Magnetic Polymer Composite as a Thermosensitive Agent for Induced Hyperthermia

Polyetheretherketone (PEEK) - magnetite (Fe3O4) blended compounds were produced by high speed vibration milling of PEEK-Fe 3O4 powders exposed to hexane and heated to the melting point (~350 °C) to form the homogeneous magnetic polymer composite, which provided a uniform dispersion of magnetite with low agglomerations in the polymer matrix. Polymer composite with 10 wt.% of magnetite displayed a magnetic saturation of 8 emu/g, tensile strength of 60 MPa and Young’s modulus of 4.4 GPa. Biotoxicity assessment was conducted via in vitro assay. The composite did not induce any adverse reactions, permitting use in medical applications. This study develops analytical relationships and computation of power dissipation of a magnetic material subjected to an alternating magnetic field. Calorimetric measurements of specific power absorption showed about 202 W/g upon cancelling the Brownian motion of magnetite through the encapsulation of the magnetic particles within the polymeric matrices leaving only Neel as the heat loss mechanism

Synthesis, Characterisation and Functionalisation of Magnetic Nanoparticles for Biomedical Applications

Nanotechnology is a relatively new interdisciplinary field to which much attention has been paid for the last years. It involves researchers from very different areas: Chemistry, Physics, Biology, Biochemistry, Chemical Engineering, Materials Science or Medicine. In the interface of all these disciplines lay the possibility to tackle new challenges, unthinkable a few years ago [Klabunde2001]. Nanoscience has opened many possibilities in most technology areas, unreachable so far. It is devoted to the studies of phenomena at the nanoscale, that is, the limit “where the smallest man-made devices meet the atoms and molecules of the natural world” [Wong1999]. Nanoscience is based on the fabrication and characterization of nanostructured, or nanophase systems. These can be three- dimensional: nanoparticles or nanospheres, two-dimensional: thin films, or one- dimensional: quantum dots. The nanoscale regime is a very special point in the length scale, at which the classical laws of physics are not suitable for the explanation of many phenomena, so quantum approaches are needed. Significant changes in the chemical and physical properties of materials take place at the limit at which the interactions correlation length (electrical, magnetic, crystalline...) is of the same order of magnitude of the system size. That opens new possibilities for the development of smart new functional materials, like improved catalysts, polymers, ceramics, tissues, solid state medicines or drug carriers..

Minimally invasive therapies for the brain using magnetic particles

Delivering a therapy with precision, while reducing off target effects is key to the success of any novel therapeutic intervention. This is of most relevance in the brain, where the preservation of surrounding healthy tissue is crucial in reducing the risk of cognitive impairment and improving patient prognosis. Our scientific understanding of the brain would also benefit from minimally invasive investigations of specific cell types so that they may be observed in their most natural physiological environment. Magnetic particles based techniques have the potential to deliver cellular precision in a minimally invasive manner. When inside the body, Magnetic particles can be actuated remotely using externally applied magnetic fields while their position can be detected non-invasively using MRI. The magnetic forces applied to the particles however, rapidly decline with increasing distance from the magnetic source. It is therefore critical to understand the amount of force needed for a particular application. The properties of the magnetic particle such as the size, shape and magnetic content, as well as the properties of the applied magnetic field, can then be tailored to that application. The aim of this thesis was to develop magnetic particle based techniques for precise manipulation of cells in the brain. Two different approaches were explored, utilising the versatile nature of magnetic actuation for two different applications. The first approach uses magnetic nanoparticles to mechanically stimulate a specific cell type. Magnetic particles conjugated with the antibody ACSA-1 would selectively bind to astrocytes to evoke the controlled release of ATP and induce a calcium flux which are used for communication with neighbouring cells. This approach allows for the investigation into the role of astrocytes in localised brain regions using a naturally occurring actuation process (mechanical force) without effecting their natural environment. The second approach uses a millimetre sized magnetic particle which can be navigated through the brain and ablate localised regions of cells using a magnetic resonance imaging system. The magnetic particle causes a distinct contrast in MRI images, allowing for precise detection of its location so that it may be iteratively guided along a pre-determined path to avoid eloquent brain regions. Once at the desired location, an alternating magnetic field can be applied causing the magnetic particle to heat and deliver controllable, well defined regions of cell death. The forces needed for cell stimulation are orders of magnitude less than the forces needed to guide particles through the brain. Chapters 4 and 5 use external magnets to deliver forces in the piconewton range. While stimulation was demonstrated in small animals, scaling up this technique to human proportions remains a challenge. Chapters 6 and 7 use a preclinical MRI system to generate forces in the millinewton range, allowing the particle to be moved several centimetres through the brain within a typical surgical timescale. When inside the scanner, an alternating magnetic field causes the particle to heat rapidly, enabling the potential for multiple ablations within a single surgery. For clinical translation of this technique, MRI scanners would require a dedicated propulsion gradient set and heating coil

