Adam M. Rauwerdink

Ovarian cancer progression is controlled by phenotypic changes in dendritic cells

Dendritic cells are transformed to become immunosuppressive during ovarian cancer progression.

Magnetic nanoparticle temperature estimation.

The authors present a method of measuring the temperature of magnetic nanoparticles that can be adapted to provide in vivo temperature maps. Many of the minimally invasive therapies that promise to reduce health care costs and improve patient outcomes heat tissue to very specific temperatures to be effective. Measurements are required because physiological cooling, primarily blood flow, makes the temperature difficult to predict a priori. The ratio of the fifth and third harmonics of the magnetization generated by magnetic nanoparticles in a sinusoidal field is used to generate a calibration curve and to subsequently estimate the temperature. The calibration curve is obtained by varying the amplitude of the sinusoidal field. The temperature can then be estimated from any subsequent measurement of the ratio. The accuracy was 0.3 degree K between 20 and 50 degrees C using the current apparatus and half-second measurements. The method is independent of nanoparticle concentration and nanoparticle size distribution.

Frequency distribution of the nanoparticle magnetization in the presence of a static as well as a harmonic magnetic field.

We explore the properties of the signal from magnetic nanoparticles. The nanoparticle signal has been used to generate images in magnetic particle imaging (MPI). MPI promises to be one of the most sensitive methods of imaging small numbers magnetic nanoparticles and therefore shows promise for molecular imaging. The nanoparticle signal is generated with a pure sinusoidal magnetic field that repeatedly saturates the nanoparticles creating harmonics in the induced magnetization that are easily isolated from the driving field. Signal from a selected position is isolated using a static magnetic field to completely saturate all of the particles outside a voxel enabling an image to be formed voxel by voxel. The signal produced by the magnetization of the nanoparticles contains only odd harmonics. However, it is demonstrated experimentally that with the addition of a static magnetic field bias even harmonics are introduced which increase the total signal significantly. Further, the distribution of signal among the harmonics depends on the static bias field so that information might be used to localize the nanoparticle distribution. Finally, the field required to completely saturate nanoparticles can be quite large and theory predicts that the field required is determined by the smallest nanoparticles in the sample.

Measurement of molecular binding using the Brownian motion of magnetic nanoparticle probes

Molecular binding is important in many venues including antibody binding for diagnostic and therapeutic agents and pharmaceutical function. We demonstrate that a method of measuring nanoparticle Brownian motion, termed magnetic spectroscopy of nanoparticle Brownian motion (MSB), can be used to monitor molecular binding and the bound fraction. It is plausible that MSB can be used to measure binding in vivo because the same signal has been used to image nanoparticles in nanogram quantities in vivo.

Nanoparticle temperature estimation in combined ac and dc magnetic fields

The harmonics produced by the nonlinear magnetization of superparamagnetic nanoparticles have been utilized in a number of budding medical devices. Here we expand on an earlier technique for quantitatively measuring nanoparticle temperature in a purely ac field by including the presence of a static field. The ability to quantify nanoparticle temperature by tracking changes in the 4th/2nd harmonic ratio is presented and shown to achieve an accuracy of 0.79 K. The advantage of even harmonics, issues with odd harmonics in the presence of a static field and the potential for future incorporation into an imaging system are discussed.

Concurrent quantification of multiple nanoparticle bound states.

PURPOSE The binding of nanoparticles to in vivo targets impacts their use for medical imaging, therapy, and the study of diseases and disease biomarkers. Though an array of techniques can detect binding in vitro, the search for a robust in vivo method continues. The spectral response of magnetic nanoparticles can be influenced by a variety of changes in their physical environment including viscosity and binding. Here, the authors show that nanoparticles in these different environmental states produce spectral responses, which are sufficiently unique to allow for simultaneous quantification of the proportion of nanoparticles within each state. METHODS The authors measured the response to restricted Brownian motion using an array of magnetic nanoparticle designs. With a chosen optimal particle type, the authors prepared particle samples in three distinct environmental states. Various combinations of particles within these three states were measured concurrently and the authors attempted to solve for the quantity of particles within each physical state. RESULTS The authors found the spectral response of the nanoparticles to be sufficiently unique to allow for accurate quantification of up to three bound states with errors on the order of 1.5%. Furthermore, the authors discuss numerous paths for translating these measurements to in vivo applications. CONCLUSIONS Multiple nanoparticle environmental states can be concurrently quantified using the spectral response of the particles. Such an ability, if translated to the in vivo realm, could provide valuable information about the fate of nanoparticles in vivo or improve the efficacy of nanoparticle based treatments.

