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PubMed | Magnetic Insight Inc., University of Washington, University of California at Berkeley and LodeSpin Labs
Type: | Journal: Nanoscale | Year: 2017

Superparamagnetic iron oxide (SPIO) nanoparticles with optimized and well-characterized properties are critical for Magnetic Particle Imaging (MPI). MPI is a novel in vivo imaging modality that promises to integrate the speed of X-ray CT, safety of MRI and sensitivity of PET. Since SPIOs are the source of MPI signal, both the core and surface properties must be optimized to enable efficient in vivo imaging with pharmacokinetics tailored for specific imaging applications. Existing SPIOs like Resovist (ferucarbotran) provide a suboptimal MPI signal, and further limit MPIs in vivo utility due to rapid systemic clearance. An SPIO agent with a long blood half-life (t


PubMed | University of Washington, LodeSpin Labs, Case Western Reserve University, University of Electronic Science and Technology of China and University of Alabama
Type: Journal Article | Journal: Journal of materials science | Year: 2015

We present an interdisciplinary overview of material engineering and emerging applications of iron oxide nanoparticles. We discuss material engineering of nanoparticles in the broadest sense, emphasizing size and shape control, large-area self-assembly, composite/hybrid structures, and surface engineering. This is followed by a discussion of several non-traditional, emerging applications of iron oxide nanoparticles, including nanoparticle lithography, magnetic particle imaging, magnetic guided drug delivery, and positive contrast agents for magnetic resonance imaging. We conclude with a succinct discussion of the pharmacokinetics pathways of iron oxide nanoparticles in the human body -- an important and required practical consideration for any


Arami H.,University of Washington | Khandhar A.P.,LodeSpin Labs | Tomitaka A.,University of Washington | Yu E.,University of California at Berkeley | And 3 more authors.
Biomaterials | Year: 2015

Magnetic Particle Imaging (MPI) is a novel non-invasive biomedical imaging modality that uses safe magnetite nanoparticles as tracers. Controlled synthesis of iron oxide nanoparticles (NPs) with tuned size-dependent magnetic relaxation properties is critical for the development of MPI. Additional functionalization of these NPs for other imaging modalities (e.g. MRI and fluorescent imaging) would accelerate screening of the MPI tracers based on their invitro and invivo performance in pre-clinical trials. Here, we conjugated two different types of poly-ethylene-glycols (NH2-PEG-NH2 and NH2-PEG-FMOC) to monodisperse carboxylated 19.7nm NPs by amide bonding. Further, we labeled these NPs with Cy5.5 near infra-red fluorescent (NIRF) molecules. Bi-functional PEG (NH2-PEG-NH2) resulted in larger hydrodynamic size (~98nm vs. ~43nm) of the tracers, due to inter-particle crosslinking. Formation of such clusters impacted the multimodal imaging performance and pharmacokinetics of these tracers. We found that MPI signal intensity of the tracers in blood depends on their plasmatic clearance pharmacokinetics. Whole body mice MPI/MRI/NIRF, used to study the biodistribution of the injected NPs, showed primary distribution in liver and spleen. Biodistribution of tracers and their clearance pathway was further confirmed by MPI and NIRF signals from the excised organs where the Cy5.5 labeling enabled detailed anatomical mapping of the tracers.in tissue sections. These multimodal MPI tracers, combining the strengths of each imaging modality (e.g. resolution, tracer sensitivity and clinical use feasibility) pave the way for various invitro and invivo MPI applications. © 2015 Elsevier Ltd.


Shah S.A.,University of Washington | Ferguson R.M.,LodeSpin Labs | Krishnan K.M.,University of Washington
Journal of Applied Physics | Year: 2014

Magnetic Particle Imaging (MPI) is a new biomedical imaging technique that produces real-time, high-resolution tomographic images of superparamagnetic iron oxide nanoparticle tracers. Currently, 25kHz and 20mT/μ0 excitation fields are common in MPI, but lower field amplitudes may be necessary for patient safety in future designs. Here, we address fundamental questions about MPI tracer magnetization dynamics and predict tracer performance in future scanners that employ new combinations of excitation field amplitude (Ho) and frequency (ω). Using an optimized, monodisperse MPI tracer, we studied how several combinations of drive field frequencies and amplitudes affect the tracer's response, using Magnetic Particle Spectrometry and AC hysteresis, for drive field conditions at 15.5, 26, and 40.2kHz, with field amplitudes ranging from 7 to 52mT/μ0. For both fluid and immobilized nanoparticle samples, we determined that magnetic response was dominated by Néel reversal. Furthermore, we observed that the peak slew-rate (ωHo) determined the tracer magnetic response. Smaller amplitudes provided correspondingly smaller field of view, sometimes resulting in excitation of minor hysteresis loops. Changing the drive field conditions but keeping the peak slew-rate constant kept the tracer response almost the same. Higher peak slew-rates led to reduced maximum signal intensity and greater coercivity in the tracer response. Our experimental results were in reasonable agreement with Stoner-Wohlfarth model based theories. © 2014 AIP Publishing LLC.


