PET Imaging of Innate Immune Activation Using 11C Radiotracers Targeting GPR84.

Chronic innate immune activation is a key hallmark of many neurological diseases and is known to result in the upregulation of GPR84 in myeloid cells (macrophages, microglia, and monocytes). As such, GPR84 can potentially serve as a sensor of proinflammatory innate immune responses. To assess the utility of GPR84 as an imaging biomarker, we synthesized 11C-MGX-10S and 11C-MGX-11Svia carbon-11 alkylation for use as positron emission tomography (PET) tracers targeting this receptor. In vitro experiments demonstrated significantly higher binding of both radiotracers to hGPR84-HEK293 cells than that of parental control HEK293 cells. Co-incubation with the GPR84 antagonist GLPG1205 reduced the binding of both radiotracers by >90%, demonstrating their high specificity for GPR84 in vitro. In vivo assessment of each radiotracer via PET imaging of healthy mice illustrated the superior brain uptake and pharmacokinetics of 11C-MGX-10S compared to 11C-MGX-11S. Subsequent use of 11C-MGX-10S to image a well-established mouse model of systemic and neuro-inflammation revealed a high PET signal in affected tissues, including the brain, liver, lung, and spleen. In vivo specificity of 11C-MGX-10S for GPR84 was confirmed by the administration of GLPG1205 followed by radiotracer injection. When compared with 11C-DPA-713-an existing radiotracer used to image innate immune activation in clinical research studies-11C-MGX-10S has multiple advantages, including its higher binding signal in inflamed tissues in the CNS and periphery and low background signal in healthy saline-treated subjects. The pronounced uptake of 11C-MGX-10S during inflammation, its high specificity for GPR84, and suitable pharmacokinetics strongly support further investigation of 11C-MGX-10S for imaging GPR84-positive myeloid cells associated with innate immune activation in animal models of inflammatory diseases and human neuropathology.

An anatomically correct 3D-printed mouse phantom for magnetic particle imaging studies.

We report anatomically correct 3D-printed mouse phantoms that can be used to plan experiments and evaluate analysis protocols for magnetic particle imaging (MPI) studies. The 3D-printed phantoms were based on the Digimouse 3D whole body mouse atlas and incorporate cavities representative of a liver, brain tumor, and orthotopic breast cancer tumor placed in anatomically correct locations, allowing evaluation of the effect of precise doses of MPI tracer. To illustrate their use, a constant tracer iron mass was present in the liver for the breast (200 µgFe) and brain tumor (10 µgFe) model, respectively, while a series of decreasing tracer iron mass was placed in the tumor region. MPI scans were acquired in 2D and 3D high sensitivity and high sensitivity/high resolution (HSHR) modes using a MOMENTUM imager. A thresholding algorithm was used to define regions of interest (ROIs) in the scans and the tracer mass in the liver and tumors was calculated by comparison of the signal in their respective ROI against that of known mass fiducials that were included in each scan. The results demonstrate that this approach to image analysis provides accurate estimates of tracer mass. Additionally, the results show how the limit of detection in MPI is sensitive to the details of tracer distribution in the subject, as we found that a greater tracer mass in the liver cavity resulted in poorer sensitivity in tumor regions. These experiments illustrate the utility of the reported 3D-printed anatomically correct mouse phantoms in evaluating methods to analyze MPI scans and plan in vivo experiments.

Tracking adoptive T cell immunotherapy using magnetic particle imaging.

Adoptive cellular therapy (ACT) is a potent strategy to boost the immune response against cancer. ACT is effective against blood cancers but faces challenges in treating solid tumors. A critical step for the success of ACT immunotherapy is to achieve efficient trafficking and persistence of T cells to solid tumors. Non-invasive tracking of the accumulation of adoptively transferred T cells to tumors would greatly accelerate development of more effective ACT strategies. We demonstrate the use of magnetic particle imaging (MPI) to non-invasively track ACT T cells in vivo in a mouse model of brain cancer. Magnetic labeling did not impair primary tumor-specific T cells in vitro, and MPI allowed the detection of labeled T cells in the brain after intravenous or intracerebroventricular administration. These results support the use of MPI to track adoptively transferred T cells and accelerate the development of ACT treatments for brain tumors and other cancers.

Long circulating tracer tailored for magnetic particle imaging.

