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Quantification of Blood Flow Using Ultrasound Contrast AgentsHudson, John Monte 31 August 2011 (has links)
Contrast enhanced ultrasound offers a unique method to measure the blood flow, perfusion, vascular volume and morphology of microvascular networks. This is achieved by exploiting the ability of microbubble contrast agents to be disrupted and preferentially detected with contrast specific imaging techniques – using a method known as disruption-replenishment. In its current form, disruption-replenishment suffers from poor reproducibility and accuracy, largely due to the inappropriate application of a mono-exponential model of microbubble replenishment, and an incomplete understanding of the dependencies of the measurement.
In this thesis, we hypothesize that disruption-replenishment measurements can be improved by applying a perfusion model that considers the physical elements of the measurement, including the haemodynamics and morphology of the vascular system, the ultrasound field distribution and microbubble properties. We present a flexible, theoretical framework to model microbubble replenishment within the microvasculature. The replenishment model is further developed by in vitro and in vivo validation, and clinical translation in a trial of anti-angiogenic therapy in patients, resulting in a proposed clinical protocol.
The presented formalism was shown to be more robust and demonstrated better agreement of both fitting quality and estimates of flow velocity when compared to the established model (accuracy to within 3-9%). The reproducibility of repeated in vivo disruption-replenishment flow measurements was 11.9% using the proposed perfusion model compared to 24% using the established model. Variability of clinical perfusion measurements was also reduced with a method that discards the contribution of flow from larger arteries. Excluding the large vessel component in clinical measurements of tumour blood volume decreased the inter-plane variability by up to 20%. The proposed perfusion model can be used to generate parametric maps of vascularity through which additional quantitative parameters become available. These improvements will help translate the method of disruption-replenishment into routine clinical practice and clinical trials.
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Quantification of Blood Flow Using Ultrasound Contrast AgentsHudson, John Monte 31 August 2011 (has links)
Contrast enhanced ultrasound offers a unique method to measure the blood flow, perfusion, vascular volume and morphology of microvascular networks. This is achieved by exploiting the ability of microbubble contrast agents to be disrupted and preferentially detected with contrast specific imaging techniques – using a method known as disruption-replenishment. In its current form, disruption-replenishment suffers from poor reproducibility and accuracy, largely due to the inappropriate application of a mono-exponential model of microbubble replenishment, and an incomplete understanding of the dependencies of the measurement.
In this thesis, we hypothesize that disruption-replenishment measurements can be improved by applying a perfusion model that considers the physical elements of the measurement, including the haemodynamics and morphology of the vascular system, the ultrasound field distribution and microbubble properties. We present a flexible, theoretical framework to model microbubble replenishment within the microvasculature. The replenishment model is further developed by in vitro and in vivo validation, and clinical translation in a trial of anti-angiogenic therapy in patients, resulting in a proposed clinical protocol.
The presented formalism was shown to be more robust and demonstrated better agreement of both fitting quality and estimates of flow velocity when compared to the established model (accuracy to within 3-9%). The reproducibility of repeated in vivo disruption-replenishment flow measurements was 11.9% using the proposed perfusion model compared to 24% using the established model. Variability of clinical perfusion measurements was also reduced with a method that discards the contribution of flow from larger arteries. Excluding the large vessel component in clinical measurements of tumour blood volume decreased the inter-plane variability by up to 20%. The proposed perfusion model can be used to generate parametric maps of vascularity through which additional quantitative parameters become available. These improvements will help translate the method of disruption-replenishment into routine clinical practice and clinical trials.
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The use of ultrasound-targeted microbubble destruction in mediated delivery of a gadolinium-based magnetic resonance imaging contrast agent into fibroblast cells in vitroRussell, C. Hunter, III. January 2004 (has links) (PDF)
Thesis (M.S.) -- University of Texas Southwestern Medical Center at Dallas, 2003. / Vita. Bibliography: 45-46.