Khandhar A.P.,LodeSpin Labs | Khandhar A.P.,University of Washington | Ferguson R.M.,LodeSpin Labs | Arami H.,University of Washington | And 2 more authors.
IEEE Transactions on Magnetics | Year: 2015

Surface coatings are important components of magnetic particle imaging (MPI) tracers - they preserve their key properties responsible for optimum tracer performance in physiological environments. In vivo, surface coatings form a physical barrier between the hydrophobic superparamagnetic iron oxide nanoparticles (SPION) cores and the physiological environment, and their design dictates the blood half-life and biodistribution of MPI tracers. Here, we show the effect of tuning poly(ethylene glycol) (PEG)-based surface coatings on both in vitro and in vivo (mouse model) MPI performance of SPIONs. Our results showed that varying PEG molecular weight had a profound impact on colloidal stability, characterized using dynamic light scattering, and the m'(H) response of SPIONs, measured in a 25 kHz/20 mTμ00max magnetic particle spectrometer. Increasing PEG molecular weight from 5 to 20 kDa preserved colloidal stability and m'(H) response of ∼25 nm SPIONs - the optimum core diameter for MPI - in serum-rich cell culture medium for up to 24 h. Furthermore, we compared the in vivo circulation time of SPIONs as a function of hydrodynamic diameter and showed that clustered SPIONs can adversely affect blood half-life; critically, SPIONs with clusters had five times shorter blood half-life than individually coated SPIONs. We anticipate that the development of MPI SPION tracers with long blood half-lives have potential not only in vascular imaging applications, but also enable opportunities in molecular targeting and imaging - a critical step toward early cancer detection using the new MPI modality. © 1965-2012 IEEE.


Arami H.,University of Washington | Khandhar A.,LodeSpin Labs | Liggitt D.,University of Washington | Krishnan K.M.,University of Washington
Chemical Society Reviews | Year: 2015

Iron oxide nanoparticles (IONPs) have been extensively used during the last two decades, either as effective bio-imaging contrast agents or as carriers of biomolecules such as drugs, nucleic acids and peptides for controlled delivery to specific organs and tissues. Most of these novel applications require elaborate tuning of the physiochemical and surface properties of the IONPs. As new IONPs designs are envisioned, synergistic consideration of the body's innate biological barriers against the administered nanoparticles and the short and long-term side effects of the IONPs become even more essential. There are several important criteria (e.g. size and size-distribution, charge, coating molecules, and plasma protein adsorption) that can be effectively tuned to control the in vivo pharmacokinetics and biodistribution of the IONPs. This paper reviews these crucial parameters, in light of biological barriers in the body, and the latest IONPs design strategies used to overcome them. A careful review of the long-term biodistribution and side effects of the IONPs in relation to nanoparticle design is also given. While the discussions presented in this review are specific to IONPs, some of the information can be readily applied to other nanoparticle systems, such as gold, silver, silica, calcium phosphates and various polymers. © The Royal Society of Chemistry 2015.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 1.13M | Year: 2013

