Supplementary Fig. S1. Representative in vivo and ex vivo images using a Maestro FLEX In Vivo Imaging System. Supplementary Fig. S2. Effect of the RF field on the temperature of brain tissues. Supplementary Fig. S3. Bright field microscopy and fluorescence was performed on an entire histological section of the brain stained with Hematoxylin-Eosin (green: CNS-1 glioma cells (GFP)). The same histological section shown in Fig. 4A was used (left panel). Higher magnification of the same section shows the H&E stain of an invasive site (right panel). Supplementary Fig. S4. Cytotoxicity of nanochain particles on CNS-1 cells. Supplementary Fig. S5. Weight progression of animals bearing orthotopic (A) CNS-1 or (B) 9L glioma tumors after DOX treatments.

This review seeks to highlight the enormous potential of targeted nanoparticles for molecular imaging applications. Being the closest point-of-contact, circulating nanoparticles can gain direct access to targetable molecular markers of disease that appear on the endothelium. Further, nanoparticles are ideally suitable to vascular targeting due to geometrically enhanced multivalent attachment on the vascular target. This natural synergy between nanoparticles, vascular targeting and molecular imaging can provide new avenues for diagnosis and prognosis of disease with quantitative precision. In addition to the obvious applications of targeting molecular signatures of vascular diseases (e.g., atherosclerosis), deep-tissue diseases often manifest themselves by continuously altering and remodeling their neighboring blood vessels (e.g., cancer). Thus, the remodeled endothelium provides a wide range of targets for nanoparticles and molecular imaging. To demonstrate the potential of molecular imaging, we present a variety of nanoparticles designed for molecular imaging of cancer or atherosclerosis using different imaging modalities.

The development of magnetic particle imaging (MPI) has created a need for optimized magnetic nanoparticles. Magnetic particle relaxometry is an excellent tool for characterizing potential tracers for MPI. In this paper, we describe the design and construction of a high-throughput tabletop relaxometer that is able to make sensitive measurements of MPI tracers without the need for a dedicated shield room.

Magnetic particle imaging (MPI) is an emerging imaging modality that allows the direct and quantitative mapping of iron oxide nanoparticles. In MPI, the development of tailored iron oxide nanoparticle tracers is paramount to achieving high sensitivity and good spatial resolution. To date, most MPI tracers being developed for potential clinical applications are based on spherical undoped magnetite nanoparticles. For the first time, we report on the systematic investigation of the effects of changes in chemical composition and shape anisotropy on the MPI performance of iron oxide nanoparticle tracers. We observed a 2-fold enhancement in MPI signal through selective doping of magnetite nanoparticles with zinc. Moreover, we demonstrated focused magnetic hyperthermia heating by adapting the field gradient used in MPI. By saturating the iron oxide nanoparticles outside of a field free region (FFR) with an external static field, we can selectively heat a target region in our test sample. By comparing zinc-doped magnetite cubic nanoparticles with undoped spherical nanoparticles, we could show a 5-fold improvement in the specific absorption rate (SAR) in magnetic hyperthermia while providing good MPI signal, thereby demonstrating the potential for high-performance focused hyperthermia therapy through an MPI-guided approach (hMPI).

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Developing tracers for MPI and related applications requires a thorough understanding of underlying relaxation processes. In X-Space MPI reconstruction, relaxation has a profound impact on the image through a decrease in SNR and direction-dependent blurring. To probe the relaxation of potential MPI tracers, Goodwill et al., have developed an X-Space Relaxometer that measures the MPI point spread function and accurately predicts image quality.[1,2] The present work introduces a new relaxometer with improved eddy current shielding to achieve a significant gain in sensitivity. A simulation of the enhanced shielding has shown to attenuate external interference by more than 40dB in the detection bandwidth.

Abstract Glioblastoma multiforme is generally recalcitrant to current surgical and local radiotherapeutic approaches. Moreover, systemic chemotherapeutic approaches are impeded by the blood–tumor barrier. To circumvent limitations in the latter area, we developed a multicomponent, chain-like nanoparticle that can penetrate brain tumors, composed of three iron oxide nanospheres and one drug-loaded liposome linked chemically into a linear chain-like assembly. Unlike traditional small-molecule drugs or spherical nanotherapeutics, this oblong-shaped, flexible nanochain particle possessed a unique ability to gain access to and accumulate at glioma sites. Vascular targeting of nanochains to the αvβ3 integrin receptor resulted in a 18.6-fold greater drug dose administered to brain tumors than standard chemotherapy. By 2 hours after injection, when nanochains had exited the blood stream and docked at vascular beds in the brain, the application of an external low-power radiofrequency field was sufficient to remotely trigger rapid drug release. This effect was produced by mechanically induced defects in the liposomal membrane caused by the oscillation of the iron oxide portion of the nanochain. In vivo efficacy studies conducted in two different mouse orthotopic models of glioblastoma illustrated how enhanced targeting by the nanochain facilitates widespread site-specific drug delivery. Our findings offer preclinical proof-of-concept for a broadly improved method for glioblastoma treatment. Cancer Res; 75(7); 1356–65. ©2015 AACR.

