MNP-enhanced microwave medical imaging by means of pseudo-noise sensing

Magnetic nanoparticles have been investigated for microwave imaging over the last decade. The use of functionalized magnetic nanoparticles, which are able to accumulate selectively within tumorous tissue, can increase the diagnostic reliability. This paper deals with the detecting and imaging of magnetic nanoparticles by means of ultra-wideband microwave sensing via pseudo-noise technology. The investigations were based on phantom measurements. In the first experiment, we analyzed the detectability of magnetic nanoparticles depending on the magnetic field intensity of the polarizing magnetic field, as well as the viscosity of the target and the surrounding medium in which the particles were embedded, respectively. The results show a nonlinear behavior of the magnetic nanoparticle response depending on the magnetic field intensity for magnetic nanoparticles diluted in distilled water and for magnetic nanoparticles embedded in a solid medium. Furthermore, the maximum amplitude of the magnetic nanoparticles responses varies for the different surrounding materials of the magnetic nanoparticles. In the second experiment, we investigated the influence of the target position on the three-dimensional imaging of the magnetic nanoparticles in a realistic measurement setup for breast cancer imaging. The results show that the magnetic nanoparticles can be detected successfully. However, the intensity of the particles in the image depends on its position due to the path-dependent attenuation, the inhomogeneous microwave illumination of the breast, and the inhomogeneity of the magnetic field. Regarding the last point, we present an approach to compensate for the inhomogeneity of the magnetic field by computing a position-dependent correction factor based on the measured magnetic field intensity and the magnetic susceptibility of the magnetic particles. Moreover, the results indicate an influence of the polarizing magnetic field on the measured ultra-wideband signals even without magnetic nanoparticles. Such a disturbing influence of the polarizing magnetic field on the measurements should be reduced for a robust magnetic nanoparticles detection. Therefore, we analyzed the two-state (ON/OFF) and the sinusoidal modulation of the external magnetic field concerning the detectability of the magnetic nanoparticles with respect to these spurious effects, as well as their practical application

