Quentin A. Pankhurst

APPLICATIONS OF MAGNETIC NANOPARTICLES IN BIOMEDICINE

A method includes providing a semiconductor substrate having first and second regions that are doped with first and second dopants respectively. The first and second dopants are of opposite types. The method further includes epitaxially growing a first semiconductor layer that is doped with a third dopant. The first and third dopants are of opposite types. The method further includes depositing a dielectric hard mask (HM) layer over the first semiconductor layer; patterning the dielectric HM layer to have an opening over the first region; extending the opening towards the semiconductor substrate; and epitaxially growing a second semiconductor layer in the opening. The second semiconductor layer is doped with a fourth dopant. The first and fourth dopants are of a same type. The method further includes removing the dielectric HM layer; and performing a first CMP process to planarize both the first and second semiconductor layers.

Progress in applications of magnetic nanoparticles in biomedicine

A progress report is presented on a selection of scientific, technological and commercial advances in the biomedical applications of magnetic nanoparticles since 2003. Particular attention is paid to (i) magnetic actuation for in vitro non-viral transfection and tissue engineering and in vivo drug delivery and gene therapy, (ii) recent clinical results for magnetic hyperthermia treatments of brain and prostate cancer via direct injection, and continuing efforts to develop new agents suitable for targeted hyperthermia following intravenous injection and (iii) developments in medical sensing technologies involving a new generation of magnetic resonance imaging contrast agents, and the invention of magnetic particle imaging as a new modality. Ongoing prospects are also discussed.

Magnetic Resonance Imaging of Mesenchymal Stem Cells Homing to Pulmonary Metastases Using Biocompatible Magnetic Nanoparticles

The ability of mesenchymal stem cells (MSC) to specifically home to tumors has suggested their potential use as a delivery vehicle for cancer therapeutics. MSC integration into tumors has been shown in animal models using histopathologic techniques after animal sacrifice. Tracking the delivery and engraftment of MSCs into human tumors will need in vivo imaging techniques. We hypothesized that labeling MSCs with iron oxide nanoparticles would enable in vivo tracking with magnetic resonance imaging (MRI). Human MSCs were labeled in vitro with superparamagnetic iron oxide nanoparticles, with no effect on differentiation potential, proliferation, survival, or migration of the cells. In initial experiments, we showed that as few as 1,000 MSCs carrying iron oxide nanoparticles can be detected by MRI one month after their coinjection with breast cancer cells that formed subcutaneous tumors. Subsequently, we show that i.v.- injected iron-labeled MSCs could be tracked in vivo to multiple lung metastases using MRI, observations that were confirmed histologically. This is the first study to use MRI to track MSCs to lung metastases in vivo. This technique has the potential to show MSC integration into human tumors, allowing early-phase clinical studies examining MSC homing in patients with metastatic tumors.

Magnetic Tagging Increases Delivery of Circulating Progenitors in Vascular Injury

OBJECTIVES We sought to magnetically tag endothelial progenitor cells (EPCs) with a clinical agent and target them to a site of arterial injury using a magnetic device positioned outside the body. BACKGROUND Circulating EPCs are involved in physiological processes such as vascular re-endothelialization and post-ischemic neovascularization. However, the success of cell therapies depends on the ability to deliver the cells to the site of injury. METHODS Human EPCs were labeled with iron oxide superparamagnetic nanoparticles. Cell viability and differentiation were tested using flow cytometry. Following finite element modeling computer simulations and flow testing in vitro, angioplasty was performed on rat common carotid arteries to denude the endothelium and EPCs were administered with and without the presence of an external magnetic device for 12 min. RESULTS Computer simulations indicated successful external magnetic cell targeting from a vessel with flow rate similar to a rat common carotid artery; correspondingly there was a 6-fold increase in cell capture in an in vitro flow system. Targeting enhanced cell retention at the site of injury by 5-fold at 24 h after implantation in vivo. CONCLUSIONS Using an externally applied magnetic device, we have been able to enhance EPC localization at a site of common carotid artery injury. This technology could be more widely adapted to localize cells in other organs and may provide a useful tool for the systemic injection of cell therapies.

Targeted magnetic delivery and tracking of cells using a magnetic resonance imaging system

The success of cell therapies depends on the ability to deliver the cells to the site of injury. Targeted magnetic cell delivery is an emergent technique for localised cell transplantation therapy. The use of permanent magnets limits such a treatment to organs close to the body surface or an implanted magnetic source. A possible alternative method for magnetic cell delivery is magnetic resonance targeting (MRT), which uses magnetic field gradients inherent to all magnetic resonance imaging system, to steer ferromagnetic particles to their target region. In this study we have assessed the feasibility of such an approach for cell targeting, using a range of flow rates and different super paramagnetic iron oxide particles in a vascular bifurcation phantom. Using MRT we have demonstrated that 75% of labelled cells could be guided within the vascular bifurcation. Furthermore we have demonstrated the ability to image the labelled cells before and after magnetic targeting, which may enable interactive manipulation and assessment of the distribution of cellular therapy. This is the first demonstration of cellular MRT and these initial findings support the potential value of MRT for improved targeting of intravascular cell therapies.

