SBIR-STTR Award

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 for development 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 relaxation of 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 three specific 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 II work 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.

Thesaurus Terms:
Algorithms;Animal Model;Animal Models And Related Studies;Automobile Driving;Biocompatible;Body Image;Body Tissues;Cancer Screening For Patients;Cancers;Cell Communication And Signaling;Cell Signaling;Cells;Cessation Of Life;Complement;Complement Proteins;Contrast Agent;Contrast Drugs;Contrast Media;Death;Development;Diagnostic Imaging;Disease;Disease By Site;Disorder;Disorder By Site;Drug Formulations;Early Diagnosis;Effectiveness;Formulation;Frequencies (Time Pattern);Frequency;Future;Goals;H+ Element;Head Start;Head Start Program;Home;Home Environment;Hydrogen Ions;Image;Imaging Procedures;Imaging Technics;Imaging Techniques;Imaging Technology;In Vitro;Intracellular Communication And Signaling;Loinc Axis 4 System;Location;Mr Imaging;Mr Tomography;Mri;Magnetic Resonance Imaging;Magnetic Resonance Imaging Scan;Magnetism;Malignant Cell;Malignant Neoplasms;Malignant Tumor;Marketing;Medical;Medical Imaging;Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance;Molecular Probes;Nci Organization;Nmr Imaging;Nmr Tomography;Names;National Cancer Institute;Noise;Nuclear;Nuclear Magnetic Resonance Imaging;Pet;Pet Scan;Pet Imaging;Petscan;Pett;Patients;Performance;Phase;Plague;Position;Positioning Attribute;Positron Emission Tomography Medical Imaging;Positron Emission Tomography Scan;Positron-Emission Tomography;Protocol;Protocols Documentation;Protons;Rad.-Pet;Radiation;Radiation, X-Rays, Gamma-Rays;Radio;Radiopaque Media;Reaction;Relaxation;Resolution;Roentgen Rays;Screening For Cancer;Signal Transduction;Signal Transduction Systems;Signaling;Site;Staging;Surface;System;Techniques;Technology;Therapeutic;Time;Tissues;Tracer;Tumor Cell;Tumor Tissue;United States;Work;X-Radiation;X-Rays;X-Rays Radiation;Xrays;Yersinia Pestis Disease;Zeugmatography;Base;Biological Signal Transduction;Body Perception;Cancer Cell;Cancer Diagnosis;Commercialization;Developmental;Disease Diagnosis;Disease/Disorder;Driving;Early Cancer Detection;Early Detection;Fight Against;Imaging;Imaging Method;Imaging Modality;Improved;In Vivo;Magnetic;Magnetite;Magnetite Ferrosoferric Oxide;Malignancy;Meter;Model Organism;Nano Meter;Nano Meter Scale;Nano Meter Sized;Nano Particle;Nano Probe;Nano Scale;Nanometer;Nanometer Scale;Nanometer Sized;Nanoparticle;Nanoprobe;Nanoscale;Neoplasm/Cancer;Neoplastic Cell;Particle;Pre-Clinical;Preclinical;Ray (Radiation);Scale Up;Success;Tumor;Tumor Growth

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 technology currently 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 future investors 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- and frequency-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 Statement:


Public Health 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 transform from 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.

Project Terms:
Agreement; Angiography; Animal Model; Animals; Anisotropy; base; Cardiac; Cardiovascular Diseases; cardiovascular imaging; Cardiovascular system; Cause of Death; Cessation of life; Chemicals; Chronic Kidney Failure; Clinical; Collaborations; commercialization; Communities; Contrast Media; Coronary; Coronary Angiography; design; Development; Diagnosis; Diagnostic Imaging; disease diagnosis; Drug Formulations; Evaluation; Foundations; Frequencies (time pattern); Funding; Funding Opportunities; Future; Germany; Goals; Gold; Grant; Image; Image Reconstructions; Imaging Techniques; Imaging technology; improved; in vivo; Ionizing radiation; Iron; iron oxide; Joint Ventures; Joints; Kidney; Leadership; Letters; Licensing; Life; Light; magnetic field; Magnetic Resonance Imaging; Magnetism; Marketing; material transfer agreement; Medical; Medical Imaging; Methods; molecular imaging; Mus; nanoparticle; next generation; novel; particle; Patients; Performance; Pharmaceutical Chemistry; Phase; Play; Positioning Attribute; pre-clinical; Procedures; Process; Production; Progress Reports; Provider; public health relevance; Regulatory Pathway; Research; Resolution; Risk; Safety; Sales; Scientist; Small Business Technology Transfer Research; System; Techniques; Technology; Three-Dimensional Image; Time; Toxicology; Tracer; United States; United States National Institutes of Health; Work; X-Ray Computed Tomography