Differential ultra-wideband microwave imaging for medical applications

Elektromagnetische Ultrabreitband-Sensorik und -Bildgebung bieten vielversprechende Perspektiven für verschiedene biomedizinische Anwendungen, da diese Wellen biologisches Gewebe durchdringen können. Dabei stellt der Einsatz von leistungsarmen und nichtionisierenden Mikrowellen eine gesundheitlich unbedenkliche Untersuchungsmethode dar. Eine der Herausforderungen im Bereich der ultrabreitbandigen Mikrowellensensorik ist dabei die Extraktion der diagnostisch relevanten Informationen aus den Messdaten, da aufgrund der komplexen Wellenausbreitung im Gewebe meist rechenaufwändige Methoden notwendig sind. Dieses Problem wird wesentlich vereinfacht, wenn sich die Streueigenschaften des zu untersuchenden Objektes zeitlich ändern. Diese zeitliche Varianz der Streueigenschaften kann mit Hilfe einer Differenzmessung über ein bestimmtes Zeitintervall ausgenutzt werden. Im Rahmen dieser Arbeit wird der differentielle Ansatz mittels Ultrabreitband-Sensorik für zwei medizinische Anwendungsszenarien betrachtet. Die dabei genutzten Messsysteme basieren auf dem M-Sequenzverfahren, welches an der Technischen Universität Ilmenau entwickelt wurde. Die erste Anwendung bezieht sich auf das nicht-invasive Temperaturmonitoring mittels Ultrabreitband-Technologie während einer Hyperthermiebehandlung. Hyperthermie ist eine Wärmetherapie zur Unterstützung onkologischer Behandlungen (z. B. Chemo- oder Strahlentherapie). Während einer solchen Behandlung wird das Tumorgewebe um 4 °C bis 8 °C erhöht. Dabei ist es wichtig, dass die Temperatur die obere Grenze von 45 °C nicht überschreitet. In diesem Zusammenhang bietet das differentielle Ultrabreitband-Monitoring eine vielversprechende Technik zur kontinuierlichen und nicht-invasiven Messung der Temperatur im Körperinneren. Der Ansatz basiert auf den temperaturabhängigen dielektrischen Eigenschaften von biologischem Gewebe. Dabei werden elektromagnetische Wellen mit einer geringen Leistung in das Untersuchungsmedium eingebracht, die sich gemäß den dielektrischen Eigenschaften von Gewebe ausbreiten. Wird eine Zielregion (bspw. Tumor) erwärmt, so ändern sich dessen dielektrische Eigenschaften, was zu einem sich ändernden Streuverhalten der elektromagnetischen Welle führt. Diese Änderungen können mittels Ultrabreitband-Sensorik erfasst werden. Für die Evaluierung der gemessenen Änderungen im Radarsignal ist es notwendig, die temperaturabhängigen dielektrischen Eigenschaften von Gewebe im Mikrowellenfrequenzbereich zu kennen. Aufgrund der wenigen in der Literatur vorhandenen temperaturabhängigen dielektrischen Eigenschaften von Gewebe über einen breiten Mikrowellenfrequenzbereich werden in dieser Arbeit die dielektrischen Eigenschaften für Leber, Muskel, Fett und Blut im Temperaturbereich zwischen 30 °C und 50 °C von 500 MHz bis 7 GHz erfasst. Hierzu wird zunächst ein Messaufbau für die temperaturabhängige dielektrische Spektroskopie von Gewebe, Gewebeersatz und Flüssigkeiten vorgestellt und die wesentlichen Einflussfaktoren auf die Messungen analysiert. Die Messdaten werden mit Hilfe eines temperaturabhängigen Cole-Cole Models modelliert, um die dielektrischen Eigenschaften für beliebige Werte im untersuchten Temperatur- und Frequenzbereich berechnen zu können. In einem weiteren Experiment wird die nicht-invasive Erfassung von Temperaturänderungen mittels Ultrabreitband-Technologie in einem experimentellen Messaufbau nachgewiesen. Die Ergebnisse zeigen, dass eine Temperaturänderung von 1 °C zu Differenzsignalen führt, welche mit der genutzten Ultrabreitband-Sensorik (M-Sequenz) detektierbar sind. Die zweite Anwendung befasst sich mit der kontrastbasierten Mikrowellen-Brustkrebsbildgebung. Aufgrund des physiologisch gegebenen geringen dielektrischen Kontrastes zwischen Drüsen- und Tumorgewebe kann durch den Einsatz von Kontrastmitteln, im Speziellen magnetischen Nanopartikeln, die Zuverlässigkeit einer Diagnose verbessert werden. Der Ansatz beruht darauf, dass funktionalisierte magnetische Nanopartikel in der Lage sind, sich selektiv im Tumorgewebe zu akkumulieren, nachdem diese intravenös verabreicht wurden. Unter der Bedingung, dass sich eine ausreichende Menge der Nanopartikel im Tumor angesammelt hat, können diese durch ein äußeres polarisierendes Magnetfeld moduliert werden. Aufgrund der Modulation ändert sich das Streuverhalten der magnetischen Nanopartikel, was wiederum zu einem sich ändernden Rückstreuverhalten führt. Diese Änderungen können mittels leistungsarmen elektromagnetischen Wellen detektiert werden. In dieser Arbeit wird die Detektierbarkeit und Bildgebung von magnetischen Nanopartikeln mittels Ultrabreitband-Sensorik im Mikrowellenfrequenzbereich