Longitudinal evaluation of tumor microenvironment in rat focal brainstem glioma using diffusion and perfusion MRI.

BACKGROUND: Brainstem gliomas are aggressive and difficult to treat. Growth of these tumors may be characterized with MRI methods. PURPOSE: To visualize longitudinal changes in tumor volume, vascular leakiness, and tissue microstructure in an animal model of brainstem glioma. STUDY TYPE: Prospective animal model. ANIMAL MODEL: Male Sprague-Dawley rats (n = 9) were imaged with 9L gliosarcoma cells infused into the pontine reticular formation of the brainstem. The MRI tumor microenvironment was studied at 3 and 10 days postimplantation of tumor cells. FIELD STRENGTH/SEQUENCE: Diffusion tensor imaging (DTI) and dynamic contrast-enhanced (DCE)-MRI were performed at 4.7T using spin-echo multislice echo planar imaging and gradient echo multislice imaging, respectively. ASSESSMENT: Tumor leakiness was assessed by the forward volumetric transfer constant, Ktrans , estimated from DCE-MRI data. Tumor structure was evaluated with fractional anisotropy (FA) obtained from DTI. Tumor volumes, delineated by a T1 map, T2 -weighted image, FA, and DCE signal enhancement were compared. STATISTICAL TESTS: Changes in the assessed parameters within and across the groups (ie, rats 3 and 10 days post tumor cell implantation) were evaluated with Wilcoxon rank-sum tests. RESULTS: Day 3 tumors were visible mainly on contrast-enhanced images, while day 10 tumors were visible in both contrast-enhanced and diffusion-weighted images. Mean Ktrans at day 10 was 41% lower than at day 3 (P = 0.23). In day 10 tumors, FA was regionally lower in the tumor compared to normal tissue (P = 0.0004), and tumor volume, segmented based on FA map, was significantly smaller (P ≤ 0.05) than that obtained from other contrasts. DATA CONCLUSION: Contrast-enhanced MRI was found to be more sensitive in detecting early-stage tumor boundaries than other contrasts. Areas of the tumor outlined by DCE-MRI and DTI were significantly different. Over the observed period of tumor growth, average vessel leakiness decreased with tumor progression. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:1322-1332.

Stability and Mobility of Magnetic Nanoparticles in Biological Environments Determined from Dynamic Magnetic Susceptibility Measurements.

Low tumor accumulation following systemic delivery remains a key challenge for advancing many cancer nanomedicines. One obstacle in engineering nanoparticles for high tumor accumulation is a lack of techniques to monitor their stability and mobility in situ. One way to monitor the stability and mobility of magnetic nanoparticles biological fluids in situ is through dynamic magnetic susceptibility measurements (DMS), which under certain conditions provide a measure of the particle's rotational diffusivity. For magnetic nanoparticles modified to have commonly used biomedical surface coatings, we describe a systematic comparison of DMS measurements in whole blood and tumor tissue explants. DMS measurements clearly demonstrated that stability and mobility changed over time and from one medium to another for each different coating. It was found that nanoparticles coated with covalently grafted, dense layers of PEG were the only ones to show good stability and mobility in all settings tested. These studies illustrate the utility of DMS measurements to estimate the stability and mobility of nanoparticles in situ, and which can provide insights that lead to engineering better nanoparticles for in vivo use.

Processing-Size Correlations in the Preparation of Magnetic Alginate Microspheres Through Emulsification and Ionic Crosslinking.

Magnetic alginate microspheres are biocompatible due to their alginate matrix, and motion-controllable by applied magnetic fields due to their magnetic character. Therefore, they have the potential of being used as vessels to a broad variety of materials, including drugs and therapeutic agents, facilitating entry to biological systems in a relatively non-invasive manner. Here, magnetic alginate microspheres were prepared through an emulsification and ionic cross-linking process, where a mixture of alginate and iron oxide magnetic nanoparticles was initially dispersed in a continuous phase, followed by gelation of this dispersed phase into microspheres by cross-linking the dispersion with calcium ions. The resulting magnetic alginate microspheres were found to be superparamagnetic and to respond to applied magnetic fields by chain formation. The effect of shear rate, alginate concentration, and magnetic nanoparticle concentration on microsphere size was investigated with the aim to control the size of microspheres with respect to process and formulation parameters. Two of these parameters, shear rate and alginate concentration, were used to correlate experimental results with a theoretical model for the case where the dispersed phase is more viscous than the continuous phase.

Optimization of synthesis and peptization steps to obtain iron oxide nanoparticles with high energy dissipation rates.

Magnetic Fluid Hyperthermia (MFH) uses heat generated by magnetic nanoparticles exposed to alternating magnetic fields to cause a temperature increase in tumors to the hyperthermia range (43-47 °C), inducing apoptotic cancer cell death. As with all cancer nanomedicines, one of the most significant challenges with MFH is achieving high nanoparticle accumulation at the tumor site. This motivates development of synthesis strategies that maximize the rate of energy dissipation of iron oxide magnetic nanoparticles, preferable due to their intrinsic biocompatibility. This has led to development of synthesis strategies that, although attractive from the point of view of chemical elegance, may not be suitable for scale-up to quantities necessary for clinical use. On the other hand, to date the aqueous co-precipitation synthesis, which readily yields gram quantities of nanoparticles, has only been reported to yield sufficiently high specific absorption rates after laborious size selective fractionation. This work focuses on improvements to the aqueous co-precipitation of iron oxide nanoparticles to increase the specific absorption rate (SAR), by optimizing synthesis conditions and the subsequent peptization step. Heating efficiencies up to 1,048 W/gFe (36.5 kA/m, 341 kHz; ILP = 2.3 nH·m2·kg-1) were obtained, which represent one of the highest values reported for iron oxide particles synthesized by co-precipitation without size-selective fractionation. Furthermore, particles reached SAR values of up to 719 W/gFe (36.5 kA/m, 341 kHz; ILP = 1.6 nH·m2·kg-1) when in a solid matrix, demonstrating they were capable of significant rates of energy dissipation even when restricted from physical rotation. Reduction in energy dissipation rate due to immobilization has been identified as an obstacle to clinical translation of MFH. Hence, particles obtained with the conditions reported here have great potential for application in nanoscale thermal cancer therapy.

