Teses / dissertações: "Ultrasound drug delivery"

1

Zderic, Vesna. "Ultrasound-enhanced ocular drug delivery /". Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/8085.

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2

Sutton, Jonathan T. "Tissue Bioeffects during Ultrasound-Mediated Drug Delivery". University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397234692.

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3

Diaz, de la Rosa Mario Alfonso. "High-frequency ultrasound drug delivery and cavitation /". Diss., CLICK HERE for online access, 2007. http://contentdm.lib.byu.edu/ETD/image/etd1679.pdf.

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4

Diaz, Mario Alfonso. "High-Frequency Ultrasound Drug Delivery and Cavitation". BYU ScholarsArchive, 2007. https://scholarsarchive.byu.edu/etd/1050.

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The viability of a drug delivery system which encapsulates chemotherapeutic drugs (Doxorubicin) in the hydrophobic core of polymeric micelles and triggers release by ultrasound application was investigated at an applied frequency of 500 kHz. The investigation also included elucidating the mechanism of drug release at 70 kHz, a frequency which had previously been shown to induce drug release. A fluorescence detection chamber was used to measure in vitro drug release from both Pluronic and stabilized micelles and a hydrophone was used to monitor bubble activity during the experiments. A threshold for release between 0.35 and 0.40 in mechanical index was found at 70 kHz and shown to correspond with the appearance of the subharmonic signal in the acoustic spectrum. Additionally, drug release was found to correlate with increase in subharmonic emission. No evidence of drug release or of the subharmonic signal was detected at 500 kHz. These findings confirmed the role of cavitation in ultrasonic drug release from micelles. A mathematical model of a bubble oscillator was solved to explore the differences in the behavior of a single 10 um bubble under 70 and 500 kHz ultrasound. The dynamics were found to be fundamentally different; the bubble follows a period-doubling route to chaos at 500 kHz and an intermittent route to chaos at 70 kHz. It was concluded that this type of "intermittent subharmonic" oscillation is associated with the apparent drug release. This research confirmed the central role of cavitation in ultrasonically-triggered drug delivery from micelles, established the importance of subharmonic bubble oscillations as an indicator, and expounded the key dynamic differences between 70 and 500 kHz ultrasonic cavitation.

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5

Mualem-Burstein, Odelia Wheatley Margaret A. "Drug loading onto polymeric contrast agents for ultrasound drug delivery /". Philadelphia, Pa. : Drexel University, 2008. http://hdl.handle.net/1860/2811.

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6

Dwaikat, Mai Al. "The Effect of Ultrasound on Transdermal Drug Delivery". Thesis, Coventry University, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492372.

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7

Mitragotri, Samir. "Ultrasound-mediated transdermal drug delivery : mechanisms and applications". Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/11263.

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8

Fowler, Robert Andrew. "Inertial Cavitation with Confocal Ultrasound for Drug Delivery". Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10024.

