We are developing best practice metrology for characterization of magnetic nanoparticle systems (e.g. blocking temperature, anisotropy, property distributions, T1 and T2 relaxation times, hysteretic energy loss, etc.) for use in biomedical applications. The emphasis is on the measurement methods to enable enhanced MRI imaging, drug delivery, and hyperthermia therapy.
The tools provided will enable industry to more effectively design and develop new magnetic nanoparticles and provide guidelines to the FDA to properly compare systems when approving nanoparticle systems for clinical trials.
Optimization of magnetic nanoparticle synthesis for a specific biomedical application necessitates a solid understanding of both the fundamental magnetism and its measurement. Since most pharmaceutical companies employ biologists and chemists without such knowledge, we will aim to develop an ASTM standard for their use, applying established bulk and thin film techniques to nanoparticles systems for determining the appropriate magnetic properties of both individual and collections of nanoparticles.
In addition, two new measurement techniques will be developed: First Order Reversal Curve (FORC) models to correlate physical size distributions with magnetic property distributions and transverse AC Susceptometry for determining interaction timescale for individual and collective systems.
There are also specific requirements for each medical application. For example, a novel variable field and frequency relaxometer will be developed for correlating the materials structure with T1 and T2 times to develop stable T1 and T2 SRMs for quantitative MRIs. For hyperthermia therapy, a micro-calorimeter will be developed for accurately measuring temperature changes in a nanoparticle suspension under the influence of a high frequency alternating magnetic field.
We recently determined that strongly interacting coated magnetic nanoparticles yield very large increases (by a factor of seven) in heat output as compared to nominally identical particles which are only weakly interacting, illustrating the enormous consequences of using improperly characterized nanoparticles for hyperthermia treatment. This behavior was found in two nanoparticle systems which were nominally identical physically (as determined by photon correlation spectroscopy, transmission electron microscopy, and x-ray diffraction), and were very similar magnetically (although the nanoparticle system with the larger heating rate had the smaller saturation magnetization). The difference between the nanoparticle systems, identified through small angle neutron scattering, was the interaction radius, which was modified by changing the dextran stabilization layer. The more closely spaced nanoparticles interacted more strongly, utilizing a collective behavior to enhance the heating properties. This finding is a significant departure from "common knowledge" in the medical community, which has long contended that non-interacting magnetic nanoparticles are the ideal material for hyperthermia treatment.
Small angle neutron scattering data showing interactions.
The exact details of the synthesis and the solvent environment in which the nanoparticles are stored plays a significant role on the magnetic properties of the nanoparticles and their aging processes. Removing a low temperature step (which nucleates the nanoparticle core) during the synthesis of cobalt nanoparticles in 1,2-dichlorobenzene yields similar nanoparticles initially, but with radically different aging processes. The lack of a nucleation stage allows the leaching of Co+2 ions into the solution, changing not only the size, shape, and distribution of the nanoparticles with time, but also the magnetic properties (since Co+2 is paramagnetic). Changing the solvent from a non-polar to polar solvent after synthesis generates a self-passivating oxide layer on the nanoparticles that is approximately 0.5-1 nm thick which forms within hours. The non-polar solvents form an oxide layer which grows continuously with time. This finding may lead to a general method for transferring metallic nanoparticles into water without changing the magnetic properties though oxidation of the entire nanoparticle.
Fresh and aged cobalt nanoparticles
Experimental measurements on a collection of strongly interacting cobalt nanoparticles demonstrated that the environment, both solvent type and temperature, plays a significant role in the magnetic behavior of the system. The competition between lattice energies and dipolar energies determines whether the forming crystal structure damages the nanoparticle chains, resulting in a net decrease in the magnetization, or vice versa. When this "chain damage" occurs, it also has consequences for the anisotropy of the chains. (Vector magnetometry measurements above and below the freezing point revealed that the anisotropy generated by the interactions along the chains cannot be easily separated from the intrinsic anisotropy of individual nanoparticles.) For cobalt nanoparticles in 1,2-dichlorobenzene, there was an increase in the uniaxial anisotropy of the chains from 61.1(7)x10-7 J to 104.2(9)x10-7 J as the liquid-to-solid transition is traversed. There was also an unreversed component which doubles with decreasing temperature as the temperature cools through the supercooling point of the solvent.
Chain damage seen in magnetization vs. temperature data