DESCRIPTION (provided by applicant): In the proposed phase II NIH STTR funding opportunity (PA-12-089), LodeSpin Labs (LSL) is developing a magnetic nanoparticle tracer for use in Magnetic Particle Imaging (MPI), a disruptive new medical imaging technologycurrently being developed as a safe, effective and quantitative alternative to existing cardiac imaging technologies like CT and MRI. MPI is a promising safer alternative to current CT angiography procedures; it uses safe magnetic fields (no ionizing radiation) and safe iron oxide nanoparticle tracers. Unlike MRI, it offers real-time imaging that is quantitative and has potential for sub-mm spatial resolution. MPI shows tremendous potential as a safe clinical imaging procedure for diagnosis and treatment of cardiovascular disease (#1 cause of deaths in the US), and opens doors to novel molecular imaging applications. However, it remains under development largely due to the unavailability of suitable tracers. While iron oxide nanoparticle tracers exist, having been developed for MRI as well as for iron replacement in CKD patients (Feraheme), LSL's tracer is the first, and only, tracer to be designed specifically for MPI. Furthermore, there is unanimous agreement in the industrial and academic research community developing MPI hardware that LSL tracers provide superior MPI imaging performance, which will enable MPI's clinical and commercial potential. Therefore, LSL has a significant opportunity to be the first provider of high-performing MPI tracers in the emerging pre-clinical MPI market and future clinical market. In Phase II, UW and LSL, in partnership with industrial giants Bruker BioSpin and Philips Medical Systems, will demonstrate real-time in vivo imaging in phantoms and live animals. LSL has further strengthened its team by including Dr. Steven Conolly, as an imaging scientist consultant, and Dr. Julian Simon, as a conjugation and medicinal chemistry consultant. LSL will also pursue pilot toxicology studies that will demonstrate tracer safety to futureinvestors and enable joint ventures that will ultimately fund future regulatory studies. In Phase I our efforts to develop optimized tracers, and strategic partnerships with Philips Medical Systems (Limited Evaluation License) and Dr. Conolly's group at UC-Berkley (Material Transfer Agreement) have positioned the LSL team as pioneers in MPI tracer technology. There is unanimous agreement in the MPI community that LSL tracers outperform any iron oxide formulation currently in the market. Thus, we envision our tracers as truly enabling MPI in achieving its clinical and commercial potential. In Phase II, LSL's immediate goals are to demonstrate our tracer's superior performance in phantom and in vivo imaging, targeting sub-mm resolution (SA1) in both time- andfrequency-domain image reconstruction methods, further enhance tracer performance to compete with current standards in x-ray CA procedures (SA2), and assess tracer safety in pilot toxicology studies in mice (SA3). PUBLIC HEALTH RELEVANCE PUBLICHEALTH RELEVANCE: Medical imaging is a crucial technique used by clinicians for diagnosing diseases and determining the correct treatment options for patients. In this project, we will develop magnetic nanoparticle tracers for a new and emerging imaging technology called Magnetic Particle Imaging (MPI), with a specific focus on cardiovascular angiography. MPI can produce real-time, quantitative 3-D images and our novel tracer technology, specifically tailored for MPI, will enable the technology to transformfrom a scientifically niche technique t a widely used clinical imaging procedure for diagnosis and treatment, initially focusing on cardiovascular disease, and subsequently on molecular imaging, and related research.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 220.32K | Year: 2011

DESCRIPTION (provided by applicant): Magnetic Resonance Imaging (MRI) is an attractive platform for medical imaging because it uses neither harmful radiation nor expensive radio-tracers; however, MRI, even with the aid of suitable contrast agents, is plagued by background noise from the host tissue and lacks the ability to quantify exactly how much contrast agent is present at a given location. Despite the fact that contrast agents are useful in imaging and differentiating abnormal tissues (tumors) from healthy tissues at much larger scales, early detection of a few-thousand cancer cells is difficult due to the lack of contrast differentiating the tumor from surrounding healthy tissue. Additionally, quantification of cells at the disease site is crucial fordevelopment of more site-specific contrast agents that will enable future developments in image-guided therapeutics. Thus, there is a critical need to develop magnetic molecular probes that, unlike contrast agents, can be directly imaged, irrespective of the surrounding tissue, and can be simultaneously targeted to disease sites for early diagnostic imaging. Our goal is to use Magnetic Particle Imaging (MPI), a new medical imaging technology recently introduced by Philips that uses the magnetic relaxationof magnetite nanoparticles in alternating fields, to produce three-dimensional images of the distribution of the nanoparticles in the tissue. The magnetic nanoparticles will have a million times more signal in MPI compared to the nuclear paramagnetism of protons used in MRI. Royal Philips and Bruker Biospin, have jointly announced the development of a preclinical MPI hardware and imaging system, to be marketed in 2011/12. However, commercially available magnetite formulations are grossly inadequate for MPI,both in terms of signal intensity and spatial resolution. In fact, if this critical component, i.e. appropriate magnetite nanoparticle-based molecular probes, that are biocompatible and surface functionalized for facile bioconjugation, and tailored for optimal, performance, are not developed now the enormous potential of MPI may never be realized. Based on our knowhow, we propose to develop the technology of the molecular probes crucially required for the success of MPI in a most timely manner. Our threespecific aims (SA) will focus on (SA1) development of monodispersed and biocompatible magnetic nanoparticles (MNPs) as molecular probes optimized for any specific driving frequency used in MPI, (SA2) functionalize the MNPs for specific targeting to tumor cells and the surrounding vasculature and determine the targeting effectiveness in vitro, and (SA3) demonstrate MPI's ability to detect and quantify our targeted MNPs in vitro using a home-built magnetic spectrometer, thereby setting the stage for Phase IIwork involving in vivo imaging and quantification. PUBLIC HEALTH RELEVANCE: Medical imaging, in its many forms, is a crucial technique used by clinicians for diagnosing diseases and determining the correct treatment options for patients. Diagnosis of cancer, a disease that has resulted in over 550,000 deaths in the United States in 2010 alone (National Cancer Institute; www.cancer.gov), is especially difficult and often detected at much later stages when patient survival chances are low. For early detection of a few-thousand cells, it is important to use nanometer-scale probes (1 nanometer = 1 billionth of a meter) that can specifically target cancer cells and be directly imaged, without any interference or noise from the patient's body. In this project, we will develop functionalized magnetic nanoparticle-based molecular probes, with a million times more signal than nuclear paramagnetism used in MRI, for early detection of cancer using a new and emerging technique called Magnetic Particle Imaging (MPI). Our technology will complement the hardware being developed by Philips, the inventors of MPI. This technology, if successful, will be superior to current imaging techniques such as Magnetic Resonance Imaging (MRI) and has the potential to enable early diagnosis, giving patients a head start in the fight against cancer.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 150.00K | Year: 2012

