MRI-Based Tumour Targeting Enhancement with Magnetotactic Bacterial Carriers

RÉSUMÉ Le cancer constitue la première cause de mortalité au Québec, avec 20,000 décès estimés par année. Parmi tous les patients atteints du cancer, une grande proportion pourrait profiter de l’avancement technologique en ce qui concerne le transport de médicaments. En effet, l’un des meilleurs moyens d’augmenter l’efficacité d’un médicament contre le cancer, tout en réduisant sa toxicité sur les cellules saines, est de le diriger vers la tumeur et de le maintenir à cet endroit jusqu’à ce qu’un effet thérapeutique se produise. Le transport ciblé de médicaments vers la tumeur peut considérablement améliorer l’efficacité thérapeutique, surtout si le transporteur est capable d’atteindre les zones nécrotiques et se répartir uniformément dans la zone à traiter. Les bactéries, de par leur motilité, sont d’excellents candidats pour une telle application, surtout qu’elles peuvent aussi être facilement fonctionnalisées. Ainsi, la recherche sur le traitement du cancer utilisant des bactéries s’est imposée comme une approche prometteuse surtout qu’elle pallie à une limitation majeure de la chimiothérapie et de la radiothérapie en permettant le traitement des zones anaérobies. Alors que des laboratoires à travers le monde tentent de fabriquer des systèmes miniatures en se basant sur le modèle bactérien, nous avons opté pour l’utilisation des bactéries qui existent dans la nature. Notre stratégie a été de trouver un système biologique ayant les caractéristiques essentielles (e.x. diamètre total de moins de deux micromètres, force de poussée de plus de 4 pN, etc.) et de concentrer nos efforts à identifier une interface et une méthode permettant son contrôle pour des fins de ciblages thérapeutiques dans les lésions tumorales. Nous avons identifié les bactéries magnétotactiques de type MC-1 comme le meilleur transporteur potentiel de médicaments pour le ciblage du cancer. Les MC-1 sont à la fois dirigeables par champs magnétiques et anaérobies, ce qui leur donne un grand avantage par rapport aux bactéries traditionnellement utilisées pour le ciblage du cancer. Le ciblage du cancer avec des bactéries exploite le plus souvent l’affinité des bactéries anaérobies à la région nécrotique faible en oxygène de la tumeur. Certes, ce ciblage manque de spécificité et un des problèmes le plus reconnu est la nécessité d’injecter une forte dose de bactéries pour assurer une croissance de celles-ci à l’intérieur de la tumeur. Ceci n’est pas le cas avec les MC-1 car elles sont à la fois anaérobies et magnétotactiques grâce à une chaîne de nanoparticules d’environ 70 nanomètres de diamètre, formant une sorte de « nano-boussole » magnétique à----------ABSTRACT Magnetotactic Bacteria (MTB) are being explored as potential drug transporters to solid tumours. The MTB’s active motility combined with magnetotaxism (their ability to swim following the direction of a magnetic field) offer new and potentially more accurate solutions in delivering drugs to tumours. In fact, the flagella bundles of the MC-1 bacteria (with an overall ideal cell diameter of approximately 50% the diameter of the tiniest human blood vessels) provide 4.0 to 4.7pN of thrust force for propulsion (roughly 10 times the value of many other well-known flagellated bacteria). Since there are no existing methods or technologies capable of inducing an equivalent force on a carrier of appropriate size for traveling inside a tumour’s microvasculature, live microorganisms are considered as a viable option. Many of the parameters in a tumour microenvironment, such as malformed angiogenesis capillaries, heterogeneous blood flow, and high interstitial pressure, hinder the delivery of blood-borne drugs to the affected area. Active motility might prove to be helpful in bypassing these limitations and may facilitate the uniform distribution of the drug in the targeted area. An MTB navigation technique that allows targeting without prior knowledge of the exact architecture of the vessels network has been developed. This navigation technique exploits both the ability of the MTB to swim following an imposed magnetic field and their random, continuous motion at low magnetic fields. Firstly, a focused magnetic field on the target sets the overall direction of the bacteria. Then, as the bacteria approach the targeted zone, the intensity of the magnetic field is decreased, which allows better bacteria repartition by exploiting their free motion. An additional approach that enhances MTB targeting relies on modulating the magnetic field direction in time, while keeping the magnetic field lines pointed toward the target. Navigation experiments in complex micro-channel networks highlight this process, where the successful targeting of bacteria is demonstrated when an appropriate magnetic field algorithm is applied, especially when it takes into account the nature of the channel network. Tridimensional control and navigation of MTB is also possible with the same technique through proper powering of the magnetic coils. In fact, by controlling their magnetic environment, it is possible to form a swarm of MTB, control its size and position within a given volume using a computer program