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Ultrasound-mediated vascular bioeffects : applications for hemostasis and sclerotherapy /Hwang, Joo Ha. January 2005 (has links)
Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 121-133).
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Acoustical behavior of single ultrasound contrast agent microbubbles / Ηχητική απόκριση των μικροφυσαλίδων ενίσχυσης της αντίθεσης στην υπερηχοτομογραφίαΔερμιτζάκης, Αριστείδης 19 April 2010 (has links)
Ultrasound contrast agents (UCA) is a relatively new tool, used in medical
ultrasound imaging to enhance the diagnostic abilities of ultrasound and potentially offer a therapeutic value in medical ultrasounds. UCAs are bi or single-layered bubbles, that
contain a highly backscattering gas. By injecting them into the blood flow, we locally increase the echogenicity and therefor enhance the contrast of the blood-tissue interface.
This way we can provide a improved image of the structure of the organs, we can more
accurately diagnose abnormal of defected areas on them, and if the containing gas is
replaced with an appropriate drug, focus drug delivery can be achieved, providing potential healing of the disease.
! Up to now, most of the studies done in order to investigate the microbubbles -
ultrasound interaction are mostly population studies, which due to their roughly approach
cannot clearly diagnose and explain the complex nonlinear and dynamic properties of
UCAs and their response to ultrasound field. Because of that, our knowledge on the
UCAsʼ, is yet limited although the potential improvements at imaging and therapeutic
technics that would be gained from a thorough understanding of this interactions can be very big.
! In this thesis, a study of single microbubbles is presented, using a system
developed by the group of Ultrasound imaging in Edinburgh University. The system uses a
specially modified commercial ultrasound machine, phased array probes and a specially
designed single microbubbles measuring system. The system has the ability to feed,
insonify and capture the backscattered echo from a single microbubble, with the use of
fully calibrated and characterized ultrasound - probe system. The aim of the project is to
contribute in the understanding of the behavior of the UCAs when insonified with an
ultrasound wave, and the underlying physical mechanism behind that.
The response of two different commercially available UCAs under insonification by
ultrasound waves of varying acoustical pressure is presented. The UCAs used are Definity
and biSphere. In total echoes from 842 biSphere and 1994 Definity microbubbles have
ben captured and the data have been analyzed with in house made matlab codes.
Also the response of the bubbles when insonified by consequent pulses of different
repetition frequency has been investigated. For this reason, echoes from other 1221
Definity and 459 biSphere microbubbles have been captured and analyzed.
The fully understanding of the agent - ultrasound interaction mechanisms can be the basis
for creating improved signal processing tools for ultrasound imaging contrast enhancement
that would improve imaging abilities of the modality, and potentially use of UCAs as a
therapeutic mean. / Οι μικροφυσαλίδες ενίσχυσης της αντίθεσης στην υπερηχοτομογραφία είναι
ένα σχετικά καινούργιο “εργαλείο”, το οποίο χρησιμοποιείται προκειμένου να
βελτιώσει τις διαγνωστικές ιδιότητες της υπερηχοτομογραφίας και δυνητικά να
προσφέρει μια θεραπευτική αξία σε αυτήν. Οι μικροφυσαλίδες είναι φυσαλίδες
μονού ή διπλού κελύφους, με διάμετρο της τάξης των 3 μm, οι οποίες περιέχουν
αέριο που αντανακλά έντονα τον ήχο. Εισάγοντας τις φυσαλίδες αυτές στην ροή
του αίματος του ασθενούς, ενισχύουμε τοπικά την ηχογένεια και κατ΄ επέκταση
βελτιώνουμε την αντίθεση μεταξύ του αίματος και των παρακείμενων ιστών. Με
αυτό τον τρόπο μπορούμε να αποκτήσουμε μια καλύτερη εικόνα της δομής των
οργάνων, να διαγνώσουμε με ακρίβεια την παθοφυσιολογία συγκεκριμένων
περιοχών πάνω σε αυτά και, εάν το αέριο των φυσαλίδων αντικατασταθεί με την
κατάλληλη φαρμακευτική ουσία, να επιτύχουμε στοχευμένη εφαρμογή της
φαρμακευτικής θεραπείας, οδηγώντας σε πιθανή ίαση της ασθένειας.
