core/shell NPs are investigated in a series of in-situ hyperthermia experiments. By comparing these results to current commercial heating agents it is shown that the Fe/FeOx core/shell NPs are promising candidates for future hyperthermia use. However, it is also found that the complex structure and synthetic protocol of the Fe/FeOx core/shell NPs requires a careful synthesis. This lead to the conclusion that the Fe/FeOx core/shell NPs are not ready for mass production and future application in in-vitro or in-vivo experimental conditions in hyperthermia.

One bottleneck for mass production is the requirement to render large quantities of NPs bio-compatible for in-vitro and in-vivo experiments. The investigations on organic capping molecules for this functionalization showed that only a novel polymer-based NP functionalization is able to comply with hyperthermia requirements. Although with this novel polymer-based functionalization the NPs showed a sufficiently low toxicity for hyperthermia application, the lag of a large scale synthesis for Fe/FeOx core/shell NPs lead to the use of a commercial FeOx NP system to develop in-vitro and in-vivo hyperthermia experiments.

The results of in-vitro and in-vivo studies with FeOx NPs on an E.G7-OVA tumor model are presented. It is found that with these rapidly growing tumors no complete regression but a significant growth suppression can be achieved by applying hyperthermia therapy at 42-43 ◦C. To further understand the impact of hyperthermia treatments on cancer tissue, the histological analysis of the microscopic heating environment is presented. It is shown that the local heating environment has as significant impact on the cell death pathways. The results also point out that a systematic NP delivery strategy for future hyperthermia experiments will be required.