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Il a été montré que la cavitation acoustique pouvait se révéler utile dans l'administration de médicaments pour de nombreuses applications biologiques et médicales. Cette thèse commence par une présentation de la cavitation ultrasonore et des mécanismes d'action mis en jeu pour la délivrance de médicaments. A la fin de ce cette synthèse, un dispositif à deux transducteurs ultrasonores disposés de manière confocale est présenté pour résoudre certains des problèmes actuels dans le domaine. Il est ensuite mis en oeuvre dans différentes études de faisabilité. La thèse est organisée en 5 chapitres : 1. L'utilisation de la cavitation acoustique dans un contexte biomédical est présentée ici dans une revue générale. Ce chapitre comprend l'état de l'art pour la génération de cavitation, les techniques expérimentales qui sont actuellement mises en oeuvre pour la mesure de la cavitation, et les approches cliniques et précliniques pour l'utilisation de la cavitation in vivo pour différents types de tissu biologique. 2. Le dispositif ultrasonore utilisé pour toutes les études de cette thèse est ensuite décrit. Il est caractérisé acoustiquement et comparé avec un simple transducteur dans le but de démontrer son efficacité pour la génération de la cavitation. Cette comparaison est d'abord faite par une quantification chimique du niveau de cavitation. A puissance constante, le dispositif à deux transducteurs confocaux est bien plus efficace pour générer de la cavitation. Les causes de cette observation, notamment la réduction de la propagation non-linéaire et la stabilisation du nuage des bulles par les forces Bjerknes, sont ensuite étudiées par des mesures acoustiques, des simulations de pression en régime linéaire et un suivi par une caméra ultra rapide des nuages de bulles induits. 3. Le prototype confocal est utilisé in vivo sur des tumeurs sous cutanées en conjonction avec des liposomes. Dans un premier temps, des essais sous IRM démontrent la possibilité de larguer le contenu des liposomes localement par la cavitation inertielle délivrée par le dispositif. Une seconde étude avec une formulation liposomale de doxorubicine a permis de démontrer l'amélioration de la réponse thérapeutique de la chimiothérapie après application de la cavitation inertielle.. 4. Une étude de faisabilité de l'interférence de l'ARN (RNAi) sur un petit nombre d'animaux est réalisée avec le dispositif confocal et des molécules de siRNA encapsulées dans des liposomes Les expériences sont conduites in vivo avec une xénogreffe de tumeur de sein humain. Après une phase de réglage des paramètres ultrasonores pour limiter la toxicité du traitement, on observe une inhibition significative du gène ciblé. 5. Une deuxième étude de faisabilité est réalisée pour étudier la potentialisation de la chimiothérapie avec l'évérolimus dans un modèle de chondrosarcome de rat. Les traitements ultrasonores et les chimiothérapies sont répétés. Sur un petit nombre d'animaux, on montre l'innocuité du traitement ultrasonore, et l'efficacité en conjonction avec l'agent anti tumoraux, évérolimus
Acoustic cavitation has been shown to be a useful tool in drug delivery for many different biological tissues and indications, and this thesis aims to contribute to the knowledge of cavitation from a drug delivery perspective. This thesis seeks to synthesize the current knowledge and practice concerning acoustic cavitation in a biomedical context, and to present a high intensity confocal ultrasound (US) prototype to address some of the current problems in the field and to give a proof of concept for the therapeutic efficacy of such a prototype. The thesis is organized in 5 chapters: 1. The use of acoustic cavitation in a biomedical context is presented here in a general review. This review comprises the state of the art for cavitation generation, experimental techniques currently being implemented for the measurement of cavitation, and the clinical and preclinical approaches to the use of cavitation in vivo on a tissue by tissue basis. 2. The high intensity confocal US prototype used for all studies in this thesis is presented here. It is characterized in terms of the advantages it gives for the generation of cavitation. Enhancement of cavitation is first demonstrated chemometrically with a fluorescent dosimeter compared to a single transducer at the ultrasonic focus. The mechanisms for cavitation enhancement are then investigated with acoustic measurements, linear pressure simulations, and high speed camera data. 3. The confocal US prototype in used in conjunction with a liposomal formulation of doxorubicin is performed in which a therapeutic enhancement of tumor inhibition is presented. The mechanism of this enhancement is investigated with liposomally encapsulated lanthanide contrast agents and magnetic resonance imaging. 4. A small scale proof of concept for the use of RNA interference using the confocal prototype, and liposomally encapsulated siRNA molecules. The experiments are performed In vivo with a xenograft of human breast tumor. This study also includes data for the safety of the US exposure on a mouse treated one time. 5. Another small scale proof of concept of the use of the confocal device on potentiating chemotherapy with the drug everolimus in a rat chondrosarcoma model. The studies presented here also investigate the use of multiple US exposures on the same tumor in a combined drug / US treatment regimen

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9

Fowler, Robert Andrew. "Inertial Cavitation with Confocal Ultrasound for Drug Delivery". Electronic Thesis or Diss., Lyon 1, 2014. http://www.theses.fr/2014LYO10024.