! Μέχρι τώρα, το μεγαλύτερο μέρος των μελετών που έχουν γίνει με σκοπό
την διερεύνηση της αλληλεπίδρασης των φυσαλίδων με τους υπερήχους
βασίζονται σε πληθυσμιακές μελέτες, οι οποίες λόγω της γενικής (σε επίπεδο
πληθυσμού) προσέγγισής τους, δεν μπορούν με σαφήνεια να διαγνώσουν και να
εξηγήσουν τις σύνθετες μη γραμμικές και δυναμικές ιδιότητες των
μικροφυσαλίδων, καθώς και την συμπεριφορά τους όταν βρεθούν μέσα στο
υπερηχητικό πεδίο. Εξαιτίας αυτού, η γνώση μας σχετικά με τις μικροφυσαλίδες
ενίσχυσης της αντίθεσης είναι ακόμα περιορισμένη, αν και οι πιθανές βελτιώσεις
τόσο στις απεικονιστικές όσο και στις θεραπευτικές τεχνικές των υπερήχων που θα
μπορούσαν να επιτευχθούν μέσα από την κατανόηση αυτής της αλληλεπίδρασης θα
ήταν ιδιαίτερα σημαντικές.
! Σε αυτή την εργασία, παρουσιάζεται μια μελέτη των μικροφυσαλίδων όχι σε
επίπεδο πληθυσμού αλλά σε επίπεδο μονάδας, η οποία έγινε με την χρήση μιας
καινοτόμου πειραματικής διάταξης που αναπτύχθηκε από την ομάδα
Υπερηχοτομογραφίας του Πανεπιστήμιου του Εδιμβούργου. Η διάταξη αυτή
χρησιμοποιεί έναν ειδικά τροποποιημένο εμπορικό υπερηχοτομογράφο, phased
array εκπομπούς, και ένα επίσης ειδικά κατασκευασμένο σύστημα μέτρησης της
απόκρισης των μιρκοφυσαλίδων σε επίπεδο μονάδας. Το σύστημα αυτό έχει την
δυνατότητα να εισάγει, να διεγείρει με υπερήχους, καθώς και να συλλέγει την
ανάκλαση από τις μικροφυσαλίδες, μία προς μία. Σκοπός της εργασίας αυτής είναι
να συμβάλει όσο το δυνατόν περισσότερο στην κατανόηση της συμπεριφοράς των
μικροφυσαλίδων όταν αυτές διεγείρονται από υπερηχητικά κύματα, καθώς και των
υπεύθυνων, για την συμπεριφορά αυτή, φυσικών μηχανισμών.
! Στην παρούσα εργασία παρουσιάζεται η απόκριση δυο διαφορετικών
εμπορικά διαθέσιμων τύπων μικροφυσαλίδων, σε υπερηχητικά κύματα
διαφορετικών ακουστικών πιέσεων. Οι μικροφυσαλίδες που χρησιμοποιήθηκαν είναι
οι Definity και οι biSphere. Συνολικά, η ανάκλαση από 842 biSphere και 1994 Definity
μικροφυσαλίδες έχει καταγραφεί, και τα δεδομένα έχουν αναλυθεί με κώδικα
Matlab, ο οποίος αναπτύχθηκε στο εργαστήριο ειδικά για την ανάλυση αυτή.
! Επίσης, ερευνάται η απόκριση των φυσαλίδων όταν διεγείρονται από
αλλεπάληλους υπερηχητικούς παλμούς, διαφορετικών συχνοτήτων επανάληψης. Για τον σκοπό αυτό, καταγράφηκαν και αναλύθηκαν ανακλάσεις από ακόμα 1221
Definity και 459 biSphere μικροφυσαλίδες.