Superparamagnetic iron oxide nanoparticle (SPION) tracers possessing long blood circulation time and tailored for magnetic particle imaging (MPI) performance are crucial for the development of this emerging molecular imaging modality. Here, single-core SPION MPI tracers coated with covalently bonded polyethyelene glycol (PEG) brushes were obtained using a semi-batch thermal decomposition synthesis with controlled addition of molecular oxygen, followed by an optimized PEG-silane ligand exchange procedure. The physical and magnetic properties, MPI performance, and blood circulation time of these newly synthesized tracers were compared to those of two commercially available SPIONs that were not tailored for MPI but are used for MPI: ferucarbotran and PEG-coated Synomag®-D. The new tailored tracer has MPI sensitivity that is ~3-times better than the commercial tracer ferucarbotran and much longer circulation half-life than both commercial tracers (t1/2=6.99 h for the new tracer, vs t1/2=0.59 h for ferucarbotran, and t1/2=0.62 h for PEG-coated Synomag®-D).

Emerging Biomedical Applications Based on the Response of Magnetic Nanoparticles to Time-Varying Magnetic Fields.

Magnetic nanoparticles are of interest for biomedical applications because of their biocompatibility, tunable surface chemistry, and actuation using applied magnetic fields. Magnetic nanoparticles respond to time-varying magnetic fields via physical particle rotation or internal dipole reorientation, which can result in signal generation or conversion of magnetic energy to heat. This dynamic magnetization response enables their use as tracers in magnetic particle imaging (MPI), an emerging biomedical imaging modality in which signal is quantitative of tracer mass and there is no tissue background signal or signal attenuation. Conversion of magnetic energy to heat motivates use in nanoscale thermal cancer therapy, magnetic actuation of drug release, and rapid rewarming of cryopreserved organs. This review introduces basic concepts of magnetic nanoparticle response to time-varying magnetic fields and presents recent advances in the field, with an emphasis on MPI and conversion of magnetic energy to heat.

Combining magnetic particle imaging and magnetic fluid hyperthermia for localized and image-guided treatment.

Magnetic fluid hyperthermia (MFH) has been widely investigated as a treatment tool for cancer and other diseases. However, focusing traditional MFH to a tumor deep in the body is not feasible because the in vivo wavelength of 300 kHz very low frequency (VLF) excitation fields is longer than 100 m. Recently we demonstrated that millimeter-precision localized heating can be achieved by combining magnetic particle imaging (MPI) with MFH. In principle, real-time MPI imaging can also guide the location and dosing of MFH treatments. Hence, the combination of MPI imaging plus real time localized MPI-MFH could soon permit closed-loop high-resolution hyperthermia treatment. In this review, we will discuss the fundamentals of localized MFH (e.g. physics and biosafety limitations), hardware implementation, MPI real-time guidance, and new research directions on MPI-MFH. We will also discuss how the scale up to human-sized MPI-MFH scanners could proceed.

Magnetic nanoparticle hyperthermia potentiates paclitaxel activity in sensitive and resistant breast cancer cells.

INTRODUCTION: Overcoming resistance to antimitotic drugs, such as paclitaxel (PTX), would represent a major advance in breast cancer treatment. PTX induces mitotic block and sensitive cells exit mitosis dying by mitotic catastrophe. Resistant cells remain in block and continue proliferation after drug decay, denoting one of the PTX resistance mechanisms. Mild hyperthermia (HT) triggers mitotic exit of PTX-pretreated cells, overcoming PTX resistance and suggesting HT-forced mitotic exit as a promising strategy to potentiate PTX. METHODS AND RESULTS: Superparamagnetic iron oxide nanoparticles (SPIONs) were used to deliver mild HT at 42°C in PTX-pretreated breast adenocarcinoma MCF-7 cells sensitive and resistant to PTX. To evaluate mechanism of cell death, cells were classified based on nuclear morphology into interphase, mitotic, micronucleated, and apoptotic. The combined PTX→SPION treatment resulted in an increase in the percentage of micronucleated cells, an indication of forced mitotic exit. Importantly, in PTX-resistant cells, the combination therapy using SPION HT helps to overcome resistance by reducing the number of cells relative to the control. CONCLUSION: SPION HT potentiates PTX by significantly reducing cell survival, suggesting potential of combined treatment for future clinical translation.