in Hinblick auf die Brustkrebsdetektion betrachtet. Dabei werden zunächst verschiedene Einflussfaktoren, wie die Abhängigkeit der Masse der magnetischen Nanopartikel, die Magnetfeldstärke des äußeren Magnetfeldes sowie die Viskosität des Umgebungsmediums, in das die Nanopartikel eingebettet sind, auf die Detektierbarkeit der magnetischen Nanopartikel untersucht. Die Ergebnisse zeigen eine lineare Abhängigkeit zwischen dem gemessenen Radarsignal und der Masse der magnetischen Nanopartikel sowie einen nichtlinearen Zusammenhang zwischen der Antwort der magnetischen Nanopartikel und der Feldstärke des äußeren Magnetfeldes. Darüber hinaus konnten die magnetischen Nanopartikel für alle untersuchten Viskositäten erfolgreich detektiert werden. Basierend auf diesen Voruntersuchungen wird ein realistischer Messaufbau für die kontrastbasierte Brustkrebsbildgebung vorgestellt. Die Evaluierung des Messaufbaus erfolgt mittels Phantommessungen, wobei die verwendeten Phantommaterialien die dielektrischen Eigenschaften von biologischem Gewebe imitieren, um eine möglichst hohe Aussagekraft der Ergebnisse hinsichtlich eines praktischen Messszenarios zu erhalten. Dabei wird die Detektierbarkeit und Bildgebung der magnetischen Nanopartikel in Abhängigkeit der Tumortiefe analysiert. Die Ergebnisse zeigen, dass die magnetischen Nanopartikel erfolgreich detektiert werden können. Dabei hängt im dreidimensionalen Bild die Intensität des Messsignals, hervorgerufen durch die magnetischen Nanopartikel, von deren Position ab. Die Ursachen hierfür sind die pfadabhängige Dämpfung der elektromagnetischen Wellen, die inhomogene Ausleuchtung des Mediums mittels Mikrowellen, da eine gleichmäßige Anordnung der Antennen aufgrund der Magnetpole des Elektromagneten nicht möglich ist, sowie das inhomogene polarisierende Magnetfeld innerhalb des Untersuchungsmediums. In Bezug auf den letzten Aspekt wird das Magnetfeld im Untersuchungsbereich ausgemessen und ein Ansatz präsentiert, mit dem die Inhomogenität des Magnetfeldes kompensiert werden kann. Weiterhin wurden die Störeinflüsse des polarisierenden Magnetfeldes auf das Messsystem untersucht. In diesem Zusammenhang werden zwei verschiedene Modulationsarten (eine Modulation mit den zwei Zuständen AN/AUS und eine periodische Modulation) des äußeren polarisierenden Magnetfeldes analysiert. Es wird gezeigt, dass mit beiden Modulationen die magnetischen Nanopartikel bildgebend dargestellt werden können. Abschließend werden die Ergebnisse in Hinblick auf die Störeinflüsse sowie ein praktisches Anwendungsszenario diskutiert.Electromagnetic ultra-wideband sensing and imaging provide promising perspectives in various biomedical applications as these waves can penetrate biological tissue. The use of low-power and nonionizing electromagnetic waves in the microwave frequency range offers an examination method that is harmless to health. One of the challenges in the field of ultra-wideband microwave sensor technology is the extraction of diagnostically relevant information from the measurement data, since the complex wave propagation in tissue usually requires computationally intensive methods. This problem is simplified when the scattering properties of the object under observation change with time. Such a time variance of the scattering properties can be exploited by means of a differential measurement over a certain time interval. In this work, a differential approach using ultra-wideband sensing is considered for two medical applications. The measurement systems used in this work are based on the M-sequence technology developed at the Technische Universität Ilmenau. The first application relates to noninvasive temperature monitoring using ultra-wideband technology during hyperthermia treatment. Hyperthermia is a thermal therapy to support oncological treatments (e.g. chemotherapy or radiotherapy). During such a treatment, the tumor tissue is heated by 4 °C to 8 °C, whereby it is important that the temperature does not exceed the upper limit of 45 °C. In this context, differential ultra-wideband monitoring offers a promising technique for continuous and noninvasive temperature monitoring inside the body. The approach is based on the temperature-dependent dielectric properties of biological tissue. In this method, low power electromagnetic waves are emitted into the medium under investigation. These waves propagate according to the dielectric properties of tissue. If a target region (e.g. tumor) is heated, its dielectric properties will change, which leads to a changing scattering behavior of the electromagnetic wave. These changes can be detected in the measured reflection signals using ultra-wideband microwave technology. To evaluate the