Synthesis and Characterization of Palladium-Cobalt Alloy for New Medical Micro-Devices

RÉSUMÉ Selon les statistiques canadiennes sur le cancer, on estime que 196 900 Canadiens développeront un cancer et que 78 000 en mourront en 2015. Étant donné que les cellules tumorales sont plus sensibles que les cellules saines à une augmentation de température, cette propriété peut être utilisée in vivo pour détruire les cellules cancéreuses par l’élévation de la température du corps, également connu sous le nom d'hyperthermie. L’hyperthermie magnétique est une technique prometteuse pour le traitement ciblé du cancer à l'aide des nanoparticules magnétiques, et ayant donc moins d'effets secondaires que la chimiothérapie et la radiothérapie. Malgré que l'hyperthermie magnétique a été utilisée depuis des milliers d’années pour le traitement du cancer, le défi de destruction des cellules cancéreuses reste très difficile. Pour cette raison, les oncologues utilisent souvent le traitement par hyperthermie magnétique en combinaison avec la radiothérapie et/ou la chimiothérapie. Cette approche thérapeutique combinée a pour but de sensibiliser les cellules cancéreuses résistantes à la radiothérapie et/ou la chimiothérapie. Pour utiliser l’hyperthermie magnétique toute seule dans le traitement du cancer, des difficultés au niveau de la modification de surface des particules magnétiques, pour une absorption sélective par les cellules cancéreuses, et au niveau de la stabilité et des propriétés magnétiques, pour une capacité de chauffage élevée (> 1000 W/g), doivent être surmontées. L'objectif ultime de cette thèse est de synthétiser un excellent candidat pour une hyperthermie magnétique puissante. En raison des progrès rapides effectués dans le domaine des nanotechnologies, un procédé de synthèse de nanoparticules ayant une capacité de contrôle rigoureux de: la structure et la morphologie, la taille, la forme et la cristallinité, est nécessaire. L'électrodéposition est un procédé polyvalent pour la synthèse des NPs métalliques directement et sélectivement sur des substrats conducteurs par simple réglage du courant ou de la tension appliquée. En outre, la taille des particules et la forme sont facilement contrôlables, et les études ont montré que l'électrodéposition est d'une grande utilité dans la fabrication d'alliages palladium-cobalt (PdCo) nanocristallins. L'objectif principal de ce projet est de synthétiser des NPs d’alliage PdCo par électrodéposition sur une électrode de graphite. Les objectifs secondaires sont d'optimiser les paramètres suivants: la composition, la taille, la forme et la surface des NPs d’alliage PdCo afin d'améliorer leur stabilité, production de chaleur et nanotoxicité pour répondre aux besoins cliniques.----------ABSTRACT According to Canadian Cancer Statistics, it is estimated that 196,900 Canadians will develop cancer and 78,000 will die of cancer in 2015. Given that tumor cells are more sensitive to a temperature increase than healthy ones, this property can be used in vivo to destroy the cancerous cells by elevation of body temperature, otherwise known as hyperthermia. Magnetic hyperthermia is a promising technique for cancer treatment because of ease in targeting the cancerous cells using magnetic nanoparticles (MNPs) and hence having fewer side effects than chemotherapy and radiotherapy. Despite the use of magnetic hyperthermia to treat cancer for thousands of years, the challenge of only heating malignant cells remains daunting. Thus, oncologists often use the heat treatment in combination with radiotherapy or chemotherapy or both. The combined approach results in eliminating many cancer cells in addition to making the resistant cancer cells more vulnerable to other treatments. To use stand-alone magnetic hyperthermia therapy, difficulties in surface modification of magnetic particles for selective uptake by cancerous cells and stability as well as magnetic properties for high heating capacity (> 1000 W/g) must be overcome. The ultimate objective of this thesis is to synthesize an excellent candidate for a powerful magnetic hyperthermia. Due to rapid advances in nanotechnology, a synthesis method of nanoparticles (NPs) with the ability to rigorously control the structure and morphology, such as size, shape and crystallinity, is needed. Electrodeposition is a versatile method for the synthesis of metal NPs directly and selectively onto conductive substrates, simply by regulating applied current or voltage. Furthermore, the particles size and the shape are easily controllable. Besides, studies have shown that the electrodeposition technique is of great utility in the fabrication of nanocrystalline palladium-cobalt (PdCo) alloys. The primary goal of this project is to synthesize monodispersed PdCo alloy NPs by electrodeposition, on graphite electrode. The secondary goals are to optimize the following parameters: composition, size, shape and surface of the PdCo alloy NPs in order to enhance its stability, heat generation and nanotoxicity facing their use for clinical applications

Nanoparticles and alloys for therapeutical and structural biomedical applications.

