Quantitative imaging of magnetic nanoparticles by magneto-relaxometric tomography for biomedical applications

Current biomedical research focuses on the development of novel biomedical applications based on magnetic nanoparticles (MNPs), e.g. for local cancer treatment. These therapy approaches employ MNPs as remotely controlled drug carriers or local heat generators. Since location and quantity of MNPs determine drug enrichment and heat production, quantitative knowledge of the MNP distribution inside a body is essential for the development and success of these therapies. Magnetorelaxometry (MRX) is capable to provide such quantitative information based on the specific response of the MNPs after switching-off an applied magnetic field. Applying a uniform (homogeneous) magnetic field to a MNP distribution and measuring the MNP response by multiple sensors at different locations allows for spatially resolved MNP quantification. However, to reconstruct the MNP distribution from this spatially resolved MRX data, an ill posed inverse problem has to be solved. So far, the solution of this problem was stabilized incorporating a-priori knowledge in the forward model, e.g. by setting priors on the vertical position of the distribution using a 2D reconstruction grid or setting priors on the number and geometry of the MNP sources inside the body. MRX tomography represents a novel approach for quantitative 3D imaging of MNPs, where the inverse solution is stabilized by a series of MRX measurements. In MRX tomography, only parts of the MNP distribution are sequentially magnetized by the use of inhomogeneous magnetic fields. Each magnetizing is followed by detection of the response of the corresponding part of the distribution by multiple sensors. The 3D reconstruction of the MNP distribution is then accomplished by a common evaluation of the distinct MRX measurement series. In this thesis the first experimental setup for MRX tomography was developed for quantitative 3D imaging of biomedical MNP distributions. It is based on a multi-channel magnetizing unit which has been engineered to generate a time-multiplexed sequence of precise magnetic fields for spatially constrained magnetizing of the MNP distribution. The unit has been integrated into a sensor system containing 304 superconducting quantum interference devices (SQUIDs) used for the spatially resolved detection of the MNP responses after each magnetizing. Furthermore, for evaluation of MRX tomography MNP phantoms reflecting the MNP distribution after magnetic drug targeting therapy in animals were designed and implemented. Using these phantoms, MNP distributions with clinical MNP doses in the milligram range could be quantitatively reconstructed by MRX tomography within a field of view up to 600 cm³ and a spatial resolution of a few cubic centimeters. The deviation between the quantified and nominal MNP amount was found to be below 10%. With the present experimental setup MRX tomography measurements of a complete MNP distribution were performed within the typical anesthesia time interval of a few minutes prevailing in preclinical animal studies. By implementing advanced magnetizing sequences this measurement time of the MRX tomography setup could be reduced to below 30 s. Finally, using the same MRX tomography setup a binding state specific quantitative imaging of MNP distributions was achieved by incorporating the temporal MNP relaxation behavior into the reconstruction. Hence, MRX tomography has the potential to image the influence of the local biological environment on the physical properties of the MNPs. The presented MRX tomography setup allows for sensitive and specific spatially resolved 3D quantification of MNPs in small animals. This represents an important step towards the development of a clinical imaging tool for the control and assessment of MNP based cancer treatments. Moreover, by adjusting the excitation coils the field of view could be easily enlarged making MRX tomography quite conceivable for human application.