measured changes in the radar signal, it is necessary to know the temperature-dependent dielectric properties of tissue in the microwave frequency range. Due to the lack of knowledge of temperature-dependent dielectric properties of tissues over a wide microwave frequency range, the dielectric properties for liver, muscle, fat and blood in the temperature range between 30 °C and 50 °C from 500 MHz to 7 GHz are acquired in this work. For this purpose, a measurement setup for the temperature-dependent dielectric spectroscopy of tissue, tissue substitutes and fluids is presented. Furthermore, the main influences on measuring the temperature-dependent dielectric properties are analyzed. The measured data are modeled using a temperature-dependent Cole-Cole model in order to calculate the dielectric properties for arbitrary values in the investigated temperature and frequency range. In a further experiment, the noninvasive detection of temperature changes using ultra-wideband microwave technology is demonstrated in an experimental measurement setup. The results show that a temperature change of 1 °C results in differential signals that are detectable by means of ultra-wideband pseudo-noise sensing (M-sequence). The second application is dealing with contrast enhanced microwave breast cancer imaging. Due to the physiologically given low dielectric contrast between glandular and tumor tissue, the use of contrast agents, specifically magnetic nanoparticles, can improve the diagnostic reliability. The approach is based on the assumption that functionalized magnetic nanoparticles are able to selectively accumulate in tumor tissue after intravenous administration. Provided that a sufficient amount of nanoparticles has accumulated in the tumor, they can be modulated by an external polarizing magnetic field. Due to the modulation, the scattering behavior of the magnetic nanoparticles changes, which results a changing backscattering behavior. This change can be detected using low-power electromagnetic waves. In this work, the detectability and imaging of magnetic nanoparticles by means of ultra-wideband pseudo-noise sensing in the microwave frequency range is considered with respect to breast cancer detection. First, various influencing factors on the detectability of the magnetic nanoparticles are investigated, such as the mass of the magnetic nanoparticles, the magnetic field strength of the external polarizing magnetic field and the viscosity of the surrounding medium in which the nanoparticles are embedded. The results reveal a linear dependence between the measured radar signal and the mass of the magnetic nanoparticles as well as a nonlinear relationship between the response signal of the magnetic nanoparticles and the magnetic field intensity of the external magnetic field. Furthermore, the magnetic nanoparticles can be successfully detected in all investigated viscosities of the surrounding medium. Based on these preliminary investigations, a realistic measurement setup for contrast enhanced microwave breast cancer imaging is presented. The evaluation of the measurement setup is performed by phantom measurements, where the used phantom materials mimic the dielectric properties of biological tissue to obtain significance of the results with respect to a practical measurement scenario. In this context, the detectability and imaging of the magnetic nanoparticles are analyzed depending on the tumor position and penetration depth, respectively. The results show that the magnetic nanoparticles can be successfully detected. However, the magnetic poles of the electromagnet limit the space for the transmitting and receiving antennas, resulting in an inhomogeneous microwave illumination of the medium under test, which leads to a location-dependent magnetic nanoparticle response. Furthermore, the intensity of the response signal caused by the magnetic nanoparticles in the three-dimensional image depends on their position due to the path-dependent attenuation and the inhomogeneous magnetic field within the investigated medium. Regarding the last point, the external polarizing magnetic field is measured in the investigation area and an approach to compensate for the inhomogeneity of the magnetic field is presented. In addition, the disturbing influences of the polarizing magnetic field on the measurement setup are analyzed. In this context, two different modulation types (a two-state and a periodic modulation) of the external polarizing magnetic field are investigated. It is shown that both modulations can be used to image the magnetic nanoparticles. Finally, the results are discussed with respect to the spurious effects as well as a practical application scenario