Magnetic particle imaging (MPI) is an emerging imaging modality with promising applications in diagnostic imaging and guided therapy. The image quality in MPI is strongly dependent on the nature of its iron oxide nanoparticle-based tracers. The selection of potential MPI tracers is currently limited, and the underlying physics of tracer response is not yet fully understood. An in-depth understanding of the magnetic relaxation processes that govern MPI tracers, gained through concerted theoretical and experimental work, is crucial to the development of optimized MPI tracers. Although tailored tracers will lead to improvements in image quality, tailored relaxation may also be exploited for biomedical applications or more flexible image contrast, as in the recent demonstration of color MPI.

An MPI spectrometer [1-3] measures the harmonics generated when a nonlinear SPIO is excited by a sinusoidal field. The harmonic peak spectrum allows for comparing SPIOs spatial resolution, since the harmonics are related to the modulation transfer function of the MPI imaging PSF [4-5]. It is also powerful to directly measure the point-spread function (PSF) by using the x-space MPI image reconstruction method [5-6], which has been shown to be equivalent to System Matrix reconstruction [7]. Here we describe a new design for an x-space relaxometer to increase sensitivity.

Targeted nanoparticle imaging agents provide many benefits and new opportunities to facilitate accurate diagnosis of cancer and significantly impact patient outcome. Due to the highly engineerable nature of nanotechnology, targeted nanoparticles exhibit significant advantages including increased contrast sensitivity, binding avidity and targeting specificity. Considering the various nanoparticle designs and their adjustable ability to target a specific site and generate detectable signals, nanoparticles can be optimally designed in terms of biophysical interactions (i.e., intravascular and interstitial transport) and biochemical interactions (i.e., targeting avidity towards cancer-related biomarkers) for site-specific detection of very distinct microenvironments. This review seeks to illustrate that the design of a nanoparticle dictates its in vivo journey and targeting of hard-to-reach cancer sites, facilitating early and accurate diagnosis and interrogation of the most aggressive forms of cancer. We will report various targeted nanoparticles for cancer imaging using X-ray computed tomography, ultrasound, magnetic resonance imaging, nuclear imaging and optical imaging. Finally, to realize the full potential of targeted nanotechnology for cancer imaging, we will describe the challenges and opportunities for the clinical translation and widespread adaptation of targeted nanoparticles imaging agents.

To evaluate the ability of radiofrequency (RF)-triggered drug release from a multicomponent chain-shaped nanoparticle to inhibit the growth of an aggressive breast tumor. A two-step solid phase chemistry was employed to synthesize doxorubicin-loaded nanochains, which were composed of three iron oxide nanospheres and one doxorubicin-loaded liposome assembled in a 100-nm-long linear nanochain. The nanochains were tested in the 4T1-Luc-GFP orthotopic mouse model, which is a highly aggressive breast cancer model. The 4T1-Luc-GFP cell line stably expresses firefly luciferase, which allowed the non-invasive in vivo imaging of tumor response to the treatment using bioluminescence imaging (BLI). Longitudinal BLI imaging showed that a single nanochain treatment followed by application of RF resulted in an at least 100-fold lower BLI signal compared to the groups treated with nanochains (without RF) or free doxorubicin followed by RF. A statistically significant increase in survival time of the nanochain-treated animals followed by RF (64.3 days) was observed when compared to the nanochain-treated group without RF (35.7 days), free doxorubicin-treated group followed by RF (38.5 days), and the untreated group (30.5 days; n = 5 animals per group). These studies showed that the combination of RF and nanochains has the potential to effectively treat highly aggressive cancers and prolong survival.

We obtain good agreement between the calculated and measured ratio of harmonics only when the model includes nanoparticles which have a distribution in the hydrodynamic diameter - that is polydisperse. We are unable to find good agreement if the diameter of the nanoparticles is constrained to only one value - that is monodisperse. In Fig. 1 we plot the measured [3] ratios of 5th/3rd harmonics of the magnetization for samples using “100 nm” iron oxide particles (top plot) and “40 nm” iron oxide particles (bottom plot). The measurements were collected with the nanoparticles in ferrofluid solutions with a range of water/glycerol ratios corresponding to different viscosities (and therefore different Brownian relaxation times.) As described in [3] the data are plotted as a function of ωτB. Also shown in Fig. 1 are the calculations of the ratios of 5th/3rd harmonics assuming both monodisperse and polydisperse ferrofluids. Details of the calculations and parameters used in the models can be found in [5].