! Η πλήρης κατανόηση της αλληλεπίδρασης των μικροφυσαλίδων με τους
υπερήχους μπορεί να αποτελέσει την βάση για την ανάπτυξη βελτιωμένων
τεχνικών επεξεργασίας σήματος για την απεικονιστική υπεηχοτομογραφία, οι
οποίες μπορούν να βελτιώσουν τις δυνατότητες των υπερήχων, και δυνητικά να
μετατρέψουν τις μικροφυσαλίδες ενίσχυσης σε ένα μέσο ίασης ασθενειών.
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Super resolution techniques for the analysis of ultrasound signals / Τεχνικές υψηλής διακριτικής ικανότητας για την ανάλυση σημάτων υπερηχοτομογραφίαςΔιαμαντής, Κωνσταντίνος 09 January 2012 (has links)
In ultrasound contrast imaging, the discrimination between acoustic echoes from tissue and contrast microbubbles would have as a result the increase of the Contrast-to-Tissue-Ratio, improving therefore the quality of the imaging. The main idea is to differentiate the responses from those two kinds of signals based on their spectral content. The most important features of those sinusoidal signals are that they are very short in duration and than they are very likely to have many closely spaced frequency components. So, in order to achieve this target a novel Bayesian parametric spectral estimation technique has been originally designed by Yan Yan (PhD University of Edinburgh), that is supposed to have greater resolving capabilities than commonly used spectral estimation methods. The new technique uses a reversible jump Markov Chain Monte Carlo (rjMCMC) algorithm so as to identify the frequency components of a signal and it is called parametric because it assumes a model and then the problem of spectral estimation is reduced to that of estimating the parameters of the model.
This new method has been initially tested with synthetic signals created in Matlab, so as to define on which parameters it depends and to extract mathematical equations that describe these dependences. And although some coarse comparisons with other techniques showed that the capabilities of this method were great, there was plenty room for improvements. Corrections in the Matlab code of this method, analysis of the code’s output in various ways so as to find which is superior, and the proposal of a new simpler model are just some of the changes that have evidently improved the method’s function. But the most important one is the completion of the amplitude estimation that was left unfinished in the past, as a complete spectral analysis implies both frequency and amplitude estimation. Now, signal reconstruction is possible and also, direct comparisons of the method’s resulting spectrum with the one of the Discrete Fourier Transform or of any other nonparametric (DFT-based) or parametric method can be made. The new version of the code has been applied apart from synthetic signals, to the real ones providing indeed information that was undisclosed in the past concerning the spectral content of those signals. However, further research is required, in order to take advantage of this information and in order to determine the exact performance and limitations of this method that remains still in experimental level. / Στην απεικόνιση με υπέρηχους όταν χρησιμοποιείται μέσο αντίθεσης, ο διαχωρισμός ανάμεσα στην ακουστική ηχώ που προέρχεται από τον ιστό και σε αυτή που προέρχεται από τo μέσο αντίθεσης όπως οι μικροφυσαλίδες, θα μπορούσε να έχει σαν αποτέλεσμα τη βελτίωση της ποιότητας της εικόνας. Η βασική ιδέα είναι να διαφοροποιηθούν οι αποκρίσεις από τα δύο διαφορετικά είδη σημάτων υπερηχοτομογραφίας με βάση το φασματικό τους περιεχόμενο. Τα κυριότερα χαρακτηριστικά αυτών των ημιτονοειδών σημάτων είναι ότι είναι πολύ μικρά σε χρονική διάρκεια και ότι είναι πολύ πιθανό να αποτελούνται από συχνοτικές συνιστώσες που βρίσκονται πολύ κοντά μεταξύ τους. Έτσι, για την επίτευξη αυτού του στόχου, μία καινούρια Μπαγιεσιανή παραμετρική μέθοδος για συχνοτική ανάλυση σχεδιάστηκε αρχικά από την Yan Yan (PhD Πανεπιστήμιο του Εδιμβούργου), η οποία θεωρητικά παρέχει μεγαλύτερη ακρίβεια από τις υπόλοιπες συμβατικές μεθόδους που ήδη χρησιμοποιούνται. Η τεχνική αυτή, κάνει χρήση ενός συγκεκριμένου αλγορίθμου (rjMCMC) έτσι ώστε να προσδιορίσει τις συχνοτικές συνιστώσες ενός σήματος και καλείται παραμετρική επειδή υποθέτει ένα αρχικό μοντέλο και στη συνέχεια «υποβιβάζει» το πρόβλημα της συχνοτικής ανάλυσης σε ένα πιο απλό, όπως αυτό του υπολογισμού των παραμέτρων του μοντέλου.