Novel Therapeutic Approaches to Treat Brain Cancer Combining Cold Atmospheric Plasma, Therapeutic Prodrugs and Gold Nanoparticles

Glioblastoma Multiforme (GBM) makes up approximately 45% of all primary brain tumours. State of the art treatment at present involves concurrent and adjuvant temozolomide (TMZ) with radical radiotherapy which extends median survival from 12.1 months (radical radiotherapy alone) to 14.6 months according to the study of the European Organization for Research and Treatment of Cancer (EORTC) Brain Tumour and Radiotherapy Groups and the National Cancer Institute of Canada (NCIC) Clinical Trials Group. Meanwhile, National Cancer Registry Ireland presented that GBM represents over 40% of all malignant brain tumours and had the worst five-year net survival (4%) compared to overall malignant brain cancer (five-year net survival, 19%) in Ireland. Long term survival of patients with GBM has not been significantly improved in the last 20 years. GBM tumours also have presented high level of resistance to normal treatments. Therefore, novel therapies to treat GBM are urgently needed. This study aimed to investigate efficient therapeutic methods by combining novel interventions, including cold atmospheric plasma (CAP), gold nanoparticles (AuNPs) and specific chemotherapeutic compounds to overcome the barriers of GBM treatment. Over the past decade CAP has emerged as a novel approach in health care area, especially cancer therapy. CAP generates chemically active species such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) and has been demonstrated to act in synergy with a selection of traditional chemotherapeutic compounds which could reduce the effective concentrations of drugs needed at the tumour and may allow for targeted toxicity at sites exposed to the plasma field. AuNPs, well known as biocompatible drug delivery and diagnosis agents for cancer therapy, have been demonstrated to have synergistic anti cancer effects in combination with CAP treatment. In this project, for the first time, we investigated and described the detailed mechanism iii behind the synergistic anti-cancer effects between AuNPs and CAP treatment. Chapter 2 and Chapter 3 demonstrated that low dose treatment of CAP treatment was capable of promoting the uptake of AuNPs into glioblastoma U373MG cells via stimulated membrane repair clathrin-dependent endocytosis. The intracellular accumulation of AuNPs was tracked using atomic absorbance spectrometry (AAS) and simulated with numerical modelling to identify the enhanced uptake routine. AuNPs were tracked into early endosomes, late endosomes and finally lysosomes using specific fluorescent probes and confocal microscope. The lipid oxidation of cancer cells induced by CAP treatment was confirmed by various methods, including confocal microscopy, Thiobarbituric Acid Reactive Substances (TBARS) assay and flow cytometry. Meanwhile, the related endocytosis pathway was determined to be clathrin dependent using multiple clathrin and caveola specific inhibitors and clathrin siRNA. In Chapter 4, we performed the screening of 47 prodrug candidates for their cytotoxicity against U373MG cells in combination with CAP treatment. The selection of chemotherapeutic compounds provided by collaborators have been tested to determine dose response curves with or without CAP treatment using Alamar Blue assay, thus, to characterise their synergistic potential in combination with CAP. Two leading candidates which showed significant cytotoxicity with CAP, have been identified from 47 compounds. Furthermore, the mechanism behind the synergistic cytotoxicity between one of the leading candidates, JW-04-061, and CAP treatment has been investigated. It has been demonstrated that reactive species, especially short-lived species, generated in culture medium may play a main role in the oxidation and activation of the prodrug during CAP treatment

Thermal ablation of biological tissues in disease treatment: A review of computational models and future directions

Percutaneous thermal ablation has proved to be an effective modality for treating both benign and malignant tumors in various tissues. Among these modalities, radiofrequency ablation (RFA) is the most promising and widely adopted approach that has been extensively studied in the past decades. Microwave ablation (MWA) is a newly emerging modality that is gaining rapid momentum due to its capability of inducing rapid heating and attaining larger ablation volumes, and its lesser susceptibility to the heat sink effects as compared to RFA. Although the goal of both these therapies is to attain cell death in the target tissue by virtue of heating above 50 oC, their underlying mechanism of action and principles greatly differs. Computational modelling is a powerful tool for studying the effect of electromagnetic interactions within the biological tissues and predicting the treatment outcomes during thermal ablative therapies. Such a priori estimation can assist the clinical practitioners during treatment planning with the goal of attaining successful tumor destruction and preservation of the surrounding healthy tissue and critical structures. This review provides current state-of- the-art developments and associated challenges in the computational modelling of thermal ablative techniques, viz., RFA and MWA, as well as touch upon several promising avenues in the modelling of laser ablation, nanoparticles assisted magnetic hyperthermia and non- invasive RFA. The application of RFA in pain relief has been extensively reviewed from modelling point of view. Additionally, future directions have also been provided to improve these models for their successful translation and integration into the hospital work flow

Application of nanoparticles and nanomaterials in thermal ablation therapy of cancer

Cancer is one of the major health issues with increasing incidence worldwide. In spite of the existing conventional cancer treatment techniques, the cases of cancer diagnosis and death rates are rising year by year. Thus, new approaches are required to advance the traditional ways of cancer therapy. Currently, nanomedicine, employing nanoparticles and nanocomposites, offers great promise and new opportunities to increase the efficacy of cancer treatment in combination with thermal therapy. Nanomaterials can generate and specifically enhance the heating capacity at the tumor region due to optical and magnetic properties. The mentioned unique properties of nanomaterials allow inducing the heat and destroying the cancerous cells. This paper provides an overview of the utilization of nanoparticles and nanomaterials such as magnetic iron oxide nanoparticles, nanorods, nanoshells, nanocomposites, carbon nanotubes, and other nanoparticles in the thermal ablation of tumors, demonstrating their advantages over the conventional heating methods