Magnetic fluid hyperthermia: advances, challenges, and opportunity.

Though the concepts of magnetic fluid hyperthermia (MFH) were originally proposed over 50 years ago, the technique has yet to be successfully translated into routine clinical application. Significant challenges must be addressed if the field is to progress and realise its potential as an option for treatment of diseases such as cancer. These challenges include determining the optimum fields and frequencies that maximise the effectiveness of MFH without significant detrimental off-target effects on healthy tissue, achieving sufficient concentrations of magnetic nanoparticles (MNPs) within the target tumour, and developing a better mechanistic understanding of MNP-mediated energy deposition and its effects on cells and tissue. On the other hand, emerging experimental evidence indicates that local thermal effects indeed occur in the vicinity of energy-dissipating MNPs. These findings point to the opportunity of engineering MNPs for the selective destruction of cells and/or intracellular structures without the need for a macroscopic tissue temperature rise, in what we here call magnetically mediated energy delivery (MagMED).

Novel methodology for measuring intraoral wear in enamel and dental restorative materials.

OBJECTIVES: To test the hypotheses that (a) the chairside/handheld dental scanner combined with a metrology software will measure clinical wear in vivo in agreement with measurements from X-ray computed microtomography and; (b) polished monolithic zirconia does not cause accelerated wear of opposing enamel. MATERIALS AND METHODS: Thirty single crowns were randomized to receive a monolithic zirconia or metal-ceramic crown. Two non-restored opposing teeth in the same quadrants were identified to serve as enamel controls. After cementation, quadrants were scanned using an intraoral dental scanner. Patients were recalled at 6-months and 1-year for re-scanning. Scanned images were compared using a metrology software to determine maximum vertical wear of teeth. The accuracy of the scanning measurements from this new method was compared with X-ray computed microtomography (micro-CT) measurements. Statistical analysis was performed using Mann-Whitney U test to determine significant differences between wear of enamel against zirconia, metal-ceramic or enamel. Linear regression analysis determined agreement between measurements obtained using intraoral scanning and micro-CT. RESULTS: Regression analysis demonstrated that there is a quantitative agreement between depth and volume measurements produced using intraoral scanning and the micro-CT methodologies. There was no significant difference between the wear of enamel against polished monolithic zirconia crowns and enamel against enamel. CONCLUSIONS: Intraoral scanning combined with a matching software can accurately quantify clinical wear to verify that monolithic zirconia exhibited comparable wear of enamel compared with metal-ceramic crowns and control enamel. Agreement between the intraoral scanner and the micro-CT was 99.8%. Clinical Trials.gov NCT02289781.

Rotational diffusion of magnetic nanoparticles in protein solutions.

The rotational diffusion of polyethylene glycol coated magnetic nanoparticles in serum albumin solutions was investigated in a range spanning 0mgmL-1 to 200mgmL-1. Rotational diffusivities were determined from dynamic magnetic susceptibility measurements, which provide a non-optical means to probe rotation of nanoparticles in small volume samples. Experimental rotational diffusivities were compared to those estimated using the Stokes-Einstein relation and macroscopic measurements of the viscosity of the protein solutions. Excellent agreement was found between experimental measurements and theoretical predictions for serum albumin solutions buffered at physiological pH and for serum albumin solutions at acidic pH prepared using simple acids at physiological ionic strengths. For serum albumin solutions prepared using citrate buffer at acidic pH, we observed a discrepancy between the experimental rotational diffusivity and that predicted from the Stokes-Einstein relation. In contrast, when the pH was adjusted with a simple acid and salt at physiological ionic strength we observed agreement between the experimental rotational diffusivity and that predicted from the Stokes-Einstein relation. Because of the role of citrate ions in causing protein aggregation, we believe these observations suggest that dynamic magnetic susceptibility measurement of the rotational diffusivity of the nanoparticles is sensitive to gelation/crosslinking of proteins.

EGFR-targeted magnetic nanoparticle heaters kill cancer cells without a perceptible temperature rise.

It is currently believed that magnetic nanoparticle heaters (MNHs) can kill cancer cells only when the temperature is raised above 43 °C due to energy dissipation in an alternating magnetic field. On the other hand, simple heat conduction arguments indicate that in small tumors or single cells the relative rates of energy dissipation and heat conduction result in a negligible temperature rise, thus limiting the potential of MNHs in treating small tumors and metastatic cancer. Here we demonstrate that internalized MNHs conjugated to epidermal growth factor (EGF) and which target the epidermal growth factor receptor (EGFR) do result in a significant (up to 99.9%) reduction in cell viability and clonogenic survival in a thermal heat dose dependent manner, without the need for a perceptible temperature rise. The effect appears to be cell type specific and indicates that magnetic nanoparticles in alternating magnetic fields may effectively kill cancer cells under conditions previously considered as not possible.