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Il a été montré que la cavitation acoustique pouvait se révéler utile dans l'administration de médicaments pour de nombreuses applications biologiques et médicales. Cette thèse commence par une présentation de la cavitation ultrasonore et des mécanismes d'action mis en jeu pour la délivrance de médicaments. A la fin de ce cette synthèse, un dispositif à deux transducteurs ultrasonores disposés de manière confocale est présenté pour résoudre certains des problèmes actuels dans le domaine. Il est ensuite mis en oeuvre dans différentes études de faisabilité. La thèse est organisée en 5 chapitres : 1. L'utilisation de la cavitation acoustique dans un contexte biomédical est présentée ici dans une revue générale. Ce chapitre comprend l'état de l'art pour la génération de cavitation, les techniques expérimentales qui sont actuellement mises en oeuvre pour la mesure de la cavitation, et les approches cliniques et précliniques pour l'utilisation de la cavitation in vivo pour différents types de tissu biologique. 2. Le dispositif ultrasonore utilisé pour toutes les études de cette thèse est ensuite décrit. Il est caractérisé acoustiquement et comparé avec un simple transducteur dans le but de démontrer son efficacité pour la génération de la cavitation. Cette comparaison est d'abord faite par une quantification chimique du niveau de cavitation. A puissance constante, le dispositif à deux transducteurs confocaux est bien plus efficace pour générer de la cavitation. Les causes de cette observation, notamment la réduction de la propagation non-linéaire et la stabilisation du nuage des bulles par les forces Bjerknes, sont ensuite étudiées par des mesures acoustiques, des simulations de pression en régime linéaire et un suivi par une caméra ultra rapide des nuages de bulles induits. 3. Le prototype confocal est utilisé in vivo sur des tumeurs sous cutanées en conjonction avec des liposomes. Dans un premier temps, des essais sous IRM démontrent la possibilité de larguer le contenu des liposomes localement par la cavitation inertielle délivrée par le dispositif. Une seconde étude avec une formulation liposomale de doxorubicine a permis de démontrer l'amélioration de la réponse thérapeutique de la chimiothérapie après application de la cavitation inertielle.. 4. Une étude de faisabilité de l'interférence de l'ARN (RNAi) sur un petit nombre d'animaux est réalisée avec le dispositif confocal et des molécules de siRNA encapsulées dans des liposomes Les expériences sont conduites in vivo avec une xénogreffe de tumeur de sein humain. Après une phase de réglage des paramètres ultrasonores pour limiter la toxicité du traitement, on observe une inhibition significative du gène ciblé. 5. Une deuxième étude de faisabilité est réalisée pour étudier la potentialisation de la chimiothérapie avec l'évérolimus dans un modèle de chondrosarcome de rat. Les traitements ultrasonores et les chimiothérapies sont répétés. Sur un petit nombre d'animaux, on montre l'innocuité du traitement ultrasonore, et l'efficacité en conjonction avec l'agent anti tumoraux, évérolimus
Acoustic cavitation has been shown to be a useful tool in drug delivery for many different biological tissues and indications, and this thesis aims to contribute to the knowledge of cavitation from a drug delivery perspective. This thesis seeks to synthesize the current knowledge and practice concerning acoustic cavitation in a biomedical context, and to present a high intensity confocal ultrasound (US) prototype to address some of the current problems in the field and to give a proof of concept for the therapeutic efficacy of such a prototype. The thesis is organized in 5 chapters: 1. The use of acoustic cavitation in a biomedical context is presented here in a general review. This review comprises the state of the art for cavitation generation, experimental techniques currently being implemented for the measurement of cavitation, and the clinical and preclinical approaches to the use of cavitation in vivo on a tissue by tissue basis. 2. The high intensity confocal US prototype used for all studies in this thesis is presented here. It is characterized in terms of the advantages it gives for the generation of cavitation. Enhancement of cavitation is first demonstrated chemometrically with a fluorescent dosimeter compared to a single transducer at the ultrasonic focus. The mechanisms for cavitation enhancement are then investigated with acoustic measurements, linear pressure simulations, and high speed camera data. 3. The confocal US prototype in used in conjunction with a liposomal formulation of doxorubicin is performed in which a therapeutic enhancement of tumor inhibition is presented. The mechanism of this enhancement is investigated with liposomally encapsulated lanthanide contrast agents and magnetic resonance imaging. 4. A small scale proof of concept for the use of RNA interference using the confocal prototype, and liposomally encapsulated siRNA molecules. The experiments are performed In vivo with a xenograft of human breast tumor. This study also includes data for the safety of the US exposure on a mouse treated one time. 5. Another small scale proof of concept of the use of the confocal device on potentiating chemotherapy with the drug everolimus in a rat chondrosarcoma model. The studies presented here also investigate the use of multiple US exposures on the same tumor in a combined drug / US treatment regimen

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10

Phan, Tu-Ai Thi. "Novel host-guest systems for ultrasound-mediated drug delivery /". Available to subscribers only, 2007. http://proquest.umi.com/pqdweb?did=1459908051&sid=2&Fmt=2&clientId=1509&RQT=309&VName=PQD.

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11

Bian, Shuning. "Real-time monitoring of ultrasound and cavitation mediated drug delivery". Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:e5a774a9-5b93-4862-8dd9-0614d234ff28.