This Small Business Innovation Research (SBIR) Phase I project addresses a fundamental problem with Magnetic Particle Imaging, a promising, yet new imaging modality. MPI uses magnetic nanoparticles (tracers) to generate a signal that can be used for fast, safe, non-invasive 3D imaging in living patients. The problem relates to the magnetic tracers: there are no existing commercial tracers that are suitable for MPI, due partly to a fundamental lack of control over the physical and magnetic properties of tracers when using existing methods of production. We have addressed this problem by identifying the desired tracer properties for any MPI imaging system and developing a method to produce particles with controlled/tailored properties. The proposed research is designed to further improve the performance of our product, both to fine-tune its physical characteristics and improve its stability in a biological environment. We will improve the stability and performance of our tracer agent by developing a new process for encapsulating the magnetic particles with a biocompatible shell. We will also further improve the performance by developing a novel filtering system to isolate desirable tracers based specifically on their suitability for MPI, as determined by their magnetic relaxation. The broader impact/commercial potential of this proposed project is an enabling technology for MPI. The goal is to develop a high performance solution that can make clinical MPI commercially viable. MPI using safe iron oxide tracers could reduce patient morbidity during the course of treatment for cardiovascular disease, where current imaging methods like x-ray angiography rely heavily on the use of iodinated contrast media even though they may cause nephrogenic systemic fibrosis in patients, especially those with chronic kidney disease. MPI with targeted tracer probes, also offers significant promise for cancer diagnosis and therapy, with outstanding signal to noise ratio and almost perfect contrast (tissue is diamagnetic and generates no signal in MPI). Finally, the projected commercial impact of MPI is significant: billions of dollars are spent on medical imaging tracers each year, with iodine the most commonly used tracer. Ultimately, MPI, which would circumvent a known hazard in iodine contrast agents, has the potential to generate billions in tracer sales.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 150.00K | Year: 2012

This Small Business Innovation Research (SBIR) Phase I project addresses a fundamental problem with Magnetic Particle Imaging, a promising, yet new imaging modality. MPI uses magnetic nanoparticles (tracers) to generate a signal that can be used for fast, safe, non-invasive 3D imaging in living patients. The problem relates to the magnetic tracers: there are no existing commercial tracers that are suitable for MPI, due partly to a fundamental lack of control over the physical and magnetic properties of tracers when using existing methods of production. We have addressed this problem by identifying the desired tracer properties for any MPI imaging system and developing a method to produce particles with controlled/tailored properties. The proposed research is designed to further improve the performance of our product, both to fine-tune its physical characteristics and improve its stability in a biological environment. We will improve the stability and performance of our tracer agent by developing a new process for encapsulating the magnetic particles with a biocompatible shell. We will also further improve the performance by developing a novel filtering system to isolate desirable tracers based specifically on their suitability for MPI, as determined by their magnetic relaxation.

The broader impact/commercial potential of this proposed project is an enabling technology for MPI. The goal is to develop a high performance solution that can make clinical MPI commercially viable. MPI using safe iron oxide tracers could reduce patient morbidity during the course of treatment for cardiovascular disease, where current imaging methods like x-ray angiography rely heavily on the use of iodinated contrast media even though they may cause nephrogenic systemic fibrosis in patients, especially those with chronic kidney disease. MPI with targeted tracer probes, also offers significant promise for cancer diagnosis and therapy, with outstanding signal to noise ratio and almost perfect contrast (tissue is diamagnetic and generates no signal in MPI). Finally, the projected commercial impact of MPI is significant: billions of dollars are spent on medical imaging tracers each year, with iodine the most commonly used tracer. Ultimately, MPI, which would circumvent a known hazard in iodine contrast agents, has the potential to generate billions in tracer sales.

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