The nature of the active site in bis(imino)pyridine iron ethylene polymerisation catalysts

Mossbauer and electron paramagnetic resonance (EPR) spectroscopic studies reveal that the iron centres in bis(imino)pyridine iron(II) olefin polymerisation pre-catalysts of the type LFeCl2 are oxidised upon treatment with methylaluminoxane (MAO) to give an active species that contains iron solely in the +3 oxidation state

Identification of active phases in Au–Fe catalysts for low-temperature CO oxidation

In the light of a recent study which identified the beneficial influence of poorly crystallised ferrihydrite Fe5HO8·4H2O on the activity of CO conversion catalysts comprising gold nanoparticles on oxidic iron, we have investigated three series of ferrihydrite-rich samples prepared by coprecipitation. The samples were structurally and chemically characterised using X-ray diffraction and both 57Fe and 197Au Mossbauer spectroscopy, and tested for CO oxidation at room temperature using a microreactor with on-line GC. The highest activity, 100% conversion after 20 min on line, was observed in a dried sample that contained ferrihydrite and a non-crystalline and possibly hydrated gold oxyhydroxide phase, AuOOH·xH2O. The activity of the same materials after calcination, where the gold was transformed to 3–5 nm Au metal particles and the ferrihydrite to hematite, was less than ca. 7%. This is the first report of a synergistic interaction between AuOOH·xH2O and ferrihydrite resulting in an active catalyst for room temperature CO oxidation, and contrasts with previous work which has been interpreted in terms of the requirement for metallic Au nanoparticles.

Preliminary evaluation of nanoscale biogenic magnetite in Alzheimer's disease brain tissue

Elevated iron levels are associated with many types of neurodegenerative disease, such as Alzheimers, Parkinsons and Huntingtons diseases. However, these elevated iron levels do not necessarily correlate with elevated levels of the iron storage or transport proteins, ferritin and transferrin. As such, little is known about the form of this excess iron. It has recently been proposed that some of the excess iron in neurodegenerative tissue may be in the form of the magnetic iron oxide magnetite (Fe3O4). We demonstrate, for the first time to our knowledge, using highly sensitive superconducting quantum interference device (SQUID) magnetometry, that the concentrations of magnetite are found to be significantly higher in three samples of Alzheimers disease tissue than in three age- and sex-matched controls. These results have implications, not only for disease progression, but also for possible early diagnosis.

On the reliable measurement of specific absorption rates and intrinsic loss parameters in magnetic hyperthermia materials

In the clinical application of magnetic hyperthermia, the heat generated by magnetic nanoparticles in an alternating magnetic �耀eld is used as a cancer treatment. The heating ability of the particles is quanti�耀ed by the speci�耀c absorption rate (SAR), an extrinsic parameter based on the clinical response characteristic of power delivered per unit mass, and by the intrinsic loss parameter (ILP), an intrinsic parameter based on the heating capacity of the material. Even though both the SAR and ILP are widely used as comparative design parameters, they are almost always measured in non-adiabatic systems that make accurate measurements dif�耀cult. We present here the results of a systematic review of measurement methods for both SAR and ILP, leading to recommendations for a standardised, simple and reliable method for measurements using non-adiabatic systems. In a representative survey of 50 retrieved datasets taken from published papers, the derived SAR or ILP was found to be more than 5% overestimated in 24% of cases and more than 5% underestimated in 52% of cases.

Carboxylic acid-stabilised iron oxide nanoparticles for use in magnetic hyperthermia

Iron oxide nanoparticles were made in the presence of three carboxylic acid functionalised organic ligands (tiopronin, oxamic acid and succinic acid) using a co-precipitation method. The iron oxide was a mixture of magnetite and maghemite with an average crystallite size less than 10 nm. The samples were all dialysed prior to analysis to ensure high purity. Without the presence of a carboxylic acid, the dialysis purification stage invoked complete precipitation and the sample was completely intractable. The carboxylic acid stabilised particles could be dissolved in water to form a stable solution. The samples prepared with tiopronin and succinic acid were close to neutral pH and were suitable for magnetic fluid hyperthermia testing on Staphyloccocus aureus. Iron oxide produced with tiopronin was able to achieve a 107-fold reduction in the viable count of the organism using a 2 × 2 minute exposure to an AC magnetic field and this bactericidal effect could still be achieved using the same batch of particles one week later. Oxidation of the samples did occur with aging or sonication and made the heating response less effective after one month. The tiopronin stabilised nanoparticles were able to achieve substantial kills of bacteria at concentrations between 6.25–50 mg/ml. This is, to our knowledge, the first time magnetic hyperthermia has been used to kill bacteria. The heating rates obtained from using an external magnetic alternating field on the iron oxide nanoparticle solutions were four times greater than the best commercially available material. This novel method of killing bacteria could form the basis of a new approach to the treatment of a variety of infectious diseases.