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Drug delivery plays a crucial role in the chemotherapeutic treatment of cancerous solid tumours. A drug, no matter how potent, is only truly effective when it can be delivered to all targeted cells. In recent years it has been recognised that the poor response of tumours to chemotherapy is in part due to inadequate drug delivery. Numerous strategies have been developed to overcome this issue. Of particular interest to the present work is the application of ultrasound and cavitation, which has been shown to be capable of enhancing drug delivery in solid tumours. These enhancements are attributed to the acoustic cavitation of microbubbles and the effects cavitation induces in the surrounding tissue. To better understand how ultrasound and cavitation can enhance drug delivery, an instrument was developed that is capable of monitoring in real-time and in-situ the effect of ultrasound and cavitation on drugs and drug analogues within flow channel models. The developed instrument was used to investigate the effect of ultrasound and cavitation on drug-eluting beads used for chemoembolisation, the effects of drug loading on microbubble dynamics, the effects produced by different cavitation agents, and the performance of passive acoustic mapping as a means of cavitation monitoring. The findings of the above investigations include: more physiologically relevant characterisations of drug-eluting beads pharmacokinetics, the possibility of significant changes in microbubble dynamics due to drug loading, a lack of general correlation between detected cavitation activity and induced effects, and the potential of passive acoustic mapping for monitoring cavitation and ultrasound induced effects. These and other findings also demonstrate the utility of the developed instrument for studying the many facets and applications of ultrasound and cavitation mediated drug delivery.

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12

Pereno, Valerio. "Characterisation of microbubble-membrane interactions in ultrasound mediated drug delivery". Thesis, University of Oxford, 2018. http://ora.ox.ac.uk/objects/uuid:515f2c15-e9d3-46b8-875c-420084fbc9a3.

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Cancer imposes a significant disease burden and constitutes a major societal challenge. Despite being widely used, chemotherapy suffers numerous disadvantages, including off-target drug toxicity, poor tumour penetration, and drug resistance. The use of ultrasound in combination with contrast agents has shown promise in enhancing outcomes in the treatment of cancerous and non-cancerous diseases. However, the underlying biophysical processes that underpin their interactions with tissues remain poorly understood. The aim of the research presented in this thesis is to develop methods to elucidate these processes. Development is hindered by the difficulties involved in isolating cellular parameters, noninvasively quantifying biological features at the molecular scale, and recreating a predictable and repeatable ultrasound field. To overcome these challenges, giant unilamellar vesicles made with 1,2-dioleoyl-sn-glycero-3-phosphocholine and cholesterol were used initially as cell models and exposed to therapeutically relevant conditions in a purpose-built acoustofluidic device. The resulting effects on the hydration and permeability of the vesicle membranes and the dynamics of their intravesicle milieu were characterised in situ using quantitative microscopy. Results show that flow, ultrasound, and microbubbles led to an increase in vesicle membrane hydration, while dehydration was seen only in the presence of microbubbles. An increase in permeability was observed for all exposure conditions, and was accentuated when microbubble shell fragments were incorporated in the vesicle bilayer. These findings thus indicate that ultrasound-mediated delivery is governed by a combination of physical and chemical mechanisms that influence the permeation of molecules through lipid membranes. Further, it was shown that exposure to the same conditions led to the onset of streaming flows within the vesicles' lumen. An experimental proof-of-concept for extending the study in vitro was also presented. Actuating the motion of cytoplasmic constituents may potentially induce a broad range of underexplored and therapeutically relevant bioeffects.

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13

Wells, Aaron M. "The Effects of Low Frequency Ultrasound in Transdermal Drug Delivery". BYU ScholarsArchive, 2010. https://scholarsarchive.byu.edu/etd/2560.

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Objective: Determine if varying ultrasound frequency affects the delivery of 10% hydrocortisone concentrations during phonophoresis. Utilize intramuscular microdialysis probe for drug collection, thus improving the experimental model. Methods: Thirty one (10 in groups 1 and 2, 11 in group 3) healthy subjects participated in this study. Interventions: Subjects were randomly assigned to one of three treatment groups receiving 10 minute ultrasound treatments applied to a standardized area of the gastrocnemius muscle of the right leg. The ultrasound was performed over the treated area using a 10% hydrocortisone compound mixed with standard ultrasound gel. The contralateral limb served as the control (no mixed compound or treatment) for all groups. Group one received sham ultrasound. Medicated gel was placed on the treatment site, the sound head moved, but no ultrasound was applied. Group two received 45 KHz at .056 w/cm2. Group three received 1 MHz at 1.0 w/cm2 at a 50 % duty cycle. Results: There was no difference in cortisol concentration change during treatment between the three treatment groups on the treated limbs (sham = 1.1 ±7.5 ng/ml, 45 KHz = 1.1 ± 1.5 ng/ml, 1 MHz = 4.1 ± 7.8 ng/ml; F2,22 = .34, P = .72) or control limbs (sham = 1.65 ± 6.6 ng/ml, 45 KHz = -1.3 ± 2.7 ng/ml, 1 MHz = 0.37 ± 8.1 ng/ml; F2,22 = .67, P = .546). No difference was found in cortisol concentration change during treatment between the treatment limbs and the control limbs (treatment = 2.1 ± 6.2 ng/ml, control = 0.20 ± 5.9 ng/ml; F1,22 = .9, P = .35). The following factors were found to influence cortisol concentrations levels in dialysate collected during treatment: depth of muscle in the treatment limbs (F1,22 = 6.4, P = .02), microdialysis probe depth in the control limbs (F1,22 = 4.1, P = .05), and pre treatment cortisol level in the control limbs (F1,22 = 10.1, P = .004. Conclusions: There was no evidence altering ultrasound frequency from 45 KHz to 1 MHZ enhanced the delivery of 10% hydrocortisone to treatment tissues under these experimental conditions.