Achieving commutation control of an MRI-powered robot actuator

Actuators that are powered, imaged, and controlled by magnetic resonance (MR) scanners could inexpensively provide wireless control of MR-guided robots. Similar to traditional electric motors, the MR scanner acts as the stator and generates propulsive torques on an actuator rotor containing one or more ferrous particles. Generating maximum motor torque while avoiding instabilities and slippage requires closed-loop control of the electromagnetic field gradients, i.e., commutation. Accurately estimating the position and velocity of the rotor is essential for high-speed control, which is a challenge due to the low refresh rate and high latency associated with MR signal acquisition. This paper proposes and demonstrates a method for closed-loop commutation based on interleaving pulse sequences for rotor imaging and rotor propulsion. This approach is shown to increase motor torque and velocity, eliminate rotor slip, and enable regulation of rotor angle. Experiments with a closed-loop MR imaging actuator produced a maximum force of 9.4 N

Usporedba fizikalno-kemijskih i senzorskih svojstava sireva u salamuri proizvedenih od mlijeka i mješavine mlijeka i maslinovog ulja

The present paper is focused on the physicochemical and sensory parameters of low-fat white brined cheese-like product obtained from the substitution of milk fat by milk-olive oil emulsion, in comparison with full and low-fat control cheeses. Formulated milk samples were initially pasteurized at 63 °C for 30 min, cooled down to 35 °C, and subsequently 0.35 mL L-1 of microbial rennet were added. The obtained cheeses were stored at 4 °C during 24 hours and then analyzed for physicochemical and sensory properties. The replacement of milk fat in white brined cheese resulted in a lower total solids content due to the higher water-binding capacity of fat replacers used. Fat content was significantly higher for low-fat white brined cheese-like product than in low-fat control cheese. This result was attributed to fat retention capacity of the fat replacers used. Lipolysis index was the highest in the case of low-fat white brined cheese-like product due to changes in cheese microstructure after fat replacers incorporation in low-fat products. Milk-olive oil emulsion showed the lowest cheese-making yield compared to its full and low-fat counterparts. The cheese like- product sample received a significantly lower overall impression score by the panelists than full and low-fat cheeses.Cilj ovog rada bio je usporediti fizikalno kemijska i senzorska svojstva posnih zamjena za sireve u salamuri proizvedenih od mješavine mlijeka i maslinovog ulja u odnosu na posne i punomasne sireve tog tipa. Pripremljeni uzorci mlijeka odnosno smjesa mlijeka i ulja pasterizirani su na 63 °C/30 min, ohlađeni na 35 °C te im je dodano 0,35 mL L-1 sirila mikrobnog porijekla. Proizvedeni uzorci sira čuvani su na 4 °C tijekom 24 sata te je potom provedena analiza fizikalno kemijskih i senzorskih svojstava. Zamjena mliječne masti uljem rezultirala je nižim udjelom suhe tvari uslijed veće sposobnosti vezanja vode od strane zamjenske masti. Udio masti je bio značajno viši u sirnim zamjenama nego u kontrolnom uzroku posnog sira, što se može povezati s kapacitetom zadržavanja masnoća od strane korištene zamjene za mliječnu mast. Najveći indeks lipolize zabilježen je u posnoj zamjeni za sir i to zbog promjena u mikrostrukturi sira koje su nastupile dodatkom zamjena za mliječnu mats i njihove ugradnje zamjenski proizvod. Mješavina maslinovog ulja i mlijeka odlikovala se najnižim prinosom sira, a tako proizvedena zamjena za sir dobila je značajno niže ocjene prilikom senzorskog ispitivanja u odnosu na punomasni i posni sir

Effects of industrial processing methods on camel skimmed milk properties

Effects of pasteurisation (high-temperature-short-time; HTST), ultra-high-temperature (UHT), and high-pressure (HP) treatments on some physical and chemical properties of camel milk (CM), including whey protein denaturation, colour change, casein micelle size, and rennet coagulation time (RCT), was investigated. UHT treatment caused the biggest colour change and highest whey protein denaturation in CM; in contrast, the effects of HP treatments on these properties were considerably less. Casein micelle size decreased after all treatments. The RCT of CM was significantly delayed and coagulum strength (G′) decreased after HTST. HP treatment at 200 and 400 MPa increased the RCT of CM and the G′ value was the highest after treatment at 200 MPa. Processing at 600 and 800 MPa inhibited coagulation of CM. The effects of both thermal and non-thermal treatments on many constituents and properties of CM were different from those on constituents and properties of bovine milk

