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James P Williams,1 Paul Southern,2 Anya Lissina,3 Helen C Christian,4 Andrew K Sewell,3 Rodney Phillips,1,5,6 Quentin Pankhurst,2 John Frater1,5,6 1Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK; 2Davy-Faraday Research Laboratory, Royal Institution of Great Britain, London, UK; 3Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK; 4Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; 5James Martin 21st Century School, John Radcliffe Hospital, Oxford, UK; 6Oxford NIHR Biomedical Research Centre, Oxford, UK Abstract: The latent HIV-1 reservoir remains the major barrier to HIV-1 eradication. Although successful at limiting HIV replication, highly active antiretroviral therapy is unable to cure HIV infection, thus novel therapeutic strategies are needed to eliminate the virus. Magnetic field hyperthermia (MFH) generates thermoablative cytotoxic temperatures in target-cell populations, and has delivered promising outcomes in animal models, as well as in several cancer clinical trials. MFH has been proposed as a strategy to improve the killing of HIV-infected cells and for targeting the HIV latent reservoirs. We wished to determine whether MFH could be used to enhance cytotoxic T-lymphocyte (CTL) targeting of HIV-infected cells in a proof-of-concept study. Here, for the first time, we apply MFH to an infectious disease (HIV-1) using the superparamagnetic iron oxide nanoparticle FeraSpin R. We attempt to improve the cytotoxic potential of T-cell receptor-transfected HIV-specific CTLs using thermotherapy, and assess superparamagnetic iron oxide nanoparticle toxicity, uptake, and effect on cell function using more sensitive methods than previously described. FeraSpin R exhibited only limited toxicity, demonstrated efficient uptake and cell-surface attachment, and only modestly impacted T-cell function. In contrast to the cancer models, insufficient MFH was generated to enhance CTL killing of HIV-infected cells. MFH remains an exciting new technology in the field of cancer therapeutics, which, as technology improves, may have significant potential to enhance CTL function and act as an adjunctive therapy in the eradication of latently infected HIV-positive cells. Keywords: nanoparticles, HIV-1, thermotherapy, cytotoxic T-cell

The localized heating of magnetic nanoparticles (MNPs) via the application of time-varying magnetic fields – a process known as magnetic field hyperthermia (MFH) – can greatly enhance existing options for cancer treatment; but for broad clinical uptake its optimization, reproducibility and safety must be comprehensively proven. As part of this effort, the quantification of MNP heating – characterized by the specific loss power (SLP), measured in W/g, or by the intrinsic loss power (ILP), in Hm2/kg – is frequently reported. However, in SLP/ILP measurements to date, the apparatus, the analysis techniques and the field conditions used by different researchers have varied greatly, leading to questions as to the reproducibility of the measurements. An interlaboratory study (across N = 21 European sites) of calorimetry measurements that constitutes a snapshot of the current state-of-the-art within the MFH community has been undertaken. Identical samples of two stable nanoparticle systems were distributed to all participating laboratories. Raw measurement data as well as the results of in-house analysis techniques were collected along with details of the measurement apparatus used. Raw measurement data was further reanalyzed by universal application of the corrected-slope method to examine relative influences of apparatus and results processing. The data show that although there is very good intralaboratory repeatability, the overall interlaboratory measurement accuracy is poor, with the consolidated ILP data having standard deviations on the mean of ca. ± 30% to ± 40%. There is a strong systematic component to the uncertainties, and a clear rank correlation between the measuring laboratory and the ILP. Both of these are indications of a current lack of normalization in this field. A number of possible sources of systematic uncertainties are identified, and means determined to alleviate or minimize them. However, no single dominant factor was identified, and significant work remains to ascertain and remove the remaining uncertainty sources. We conclude that the study reveals a current lack of harmonization in MFH characterization of MNPs, and highlights the growing need for standardized, quantitative characterization techniques for this emerging medical technology. [ABSTRACT FROM AUTHOR]

Author(s): F. E. Wagner [1]; S. Haslbeck [1]; L. Stievano [2]; S. Calogero [2]; Q. A. Pankhurst [3]; K. -P. Martinek [4] The red colour of gold-ruby glass is caused [...]

We review current synthetic routes to magnetic iron oxide nanoparticles for biomedical applications. We classify the different approaches used depending on their ability to generate magnetic particles that are either single-core (containing only one magnetic core, i.e. a single domain nanocrystal) or multi-core (containing several magnetic cores, i.e. single domain nanocrystals). The synthesis of single-core magnetic nanoparticles requires the use of surfactants during the particle generation, and careful control of the particle coating to prevent aggregation. Special attention has to be paid to avoid the presence of any toxic reagents after the synthesis if biomedical applications are intended. Several approaches exist to obtain multi-core particles based on the coating of particle aggregates; nevertheless, the production of multi-core particles with good control of the number of magnetic cores per particle, and of the degree of polydispersity of the core sizes, is still a difficult task. The control of the structure of the particles is of great relevance for biomedical applications as it has a major influence on the magnetic properties of the materials. [ABSTRACT FROM AUTHOR]

A study of the magnetic properties of superior temporal gyrus brain tissue from 11 Alzheimer's disease (AD) and 11 age-matched control subjects demonstrates an exponential correlation between the concentrations of the Fe;{2+}-ion-containing iron oxide, magnetite (Fe{3}O{4}), and the fraction of those particles that are smaller than 20 nm in diameter. These data provide circumstantial evidence in favor of their genesis within the 8 nm diameter cores of the iron storage protein ferritin. We also show, for the first time, that the total concentration of biogenic magnetite is generally higher in the AD brain (in some cases as much as 15 times greater than controls) and that there are gender-based differences, with AD female subjects having significantly higher concentrations than all other groups. These results provide insights which may guide current efforts to develop iron-based MRI diagnosis of AD. [ABSTRACT FROM AUTHOR]

Superconducting quantum interference device (SQUID) magnetometers are very high precision instruments: for example, the Quantum Design MPMS-7 instrument capable of measuring an absolute magnetization of ≈10-7 to 10-11 emu (10-10 to 10-14 Am2), corresponding to better than ≈1 ng of magnetite, Fe3O4. However, in biological samples, such precision is rarely achieved. In the presence of ≈100 mg of biological tissue there is a diamagnetic contribution of ≈-9×10-9 emu/Oe so that at 10 kOe the measurement of 1 ng of magnetite in 100 mg of tissue has its precision reduced by a factor of 10, with a loss in accuracy of a factor of 2.5. The extra volume of the biological material also reduces accuracy, typically by ≈25%. We describe here a measurement protocol that increases the obtainable precision and improves accuracy by a factor of 5, and which limits the sample volume effects to ≈2%–3%. This then allows accurate measurement of magnetic biominerals in a biological/diamagnetic matrix. Details on how to prepare, mount, and accurately measure dilute magnetic samples are given. The improvement in data quality comes at the cost of extended measurement periods and slightly increased helium consumption. [ABSTRACT FROM AUTHOR]

The physical principles underlying some current biomedical applications of magnetic nanoparticles are reviewed. Starting from well-known basic concepts, and drawing on examples from biology and biomedicine, the relevant physics of magnetic materials and their responses to applied magnetic fields are surveyed. The way these properties are controlled and used is illustrated with reference to (i) magnetic separation of labelled cells and other biological entities; (ii) therapeutic drug, gene and radionuclide delivery; (iii) radio frequency methods for the catabolism of tumours via hyperthermia; and (iv) contrast enhancement agents for magnetic resonance imaging applications. Future prospects are also discussed. [ABSTRACT FROM AUTHOR]