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14

Podaru, George. "Exploring controlled drug release from magneto liposomes". Diss., Kansas State University, 2017. http://hdl.handle.net/2097/35544.

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Doctor of Philosophy
Department of Chemistry
Viktor Chikan
This thesis focuses on exploring fast and controlled drug release from several liposomal drug delivery systems including its underlying mechanics. In addition, the construction of a pulsed high-voltage rotating electromagnet is demonstrated based on a nested Helmholtz coil design. Although lots of different drug delivery mechanisms can be used, fast drug delivery is very important to utilize drug molecules that are short-lived under physiological conditions. Techniques that can release model molecules under physiological conditions could play an important role to discover the pharmacokinetics of short-lived substances in the body. In this thesis, an experimental method is developed for the fast release of the liposomes’ payload without a significant increase in (local) temperatures. This goal is achieved by using short magnetic pulses to disrupt the lipid bilayer of liposomes loaded with magnetic nanoparticles. This thesis also demonstrates that pulsed magnetic fields can generate ultrasound from colloidal superparamagnetic nanoparticles. Generating ultrasound remotely by means of magnetic fields is an important technological development to circumvent some of the drawbacks of the traditional means of ultrasound generation techniques. In this thesis, it is demonstrated that ultrasound is generated from colloidal superparamagnetic nanoparticles when exposed to pulsed and alternating magnetic fields. Furthermore, a comparison between inhomogeneous and homogeneous magnetic fields indicates that both homogeneous and inhomogeneous magnetic fields could be important for efficient ultrasound generation; however, the latter is more important for dilute colloidal dispersion of magnetic nanoparticles. In strong magnetic fields, the ultrasound generated from the colloidal magnetic nanoparticles shows reasonable agreement with the magnetostriction effect commonly observed for bulk ferromagnetic materials. At low magnetic fields, the colloidal magnetic nanoparticle dispersion produces considerable amount of ultrasound when exposed to a.c. magnetic fields in the 20−5000 kHz frequency range. It is expected that the ultrasound generated from magnetic nanoparticles will have applications toward the acoustic induction of bioeffects in cells and manipulating the permeability of biological membranes

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15

Tinkov, Steliyan. "Development of Ultrasound Contrast Agents for Targeted Drug and Gene Delivery". Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-107213.