Αρχικά, η μέθοδος δοκιμάστηκε σε συνθετικά σήματα, που δημιουργήθηκαν στο Matlab, ούτως ώστε να προσδιοριστούν οι παράμετροι από τις οποίες εξαρτάται και να εξαχθούν μαθηματικές εξισώσεις που να περιγράφουν τις εξαρτήσεις αυτές. Αν και από τις πρώτες συγκρίσεις με άλλες μεθόδους ήταν φανερό ότι η συγκεκριμένη έχει πολύ μεγάλες δυνατότητες, υπήρχαν πολλά περιθώρια βελτίωσης. Διορθώσεις στον κώδικα Matlab της μεθόδου, ανάλυση της εξόδου του με διάφορους τρόπους με σκοπό να προσδιοριστεί ο πιο αποτελεσματικός και η πρόταση ενός νέου πιο απλού μοντέλου είναι κάποιες από τις αλλαγές που αποδεδειγμένα βελτίωσαν τη λειτουργία της μεθόδου. Αλλά η πιο σημαντική αλλαγή είναι η ολοκλήρωση του κώδικα έτσι ώστε να περιλαμβάνει και προσδιορισμό των πλατών που αντιστοιχούν σε κάθε μια συχνότητα. Ο κώδικας για την εκτίμηση των πλατών αν και προϋπήρχε ως ένα βαθμό, δεν είχε ενσωματωθεί στον κυρίως κώδικα και έτσι η μέθοδος δεν μπορούσε να χαρακτηριστεί ολοκληρωμένη. Τώρα η ανακατασκευή σήματος είναι εφικτή καθώς και οι άμεσες συγκρίσεις του φάσματος της μεθόδου με το αντίστοιχο που προκύπτει από τον διακριτό μετασχηματισμό Fourier ή από άλλες μη παραμετρικές και παραμετρικές μεθόδους. Η καινούρια έκδοση του κώδικα εφαρμόστηκε, εκτός από τα συνθετικά σήματα, στα πραγματικά σήματα παρέχοντας πράγματι πληροφορίες που δεν είχαν φανερωθεί στο παρελθόν, σχετικά με το φασματικό περιεχόμενο των σημάτων αυτών. Ωστόσο, περαιτέρω έρευνα απαιτείται για να αξιοποιηθούν οι πληροφορίες αυτές αλλά και για να προσδιοριστούν οι ακριβείς περιορισμοί και οι επιδόσεις της μεθόδου που ακόμα και τώρα παραμένει σε πειραματικό στάδιο.