Magnetoliposomes : effect of nanoparticles spatial distribution

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Física Teórica de la Materia Condensada. Fecha de lectura: 17-07-2019Esta tesis tiene embargado el acceso al texto completo hasta el 17-01-2021This thesis is focused on the design of nanocarries based on iron oxide nanoparticles and liposomes, that can be loaded with drugs for improving their targeting and efficiency. The combination of these two components represents a unique opportunity for achieving multiple therapeutic objectives. First of all it was studied the preparation and characterization of uniform iron oxide nanoparticles obtained by microwave assisted synthesis and compared them to those obtained by coprecipitation and thermal decomposition techniques, achieving core sizes from 8 to 15 nm (chapter 4.1). Selected samples were encapsulated in liposomes resulting in different spatial distributions: attached to the liposome surface, inside the lipid bilayer or inside the aqueous volume. Structural and magnetic characterization were also performed (chapter 4.2). The effect of the aggregation processes on magnetic properties have been analyzed in systems with different spatial distributions of the nanoparticles, as free nanoparticles, magnetoliposomes and cells incubated with nanoparticles (chapter 4.3). Finally, nanoparticles and magnetoliposomes are evaluated in-vitro to verify its limits of cytotoxicity in cells and then assessed as negative contrast agents for diagnosis with magnetic resonance imaging, for magnetic hyperthermia treatment and as carriers for doxorubicin, with controlled release by an applied alternate magnetic eld in different cell lines (chapter 4.4).Esta tesis se centra en el dise~no de nanoestructuras basado en nanopart culas de oxido de hierro y liposomas. Pueden transportar medicamentos mejorando su localizaci on y e ciencia. La combinaci on de estos dos componentes representa una oportunidad unica para lograr m ultiples objetivos terap euticos. En primer lugar, se estudi o la preparaci on y caracterizaci on de nanopart culas uniformes de oxido de hierro obtenidas atrav es de s ntesis por microondas y se compararon con las obtenidas mediante t ecnicas de coprecipitaci on y descomposici on t ermica, logrando tama~nos de n ucleo de 8 a 15 nm (cap. 4.1). Muestras seleccionadas se encapsularon en liposomas que dieron lugar a diferentes distribuciones espaciales de las nanoparticulas: unidas a la super cie del liposoma, dentro de la bicapa lip dica o dentro del volumen acuoso. Tambi en se realiz o la caracterizaci on estructural y magn etica (cap. 4.2). El efecto de los procesos de agregaci on en las propiedades magn eticas se ha analizado en sistemas con diferentes distribuciones espaciales de las part culas, como part culas libres, magnetoliposomas y c elulas incubadas con part culas (cap. 4.3). Finalmente, se eval uan las part culas y los magnetoliposomas in-vitro para veri car sus l mites de citotoxicidad en las c elulas y se analiza su posible aplicaci on como agentes de contraste negativo para el diagn ostico con im agenes de resonancia magn etica, para el tratamiento de hipertermia magn etica y como portadores de doxorubicina, con liberaci on controlada por un campo magn etico alterno aplicado en diferentes l neas celulares (cap. 4.4)