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16

Seto, Jennifer Elizabeth. "Experimental strategies for investigating passive and ultrasound-enhanced transdermal drug delivery". Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/65765.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2011.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 159-167).
Transdermal drug delivery offers many advantages over traditional drug delivery methods. However, the natural resistance of the skin to drug permeation represents a major challenge that transdermal drug delivery needs to overcome in a safe and reversible manner. One method for enhancing transdermal drug delivery involves the application of ultrasound (US) to skin to physically overcome the skin's barrier properties. To advance this method, the focus of this thesis has been to develop novel experimental strategies and data analyses that can be utilized in in vitro investigations of passive and US-enhanced transdermal drug delivery. US treatment is often combined with a chemical enhancer such as the surfactant sodium lauryl sulfate (SLS). The simultaneous application of US and SLS (referred to as US/SLS) to skin exhibits synergism in enhancing transdermal drug delivery and has been utilized in clinical settings. In order to study the delivery of therapeutic macromolecules into US/SLS-treated skin, e.g. vaccine delivery to the Langerhans cells or drug delivery to the blood capillaries near the epidermis-dermis junction, it would be desirable to conduct in vitro US/SLS-enhanced transdermal diffusion experiments using split-thickness skin (STS) models, in which much of the dermis is removed in order to simulate the in vivo transdermal diffusion to the desired skin component. Therefore, STS was evaluated as an alternative to the well-established US/SLStreated full-thickness skin (FTS) model for the delivery of hydrophilic permeants. The skin permeabilities and the aqueous pore radii of US/SLS-treated pig FTS, 700-pm-thick pig STS, human FTS, 700-pm-thick human STS, and 250-pm-thick human STS were compared over a range of skin electrical resistivity values. The US/SLS-treated pig skin models were found to exhibit similar permeabilities and pore radii, but the human skin models did not. Furthermore, the US/SLS-enhanced delivery of gold nanoparticles and quantum dots (two model hydrophilic macromolecules) was found to be greater through pig STS than through pig FTS, due to the presence of less dermis that acts as an artificial barrier to macromolecules. In spite of greater variability in correlations between STS permeability and resistivity, the results strongly suggest the use of 700-pm-thick pig STS to investigate the in vitro US/SLS-enhanced delivery of hydrophilic macromolecules. After the validation of the pig STS for US/SLS studies, this skin model was used to study the transdermal delivery of nanoparticles. While nanoparticles have potential as transdermal drug carriers, many studies have shown that nanoparticle skin penetration is limited. Therefore, the US/SLS treatment was evaluated as a skin pre-treatment method for enhancing the passive transdermal delivery of nanoparticles. Quantitative and qualitative methods (elemental analysis
(cont.) and confocal microscopy, respectively) were utilized to compare the delivery of 10-nm and 20- nm cationic, neutral, and anionic quantum dots into US/SLS-treated and untreated pig STS. The findings include: (a) ~0.01% of the quantum dots penetrated the dermis of untreated skin (which was quantified for the first time), (b) the quantum dots fully permeated US/SLS-treated skin, (c) the two cationic quantum dots studied exhibited different extents of skin penetration and dermal clearance, and (d) the quantum dot skin penetration is heterogeneous (which was determined using a novel application of confocal microscopy). Routes of nanoparticle skin penetration are discussed, as well as the application of the methods described herein to address conflicting literature reports on nanoparticle skin penetration in the context of nanoparticle skin toxicity. US/SLS treatment is concluded to significantly enhance quantum dot transdermal penetration by 500 - 1300%. The findings suggest that an optimum surface charge exists for nanoparticle skin penetration, and motivate the application of nanoparticle carriers to US/SLS-treated skin for enhanced transdermal drug delivery. The final investigation of this thesis focused on chemical penetration enhancers, which are used to enhance drug delivery through several biological membranes, particularly the stratum corneum of the skin. However, the fundamental mechanisms that govern the interactions between penetration enhancers and membranes are not fully understood. Therefore, the goal of this work was to identify naturally fluorescent penetration enhancers (FPEs) in order to utilize well-established fluorescence techniques to directly study the behavior of FPEs within the skin. In this study, 12 FPE candidates were selected and ranked according to their potency as skin penetration enhancers. The best FPEs found compared well to SLS, a well-known potent skin penetration enhancer. Based on the ranking of the FPEs, FPE design principles are presented. In addition, to illustrate the novel, direct, and non-invasive visualization of the behavior of FPEs within skin, three case studies involving the use of two-photon fluorescence microscopy are presented, including visualizing glycerol-mitigated and US-enhanced FPE skin penetration. Previous two-photon fluorescence microscopy studies have indirectly visualized the effect of penetration enhancers on skin by using a fluorescent permeant to probe the transdermal pathways of the penetration enhancer. These effects can now be directly visualized and investigated using FPEs. The combination of FPEs with fluorescence techniques represents a useful new approach for elucidating the mechanisms involved in penetration enhancement and membrane irritation, and for improving structure-activity relationships for penetration enhancers. The new physical insights obtained using FPEs will aid in designing effective penetration enhancers for drug delivery applications, including penetration enhancers to be combined with US for synergistically enhancing transdermal drug delivery. The experimental strategies presented in this thesis pave the way for investigations in several transdermal fields, including evaluating nanoparticle skin toxicity, designing nanoparticle drug delivery carriers, evaluating ultrasound-assisted transdermal vaccination, elucidating mechanisms of chemical penetration enhancer-induced skin irritation, designing topical formulations with penetration enhancers, and elucidating mechanisms of ultrasound and penetration enhancer synergism in enhancing skin permeability.
by Jennifer Elizabeth Seto.
Ph.D.

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17

Xu, Doudou. "Targeted drug delivery with cyclodextrin-based nanocarriers and focused ultrasound triggering". Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/e7aa1925-3553-48e4-90e7-dcccdf8f8c05.

