Magnetic iron oxide nanoparticles as potential contrast agents for magnetic resonance imaging

This thesis presents the development of novel formulations on the basis of magnetic iron oxide nanoparticles. Optimization of the synthesis route resulted in the development of particles meeting general requirements for eventual applications. Furthermore, the selection of appropriate stabilizing agents imparted the nanoparticles with beneficial features, making an in vivo application possible. In doing so, the formulations seem to be especially promising for the application as contrast agents in magnetic resonance imaging. Chapter 1 gives a brief insight into current research in the field of magnetic nanoparticles. While the originally promoted idea of dragging nanoparticles to the site of action by a massive external field is becoming less important, the use of magnetic carriers as single and multifunctional imaging agents is gaining in importance. Chapter 2 describes the synthesis of magnetic iron oxide nanoparticles with optimal properties for MRI contrast enhancement and the comparative assessment of polymeric macromolecules as stabilizers for such nanoparticles. It was revealed that particles covered by poly(ethylene imine)-g-poly(ethylene glycol) performed better than their poly(ethylene imine) counterparts, in terms of stability and cytotoxicity. The systems containing the former polymer showed pronounced colloidal stability even in protein-rich cell media. In addition, cytotoxicity was reduced by more than an order of magnitude. In this respect, the assumptions made in the run-up to the studies have found confirmation. Indeed, the introduction of hydrophilic poly(ethylene glycol) moieties to the polymer backbone positively manipulated the above properties. In addition, the physicochemical properties of the generated iron oxide nanoparticles were found to be excellent, despite the simplicity of the synthesis procedure. The iron oxide cores displayed high crystallinity, high saturation magnetization and superparamagnetic features. The polymer-coated nanoparticles were narrowly distributed around an average diameter of 40 nm and showed relaxation parameters comparable to presently marketed products. Given these results, the established magnetic ferrofluids appear to be interesting for an intracorporal application as an MRI contrast agent. The assumption that the configuration of magnetic nanoparticles affects cell uptake (mechanisms) and localization, and subsequently cellular MRI signaling, provided a basis for further studies. Chapter 3 includes the evaluation of oppositely charged iron oxide nanoparticle systems with regard to physicochemical properties, cell interaction and cell-constrained relaxometry. The findings of this section confirm that surface potential is the key factor controlling cell internalization of magnetic iron oxide nanoparticles. Particles with a positive zeta potential were taken up to an almost tenfold extent after 24 hours, and with faster kinetics than the negatively charged counterparts. Basically, these results confirm the preliminary assumptions that electrostatic attractive forces between the cell membrane and the nanoparticles favor an enhanced internalization of positive carriers. However, the clear discrepancy in overall uptake led to the conclusion that synergistic effects, such as colloidal stability, also influence the rate of particle accumulation in cells. Both systems were found to be compartmentalized in endosomes after their uptake into cells by a correspondent endocytotic pathway. This cellular confinement caused the relaxation parameters to change in comparison to freely dispersed nanosuspensions, in such a way that the signal contrast in T2-weighted MRI sequences degraded. Nevertheless, phantoms of cells incubated with positively charged nanoparticles still revealed effective signal darkening in these MRI sequences. The results suggest the suspensions examined as promising agents for cell tracking purposes, as here high iron uptake in combination with pronounced relaxivity is required