Nanomateriales para imagen molecular multimodal

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, leída el 05-09-2022The development of hybrid probes for multimodal molecular imaging is changing the diagnosis and characterisation of complex pathologies. The fusion of the outstanding sensitivity of positron emission tomography (PET) and the excellent anatomical resolution of magnetic resonance imaging (MRI), provides an ideal combination of structural and anatomical information, which is key to expand the application of molecular imaging for the diagnosis of complex and multifactorial diseases. Iron oxide nanoparticles (IONPs) have been traditionally used as negative (T2) contrast agents, darkening tissues or areas in which they accumulate. However, in recent years there has been a great amount of research focusing on the production of IONPs for positive (T1) contrast MRI. One of the most appealing properties that nanoparticles usually offer is the possibility of tailoring their synthesis and functionalisation to obtain probes that generate or enhance the signal in more than one imaging modality, via incorporation of moieties in the core or the surface of the nanoparticle. In this thesis, we developed a novel microwave-assisted method for the synthesis of IONPs coredoped with the positron emitter 68Ga and with relaxometric properties suitable for hybrid T1 MRI/PET imaging. Full characterisation revealed optimal radiochemical properties for PET imaging and excellent relaxometric properties for T1 MR imaging, demonstrating that the combined use of nanotechnology and radiochemistry can render an innovative tool for the dual imaging of biological processes in vivo...El desarrollo de sondas de imagen duales para imagen molecular es una posibilidad fascinante para el diagnóstico de enfermedades complejas. La fusión de la alta sensibilidad que ofrece la imagen de tomografía por emisión de positrones (PET por sus siglas en inglés) con la detallada información anatómica que ofrece la imagen por resonancia magnética (MRI por sus siglas en inglés) combina la obtención de imágenes con detallada información funcional y estructural, clave para extender el uso dela imagen molecular para el diagnóstico de enfermedades complejas y multifactoriales. Las nanopartículas de óxido de hierro (IONPs por sus siglas en inglés) se han usado tradicionalmente para imagen por resonancia T2, oscureciendo las áreas y órganos en los que se acumulan. Sin embargo, en los últimos años ha habido bastante investigación en la producción de IONPs para contraste positivo en imagen por resonancia magnética. Una de las propiedades más atractivas de las nanopartículas es la posibilidad de hacer una síntesis y funcionalización “a la carta” para obtener sondas que generan o ensalzan la señal en más de una modalidad de imagen, ya sea incorporando, por ejemplo, algún metal en su núcleo o biomolécula en su superficie. También hemos estudiado el efecto que tiene un metal dopante en el núcleo de las IONPs en sus propiedades relaxométricas y capacidades de contraste. En este caso usamos cobre y sintetizamos muestras con diferentes cantidades de dopaje. Obtuvimos tres muestras con capacidades de contraste y propiedades relaxométricas distintas. Llevamos a cabo experimentos in vivo de angiografía por resonancia magnética en ratón con las tres muestras que revelaron que nuestras nanopartículas son un candidato excelente para T1 MRI, mostrando unas propiedades relaxométricas y capacidad de contraste mejoradas con respecto a las IONPs sin dopar. Esta muestra dopada con cobre se dirigió a tumores mediante la conjugación de un péptido que se une a integrinas, obteniendo un excelente contraste parala detección de tumores en ratones por T1 MRI...Fac. de FarmaciaTRUEunpu

Dual-modality thermoacoustic and photoacoustic imaging

Diagnosis of early breast cancer is the key to survival. The combined contrasts from thermoacoustic and photoacoustic tomography: TAT and PAT) can potentially predict early stage breast cancer. We have designed and engineered a breast imaging system integrating both thermoacoustic and photoacoustic imaging techniques to achieve dual-contrast: microwave and light absorption), non-ionizing, low-cost, high-resolution, three-dimensional breast imaging. We have also developed a novel concept of using a negative acoustic lens to increase the acceptance angle of an unfocused large-area ultrasonic transducer: detector), leading to more than twofold improvement of the tangential resolution in both TAT and PAT when the object is far from the scanning center. A contrast agent could be greatly beneficial for early cancer diagnosis using TAT/PAT, because the early stage intrinsic contrast can be low. We have developed a carbon nanotube-based contrast agent for both TAT and PAT. In comparison with deionized water, single-walled carbon nanotubes: SWNTs) exhibited more than twofold signal enhancement for TAT at 3 GHz, and in comparison with blood, they exhibited more than sixfold signal enhancement for PAT at 1064 nm wavelength. Using PAT in conjunction with an intradermal injection of SWNTs, we also showed the feasibility of noninvasive in vivo sentinel lymph node imaging in a rat model. We have also developed and demonstrated molecular photoacoustic imaging using unique soft-type colloidal gold nanobeacons: GNBs) in the near-infrared region. GNBs represent a novel class of stable, colloidal gold nanoparticles, incorporating small metallic gold nanoparticles that can clear from the body when the particles are metabolically disrupted. We have also imaged the sentinel lymph node using different sizes of GNBs, showing that size plays an important role in their in vivo behavior and uptake to the lymph nodes. In addition to providing diagnostic imaging, TAT and PAT can be used in therapy for real-time temperature monitoring with high spatial resolution and high temperature sensitivity, which are both needed for safe and efficient thermotherapy. Using a tissue phantom, these noninvasive methods have been demonstrated to have a high temperature sensitivity of 0.15 0C at 2 s temporal resolution: 20 signal averages)