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Background: The Nanoporation project set out to explore specific solutions to overcome the current challenges of targeted drug delivery (TDD) to tumours using magnetic resonance imaging guided focused ultrasound (MRgFUS) to cavitate microbubbles (MBs) for increasing cell permeability and to open ‘drug nano-capsules’ to release proven active anticancer drugs directly to the tumour site with reduction of systemic drug dosage needed for the desired therapeutic effect. Objective: The work reported here aimed to develop novel nano-carriers for existing anticancer drugs, by establishment of human cancer cell models to evaluate the carriers’ encapsulation efficiency in vitro and in vivo, by using animal models and a clinical MRgFUS system to investigate the carrier-drug vehicles’ in vivo distribution and localised drug release / cellular drug uptake. Methods: A novel ?-cyclodextrin (?-CD) based carrier for encapsulation of doxorubicin (DOX) was synthesised and fully characterised. The encapsulation efficiency was assessed under various temperatures and pH levels by both chemical analysis and in vitro human cancer cell modeling with KB and HCT116 cells. A high-throughput in vitro FUS device was designed and applied, in combination with carrier-DOX inclusion. SonoVue® MBs was used to investigate TDD in cell monolayers. Ex vivo and in vivo trials were carried out with a clinically approved ExAblate MRgFUS system (InSightec, Israel) to establish a safe and efficient clinical TDD protocol on small rodents. Results: The desired ?-CD based carrier greatly reduced DOX’s toxicity and the carrier-DOX inclusion was highly stable under physiological temperature conditions as well as under a wide range of acidic conditions (pH 1.0 ~ 7.0); the encapsulated DOX is slowly released under hyperthermic conditions (up to 50 °C). In the presence of MBs, application of FUS with low mechanical indexes, under which no thermal effect was observed, enhanced the drug uptake into tumour cells for both encapsulated and free DOX. Optimal setups of MR parameters and FUS parameters were identified ex vivo and in vivo, allowing application of MRgFUS treatments to 4 live mice bearing tumours (human colorectal carcinoma, up to 1059.71 mm3) under anaesthesia with full recovery. Conclusions: The study demonstrated the possibility of translation of the constructed ?-CD derivative to potential clinical use as a delivery vehicle for DOX using combined thermal and mechanical release mechanisms by clinically applicable MRgFUS– triggered TDD with the potential for cancer therapy.

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18

Gourevich, Dana. "Ultrasound mediated Targeted Drug Delivery in vitro : design, evaluation and application". Thesis, University of Dundee, 2013. https://discovery.dundee.ac.uk/en/studentTheses/0a3943df-4330-44b5-9f06-814ba2379d11.

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Background Targeted Drug Delivery (TDD) is a therapeutic modality which allows an increase in the medication dose at a treatment site, while simultaneously avoiding effects in the rest of the human body. This can be achieved via different types of delivery vehicles or carriers which encapsulate the free drug and release it only at the needed location. There are various methods of drug release, one of which is ultrasound, as in ultrasound-mediated TDD (USmTDD). The combination of focused ultrasound (FUS) and magnetic resonance imaging (MRI) provides a controllable system of drug release and impact assessment.In the work reported here, a novel drug carrier was synthesized and assessed. Ultrasonic drug release from the carrier was evaluated in vitro using a clinical MRI-guided Focused Ultrasound Surgery (MRgFUS) system. As there was no properly controllable research environment for in-vitro studies available prior to the investigation of the carriers, such an environment was built and characterized.Methods MCF7 and A375m human cancer cell lines were subjected to FUS using the ExAblate 2000 and 2100 systems (InSightec, Haifa, Israel). The experiments were conducted in a specially designed research environment, which was comprehensively evaluated to ensure both cell sterility and proper FUS propagation. Various sonication parameters were applied, in conjunction with a commercially available ultrasound contrast agent (USCA), to achieve maximal cellular uptake of Doxorubicin (Dox) with minimal decrease in cell viability. A novel cyclodextrin (CD) based drug carrier was synthesized, chemically evaluated, and investigated in vitro via two release mechanisms: heating and physical effects.Results Two clinical MRgFUS systems were adapted for in-vitro work, showing controllable and repeatable results. Both of the assessed release mechanisms showed their competency: the application of FUS in the presence of USCA increased the cellular drug uptake of Dox by an average factor of 3 ±0.9, and up to a factor of 4 due to heating. The Dox release from the CD-based carrier was around 100% with both mechanisms.Conclusions Adaptation of a clinical MRgFUS system for in-vitro research allows the use of a single system starting from in-vitro studies, through the pre-clinical stage to clinical trials. This gives physicians the ability to be a part of a wider USmTDD research group, from the beginning of the product definition, bringing real meaning to the term “from bench to bedside”. The baseline studies reported here have verified that intracellular drug uptake is increased through heating and sonoporation processes. The release mechanisms from the carriers were also observed, validating the concept of USmTDD from CD-based carriers.