While potent cytotoxic agents are available to oncologists, the clinical utility of these agents is limited due to their non-specific distribution in the body and toxicity to normal tissues leading to use of suboptimal doses for eradication of metastatic disease. Furthermore, treatment of micrometastases is impeded by several biobarriers, including their small size and high dispersion to organs, making them nearly inaccessible to drugs. To circumvent these limitations in treating metastatic disease, we developed a multicomponent, flexible chain-like nanoparticle (termed nanochain) that possesses a unique ability to gain access to and be deposited at micrometastatic sites. Moreover, coupling nanochain particles to radiofrequency (RF)-triggered cargo delivery facilitated widespread delivery of drug into hard-to-reach cancer cells. Collectively, these features synergistically facilitate effective treatment and ultimately eradication of micrometastatic disease using a low dose of a cytotoxic drug.

Several harmonic spectra are plotted in Figure 2. An important result is the comparison of free particles embedded in agar and films (Figure 2c). The particles embedded in the films are “frozen” in place, while those in agar, unless bound within the matrix, should still have some freedom to rotate. Particles in both should have identical Neel relaxation times, as that is dependent only on the structure of the iron core and not local environment, provided magnetic interactions can be excluded. A calculation of the Neel relaxation time yields values in the range of 0.12-171 microseconds (for crystal anisotropies in the range of 11-21kJ/m3). The Brownian relaxation time for the films is assumed to be infinite, such that relaxation is only possible through the Neel mechanism. However, the Brownian relaxation times for particles in agar are long enough that relaxation is also assumed to be dominated by the Neel mechanism. While Brownian relaxation may play a role in explaining the signal difference, it is likely due to magnetic interactions between neighboring particles that steepen the magnetization curve. Figure 2c demonstrates that a low interparticle distance generally results in a higher signal. In samples with high local concentrations (such as the films presented here, or samples that exhibit significant aggregation), the average distance between two particles is small enough that dipole-dipole interactions must be considered. Such interactions are one possible explanation for the performance of Feridex IV and Resovist.

Therapeutic efficacy was evaluated by comparing survival times of treated animals with untreated animals and control groups. The mean survival time for animals receiving a single treatment of Drug-NC followed by RF exposure was 25.1 days, compared to 15.2 days for untreated and control groups. A two-cycle treatment prolonged survival to an average of 46 days. Significant cell death was observed in the Drug-NC+RF group in histological sections of the tumors, while nearly no cell death was observed in any of the control groups. The iron oxide nanoparticles used in the chain are an effective tool for converting magnetic energy into mechanical energy. The current application makes use of restricted Brownian motion of the nanoparticles in the nanochain. The movement of the iron oxide chain is restricted due to bonding, preventing true rotation to align with the field.2 We believe the result is a mechanical “vibration” that causes imperfections in the liposome though which the drug is able to escape. To investigate this hypothesis, drug release was measured from several concentrations of Drug-NC exposed to the same magnetic field, and all samples exhibited the same release rate, suggesting that a high concentration of iron oxide nanoparticles is not necessary for drug release. Further, no global heating was observed, and the possibility of local heating was excluded through linking a fluorophore (Alexa 488) to the iron oxide chain of the Drug-NC particle.3 Multiple Drug-NC suspensions were exposed to direct heating (ΔT=0-9°C), causing a measureable decrease in fluorescence intensity. However, when the suspensions were only exposed to RF, no change in fluorescence intensity was observed.

While nanoparticles maximize the amount of chemotherapeutic drug In tumors relative to normal tissues, nanoparticle-based drugs are not accessible to the majority of cancer cells because nanoparticles display patchy, near-perivascular accumulation in tumors. To overcome the limitations of current drugs In their molecular or nanoparticle form, we developed a nanoparticle based on multicomponent nanochains to deliver drug to the majority of cancer cells throughout a tumor while reducing off-target delivery. The nanoparticle Is composed of three magnetic nanospheres and one doxorubicin-loaded liposome assembled In a 100 nm long chain. These nanoparticles display prolonged blood circulation and significant intratumoral deposition in tumor models In rodents. Furthermore, the magnetic particles of the chains serve as a mechanical transducer to transfer radio frequency energy to the drug-loaded liposome. The defects on the liposomal walls trigger the release of free drug capable of spreading throughout the entire tumor, which results In a widespread anticancer effect.

Knowing where the tumor is at all times during treatment is the next challenge in the field of radiation therapy. This issue has become more important because with treatments such as Intensity Modulated Radiation Therapy (IMRT), healthy tissue is spared by using very tight margins around the tumor. These fight margins leave very small room for patient setup errors. The use of an imaging modality in the treatment room as a way to localize the tumor for patient set up is generally known as "Image Guided Radiation Therapy" or IGRT. This article deals with a form of IGRT known as Megavoltage Cone Beam Computed Tomography (MCBCT) using a Siemens Oncor linear accelerator currently in use at Firelands Regional Medical Center. With MCBCT, we are capable of acquiring CT images right before the treatment of the patient and then use this information to position the patient tumor according to the treatment plan. This article presents the steps followed in order to clinically implement this system, as well as some of the quality assurance tests suggested by the manufacturer and some tests developed in house.