This thesis addresses 2 challenges in biomaterials research: 1) diffusion phenomena in Ti-Al-Nb alloys as materials for structural applications; and 2) the development of magnetic hyperthermia therapies against cancer more efficient and less invasive. Both challenges share a characteristic physical ground, which is the guideline of this work: they are based on transfer phenomena, mass transfer in the first case, and heat transfer in the second.Biomaterials research has been in an ascendant trend over the last decades. In biomedical applications, the first thing to be taken into consideration is biocompatibility. This property together with high specific strength, and good corrosion resistance has made titanium and its alloys the preferred materials for structural applications in the human body. Moreover, they have also been widely used in other fields like aerospace and marine industries. The composition of alloys is the most basic parameter that determines their properties. For instance, compared with the conventional Ti-6Al-4V alloy, some vanadium free titanium alloys like Ti-Al-Nb alloys, have higher fatigue strength, lower modulus of elasticity, and improved biocompatibility. All these properties are closely related to their microstructures that can be engineered by recovery, recrystallization, grain growth, transformation and precipitation. Furthermore, microstructural features can also be controlled to some extent by diffusion phenomena.Bibliometric studies show that in the uprising of Biomaterials research "Nanoparticles" has become the hottest topic after the turn of millennium. Indeed, nanotechnology, having been at the forefront of research for many years, has brought new genuine technical solutions in many different fields like biology, materials, electronics and medicine etc. One of the most exciting among them is that of therapeutical applications of nanoparticles (NPs), in which toxicity is also the main concern. For instance, in NP mediated magnetic hyperthermia for cancer therapy, only iron oxide nanoparticles (IONP), and particularly maghemite (-Fe2O3), are clinically accepted, in spite of existence of other materials like Co ferrite (CoFe2O4) that present clear advantages in terms of heating performance but show toxicity issues. Therefore, research efforts in this area have been mostly devoted to improve the performance of maghemite NPs by optimizing their structural parameters such as size, size distribution, shape, crystallinity, etc. There is however another polymorph of iron oxide, -Fe2O3, that has exceptional magnetic properties, but nevertheless has never been explored as a potential candidate for magnetic hyperthermia therapy.The idea of hyperthermia is to elevate the temperature of the tumor tissue over 42 ℃, in a selective way, to cause the apoptotic death of cancer cells. In order to heat selectively the tumor, it is peremptory to precisely monitor and control the temperature of the surrounding healthy tissue. Moreover, actual clinical magnetic hyperthermia technology uses massive direct injection of nanoparticles, which carries out some degree of invasiveness and toxicity issues. In order to avoid these problems and to expand the use of this technology in clinics, a new strategy has emerged that requires a reduced heat production. It is based on applying small amounts of heat but concentrated at certain intracellular regions that may lead to cancer cell apoptosis. To proof this hypothesis, it is first necessary to determine whether the heat produced by the MNPs is enough to generate large temperature gradients in small intracellular regions in the competition with heat dissipation process across the cell cytoplasm and then to the extracellular matrix. For this purpose, a non-invasive thermometric technique is required capable to determine local temperatures inside the cells with ultra-high spatial resolution. In this matter the use of lanthanide-based luminescent molecular thermometers can be a good option, as it will be shown in this thesis.This thesis is about: the diffusion phenomenon in the Ti-Al-Nb alloys, the hyperthermia performance of epsilon iron oxide nanoparticles, the fine-tuning of a ultra-high spatial and time resolution 2D temperature imaging system, the performance of Ln3+-bearing nanoparticles as nano-thermometry probes, obtaining intracellular temperature images, and the determination of temperature gradients in magnetic nanoparticles inside cancer cells under an ac magnetic field irradiation, and finally to investigate the validity of the local hyperthermia hypothesis.Chapter 1 will give a general introduction to the application of Titanium alloys and magnetic nanoparticles. The focus concerning titanium alloys will be put on diffusion phenomena, while in the case of magnetic nanoparticles, it will be mainly directed to magnetic hyperthermia and molecular nanothermometry.Chapter 2 contains the experimental section including methods, preparation and characterization of Titanium alloys, and magnetic and thermometric nanoparticle suspensions, and a description of the temperature imaging system.Chapter 3 is focused on diffusion phenomenon study of body centered cubic Ti-Al-Nb alloys by both experimental and computational methods, and the construction of a diffusion kinetic database. The experiments were conducted by the diffusion couple technique, and the computational work thereafter was accomplished by the DICTRA software.Chapter 4 and 5 demonstrates the hyperthermia performance of pure and Ga-doped epsilon iron oxide nanoparticles, in comparison with that of gamma iron oxide nanoparticles.Chapter 6 is dedicated to intracellular 2D temperature imaging and local magnetic hyperthermia by using Ln3+-bearing polymeric micelles.Chapter 7 is dedicated to the study of local hyperthermia by means of intracellular 2D temperature imaging of Ln3+-bearing iron oxide nanoparticles ac magnetic field application to cell cultures.<br /