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Thérapie par ultrasons et microbulles : application au transfert de gènes. / Therapy with ultrasound and microbubbles : application to gene transferKaddur, Kadija 11 September 2009 (has links)
Des études récentes ont démontré que les activités des agents de contraste ultrasonoresous l’effet des ultrasons modulent transitoirement la perméabilité de la membraneplasmique des cellules. Ce procédé aussi appelé sonoporation est étudié pour incorporer desmolécules extracellulaires telles que des gènes thérapeutiques. Le but de la thèse fut d’étudierl’effet des paramètres acoustiques et expérimentaux pour une transfection efficace des cellulesin vitro et in vivo. Parallèlement, afin de clarifier le mécanisme de perméabilisation induit lorsde la sonoporation, nous avons, d’une part, étudié l’effet des ultrasons et des microbulles surla libération de molécules intracellulaires et d’autre part, observé en microscopie électroniqueles effets des ultrasons et des microbulles sur la membrane plasmique et sur l’incorporation denanoparticules d’or. / Future applications of ultrasound and microbubbles extend beyond imaging applications.Over the last few years, reports have shown that the activation of contrast microbubblesunder ultrasound waves, transiently modulates the cell membrane permeability. This process,named sonoporation has been studied to incorporate extracellular molecules such as therapeuticgenes. The aim of this work was to study the effect of various interrogation parameters toachieve an efficient cell transfection in vitro as well as in vivo. In parallel, and in order to clarifythe mechanism of permeabilization induced by sonoporation, we investigated the effect ofultrasound and microbubbles on release of intracellular molecules from fluorescent cells. Moreover,using electron microscopy, we examined the effect of the sonoporation process on thecell membrane and on incorporation of gold nanoparticles.
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Development, Characterization, and Implementation of a System for Focused Ultrasound-Mediated Blood-Brain Barrier Opening In MiceValdez, Michael Aaron, Valdez, Michael Aaron January 2017 (has links)
The blood-brain barrier BBB refers to the set of specialized endothelial cells that line the vasculature in the brain and effectively control movement of molecules into and out of the brain. While necessary for proper brain function, the BBB blocks 98% of drugs from entering the brain and is the most significant barrier to developing therapies for neurodegenerative diseases. Active transport allows some specific molecules to cross the BBB, but therapeutic development using this route has had limited success. A number of techniques have been used to bypass the BBB, but are often highly invasive and ineffective. Over the last two decades, a minimally invasive technique to transiently open the BBB has been under development that utilizes transcranial focused ultrasound (FUS) in combination with intravascular microbubble contrast agents. This method is often carried out in conjunction with magnetic resonance imaging (MRI) to guide and assess BBB opening and has been referred to as MRI guided FUS (MRgFUS).
Because of the utility of mouse models of neurological disease and the exploratory nature of MRgFUS, systems that allow BBB opening in mice are a useful and necessary tool to develop and evaluate this method for clinical application. In this dissertation project, a custom built, cost-effective FUS system for opening the BBB in mice was developed, with the objective of using this device to deliver therapeutics to the brain. Being a custom device, it was necessary to evaluate the ultrasound output, verify in vivo safety, and anticipate the therapeutic effect. The scope of the work herein consists of the design, construction, and evaluation of system that fulfills these requirements. The final constructed system cost was an order of magnitude less than any commercially available MRgFUS system. At this low price point, the hardware could allow the implementation of the methodology in many more research areas than previously possible. Additionally, to anticipate the therapeutic effect, molecules of pharmacologically-relevant sizes were delivered to brain with a novel, multispectral approach. Results demonstrated that the device was able to safely open the BBB, and macromolecule delivery showed that both molecule size and FUS pressure both influence the amount and distribution of molecules in the brain. Using different ultrasound pressures, the threshold for BBB opening was found to be ≥ 180 kPa (0.13 MI). The threshold for damage was found to be ≥ 420 kPa (0.30 MI), and was minor at this pressure, but extensive for higher pressure (870 kPa, 0.62 MI), in which minor damage was caused by this pressure. Performing a novel implementation of a diffusion model on the fluorescence images of 500, 70, and 3 kDa dextran resulted in calculated diffusion coefficients of 0.032 ± 0.015, 12 ± 6.0, and 0.13 ± 0.094 square microns per second, respectively.