Harmonic phase angle as a concentration‐independent measure of nanoparticle dynamics

PURPOSE The harmonic spectrum of magnetic nanoparticles contains valuable information about the quantity and environment of the particles. Harmonic amplitudes have been used to produce quantitative images and ratios of these amplitudes have been used to monitor changes in the particle environment. Harmonic phase angles have not yet been utilized in these pursuits. The authors explore harmonic phase angle as a concentration-independent means of remotely monitoring the dynamic magnetization of nanoparticles. METHODS A magnetic nanoparticle spectrometer was used to explore the impacts of viscosity and excitation frequency and amplitude on the phase angle of magnetization harmonics. A dynamic model, which accounts for particle relaxation times, was used to model some results. RESULTS Harmonic phase angle can undergo large changes when a nanoparticles Brownian motion is altered. Excitation parameters and particle characteristics have a profound effect on the extent of these changes. CONCLUSIONS Phase angle can allow for monitoring of various impacts on a nanoparticles Brownian motion. When combined with other concentration-independent metrics, such as ratios of harmonic amplitudes, valuable information about the particles environment can be gathered.

Simultaneous quantification of multiple magnetic nanoparticles.

Distinct magnetic nanoparticle designs can have unique spectral responses to an AC magnetic field in a technique called the magnetic spectroscopy of Brownian motion (MSB). The spectra of the particles have been measured using desktop spectrometers and in vivo measurements. If multiple particle types are present in a region of interest, the unique spectral signatures allow for the simultaneous quantification of the various particles. We demonstrate such a potential experimentally with up to three particle types. This ability to concurrently detect multiple particles will enable new biomedical applications.

Magnetic spectroscopy of nanoparticle Brownian motion measurement of microenvironment matrix rigidity.

Abstract The rigidity of the extracellular matrix and of the integrin links to the cytoskeleton regulates signaling cascades, controlling critical aspects of cancer progression including metastasis and angiogenesis. We demonstrate that the matrix stiffness can be monitored using magnetic spectroscopy of nanoparticle Brownian motion (MSB). We measured the MSB signal from nanoparticles bound to large dextran polymers. The number of glutaraldehyde induced cross-links was used as a surrogate for material stiffness. There was a highly statistically significant change in the MSB signal with the number of cross-links especially prominent at higher frequencies. The p-values were all highly significant. We conclude that the MSB signal can be used to identify and monitor changes in the stiffness of the local matrix to which the nanoparticles are bound.

MO‐E‐204C‐09: Quantitation of Nanoparticle Concentrations in Microscopic Bound States

Purpose: To measure the distribution of nanoparticles into microscopic bound states. Antibody targeting has had varying success primarily due to competing mechanisms of uptake, including nonspecific binding and phagocytic activity, and the inability of nanoparticles to penetrate the vascular barrier. Methods of estimating the number of nanoparticles in each bound state will allow us to understand the mechanisms that deprive nanoparticles of their ability to bind targeted antigens and allow us to design methods to enhancing the antigen binding. Method and Materials: When a pure sinusoidal magnetic field is applied to magnetic nanoparticles, the signal at the harmonics of the applied field can be detected at very low concentrations of nanoparticles because there are no other sources of signal and the bandwidth of the measurement can be very narrow. Identical iron oxide nanoparticles (25nm) were a) in aqueous solution and b) bound to two‐micron polystyrene beads. The phase and amplitude of the third and fifth harmonics were measured using applied fields with different frequencies and amplitudes. The signals from the two pure solutions were fit the signals from known combinations of the two solutions using a linear mixture model. Results: The harmonics as a function of frequency and amplitude of the applied field from the two samples were linearly independent. The condition number was 31.8 when the amplitude was varied from 10mT to 24mT and 14.8 when frequency was changed over the range 300Hz to 2700Hz. For two frequencies, 570, 2100 Hz, the average measured error from a linear least squares fit of the data for three mixtures was 4.7% and the maximum was 28%. Conclusion: MSB can be used to monitor the concentrations of nanoparticles in at least two bound states remotely with reasonable accuracy. The system is nonlinear so a nonlinear model would reduce the errors significantly.