Enabling automated magnetic resonance imaging-based targeting assessment during dipole field navigation

The magnetic navigation of drugs in the vascular network promises to increase the efficacy and reduce the secondary toxicity of cancer treatments by targeting tumors directly. Recently, dipole field navigation (DFN) was proposed as the first method achieving both high field and high navigation gradient strengths for whole-body interventions in deep tissues. This is achieved by introducing large ferromagnetic cores around the patient inside a magnetic resonance imaging (MRI) scanner. However, doing so distorts the static field inside the scanner, which prevents imaging during the intervention. This limitation constrains DFN to open-loop navigation, thus exposing the risk of a harmful toxicity in case of a navigation failure. Here, we are interested in periodically assessing drug targeting efficiency using MRI even in the presence of a core. We demonstrate, using a clinical scanner, that it is in fact possible to acquire, in specific regions around a core, images of sufficient quality to perform this task. We show that the core can be moved inside the scanner to a position minimizing the distortion effect in the region of interest for imaging. Moving the core can be done automatically using the gradient coils of the scanner, which then also enables the core to be repositioned to perform navigation to additional targets. The feasibility and potential of the approach are validated in an in vitro experiment demonstrating navigation and assessment at two targets

Biohybrid microtube swimmers driven by single captured bacteria

Bacteria biohybrids employ the motility and power of swimming bacteria to carry and maneuver microscale particles. They have the potential to perform microdrug and cargo delivery in vivo, but have been limited by poor design, reduced swimming capabilities, and impeded functionality. To address these challenge, motile Escherichia coli are captured inside electropolymerized microtubes, exhibiting the first report of a bacteria microswimmer that does not utilize a spherical particle chassis. Single bacterium becomes partially trapped within the tube and becomes a bioengine to push the microtube though biological media. Microtubes are modified with "smart" material properties for motion control, including a bacteria-attractant polydopamine inner layer, addition of magnetic components for external guidance, and a biochemical kill trigger to cease bacterium swimming on demand. Swimming dynamics of the bacteria biohybrid are quantified by comparing "length of protrusion" of bacteria from the microtubes with respect to changes in angular autocorrelation and swimmer mean squared displacement. The multifunctional microtubular swimmers present a new generation of biocompatible micromotors toward future microbiorobots and minimally invasive medical applications

Flow cytometry as a rapid analytical tool to determine physiological responses to changing O2 and iron concentration by Magnetospirillum gryphiswaldense strain MSR-1

Magnetotactic bacteria (MTB) are a diverse group of bacteria that synthesise magnetosomes, magnetic membrane-bound nanoparticles that have a variety of diagnostic, clinical and biotechnological applications. We present the development of rapid methods using flow cytometry to characterize several aspects of the physiology of the commonly-used MTB Magnetospirillum gryphiswaldense MSR-1. Flow cytometry is an optical technique that rapidly measures characteristics of individual bacteria within a culture, thereby allowing determination of population heterogeneity and also permitting direct analysis of bacteria. Scatter measurements were used to measure and compare bacterial size, shape and morphology. Membrane permeability and polarization were measured using the dyes propidium iodide and bis-(1,3-dibutylbarbituric acid) trimethine oxonol to determine the viability and ‘health’ of bacteria. Dyes were also used to determine changes in concentration of intracellular free iron and polyhydroxylakanoate (PHA), a bacterial energy storage polymer. These tools were then used to characterize the responses of MTB to different O2 concentrations and iron-sufficient or iron-limited growth. Rapid analysis of MTB physiology will allow development of bioprocesses for the production of magnetosomes, and will increase understanding of this fascinating and useful group of bacteria

Techniques de positionnement d'objets ferromagnétiques en IRM

Robot endovasculaire -- Intervention endoscopique guidée par IRM -- Capteurs magnétiques -- Magnétisme et localisation de source par mesure du champ magnétique -- Susceptibilité et perméabilité -- Modèle mathématique d'une sphère uniformément magnétisée -- Mesure du champ magnétique -- Localisation avec des capteurs magnétiques -- Principe de l'imagerie par résonance magnétique -- Image d'amplitude d'une sphère ferromagnétique -- Image de phase -- Image de projection -- Reconstruction d'image -- Localisation par IRM -- Localisation de l'imagerie d'amplitude -- Localisation par images de phase -- Localisation par images de projection