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Non-destructive Evaluation of Ultrasound Contrast Agent / Icke-destruktiv utvärdering av ultraljudskontrastmedelLöffler, Wendi January 2019 (has links)
Clinical ultrasound imaging techniques can be greatly improved by the use of ultrasound contrast agents (UCAs). While microbubbles (MBs) without shell are unstable and cannot be used for practical applications,a shell produced from biocompatible polyvinylalcohol (PVA) significantly improves chemical versatility and stability. The oscillation characteristics of a UCA are strongly dependent on concentration, applied pressure and viscoelastic parameters of the shell. Modifications in the shell as incorporation of antibodies or targeted molecules affect the bubble oscillation and resonance frequency of the MB suspension. In this presented work a tool for systematic characterization of UCAs is developed. Linear acoustic behaviour of PVA shelled MBs is examined. The acoustic driving pressure is kept below 100 kPa. The MB concentration is 1·10^{6} ml^{-1}. Attenuation and phase velocity profiles of ultrasound waves propagating through the UCA are measured using six narrow-band single crystal transducers that cover a frequency range between 1 and 15 MHz. The oscillation of a single bubble is modeled as a linear oscillator adapting HOFF’s model suitable for allshell thicknesses. The suspension is modeled through superposition of single bubbles. Knowing all parameters the resonance frequency of a MB suspension can be predicted. The model is fitted to experimental data to determine the viscoelastic shell parameters. The shell thickness is challenging to determine exactly and assumed to be either proportional to the outer shell radius or constant. Assuming a proportional shell thickness the calculated resulting shell parameters were shear modulus G_s = 14.5 MPa, shear viscosity η_s = 0.322 Pa·s and shell thickness d_s = 16 % of the outer radius. When instead assuming a constant shell thickness the determined parameters were in similar order of magnitude. Resonance frequency of the suspension was determined to 11.6 MHz. The developed tool can be used to characterize MBs with a modified shell independently of shell thickness and to predict resonance frequency of gas or air filled UCAs with known shell parameters.
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The Development and Evaluation of Multi-Modal Microbubbles and New Strategies for Targeted Ultrasound, Nuclear and Optical ImagingZlitni, Aimen January 2016 (has links)
Gas filled microbubbles (MBs) stabilized by a shell (e.g. lipids) are commonly used as ultrasound (US) contrast agents. Attaching biomolecules to the surface of MBs allows for molecular US imaging of various diseases. With the increased interest in targeted US imaging, new platforms to prepare disease-targeted MBs are necessary. Furthermore, attaching signaling agents to MBs creates multi-modal imaging opportunities, enhancing visualization and quantification of disease biomarkers.
In this thesis, MBs labeled with 99mTc and/or rhodamine dye by taking advantage of the strong interaction between biotin and streptavidin are reported. Radiolabeling of MBs was achieved in good radiochemical yield (~ 30%). 99mTc-labeled MBs were targeted to vascular endothelial growth factor receptor 2 (VEGFR2) using an anti-VEGFR2 antibody and to prostate specific membrane antigen (PSMA) using small-molecule based PSMA inhibitors. In vitro evaluations showed successful binding of MBs to the target while in vivo targeting assessments were unsuccessful.
New strategies to target MBs to the site of interest were then developed through the use of the bioorthogonal reaction between tetrazine (Tz) and trans-cyclooctene (TCO). A biotinylated derivative of Tz was loaded on streptavidin coated MBs to create a Tz-derivatized MB (MBTz). Targeting MBTz to extracellular markers of cancer such as VEGFR2, PSMA and urokinase plasminogen activator receptor (uPAR) in vitro was achieved using TCO-conjugated antibodies. In vivo targeting was successful for VEGFR2 and PSMA, but not uPAR.
Translating the new strategy to other US contrast agents was then investigated. Gas vesicles (GVs) produced in halobacteria were conjugated with TCO using amide-coupling chemistry. A 99mTc-labeled derivative of Tz was loaded on TCO-GVs (RCY= 59%) and their distribution assessed by SPECT/CT imaging and ex vivo tissue counting. Having established a convenient platform to conjugate molecules to GVs and MBs, future work focuses on developing a new generation of human compatible molecular US imaging probes. / Dissertation / Doctor of Philosophy (PhD)
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