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Hitchcock, Kathryn E. "Ultrasound-enhanced drug delivery in a perfused ex vivo artery model". University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1275922520.

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Eisenbrey, John Wheatley Margaret A. "Ultrasound sensitive polymeric drug carriers for treatment of solid tumors /". Philadelphia, Pa. : Drexel University, 2010. http://hdl.handle.net/1860/3218.

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Kushner, Joseph IV. "Theoretical and experimental investigations of passive and ultrasound-enhanced transdermal drug delivery". Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/38980.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2007.
Includes bibliographical references.
In the initial investigation of this thesis, Fick's second law of diffusion was modified to describe both the transient, and the steady-state, transdermal transport of hydrophilic permeants through unbranched, aqueous pore channels. This new transport model, combined with dual radiolabeled diffusion experiments, was then used to separately evaluate how the porosity, the tortuosity, and the hindrance factor of the aqueous pore channels that exist in the skin varied as the extent of skin perturbation due to simultaneous treatment of the skin with low-frequency ultrasound (US) and a chemical enhancer, the surfactant sodium lauryl sulfate (SLS), and as the radius of the hydrophilic permeant delivered across the skin, were increased. This investigation revealed that the values of the hindrance factor and of the tortuosity decreased as the radius of the hydrophilic permeant increased, and that the value of the porosity of the aqueous pore channels increased as the extent of skin perturbation due to the application of US increased. This last result suggested that low-frequency US primarily enhances the transport of hydrophilic permeants by increasing the fraction of the skin surface occupied by the aqueous pore channels.
(cont.) This modeling approach was next applied to the passive delivery of hydrophobic permeants through the branched pathways located in the intercellular lipid bilayer domain of untreated stratum corneum (SC), the outermost layer of the skin. The existence of these branched pathways led to the development of a new theoretical model, the Two-Tortuosity Model, which requires two tortuosity factors to account for: 1) the effective diffusion path length, and 2) the total volume of the branched, intercellular transport pathways, both of which may be evaluated from known values of the SC structure. After validating the Two-Tortuosity model with simulated SC diffusion experiments in FEMLAB (a finite element software package), the vehicle-bilayer partition coefficient, Kb, and the lipid bilayer diffusion coefficient, Db, in untreated human SC were evaluated using this new model for two hydrophobic permeants, naphthol (Kb = 233 + 44, Db = 1.6*10-7 + 0.3*10-7 cm2/s) and testosterone (Kb = 100 + 14, Db = 1.8*10-8 + 0.2*10-8 cm2/s). This investigation demonstrated that the new proposed method to evaluate Kb and Db is more direct than previous methods, in which SC permeation experiments were combined with octanol-water partition experiments, or with SC solute release experiments, to evaluate Kb and Db.
(cont.) Previous studies on ultrasound-mediated transdermal drug delivery had hypothesized that the discrete regions which form on the surface of skin treated with low-frequency US in the presence of a colored permeant are regions of high permeability. To test this hypothesis, full-thickness pig skin was treated simultaneously with low-frequency US and SLS in the presence of a hydrophilic fluorescent permeant, sulforhodamine B (SRB), which was used to observe the location of the hypothesized localized transport regions (LTRs) and of the surrounding regions of US-treated skin (the non-LTRs). After US-pretreatment, diffusion masking experiments, a novel experimental method in which hydrophobic vacuum grease was selectively applied to the skin surface, demonstrated that the permeability of calcein, another hydrophilic fluorescent permeant, in the LTRs was -80-fold greater than in the non-LTRs. Furthermore, measurements of the skin electrical resistivity in both the LTRs and the non-LTRs revealed significant decreases relative to the skin electrical resistivity in untreated skin (-5000-fold and -170-fold, respectively), suggesting that two levels of significant structural perturbation exist in skin treated simultaneously with ultrasound and SLS.
(cont.) Finally, an analysis of the porosity-to-tortuosity ratio values suggested that transcellular transdermal transport pathways exist within the LTRs. To confirm the results of the previous investigation, the transdermal delivery of SRB and of rhodamine B hexyl ester (RBHE), a fluorescent hydrophobic permeant, in skin treated with low-frequency ultrasound (US) and/or a chemical enhancer (SLS) relative to untreated skin (the control) was analyzed with dual-channel two-photon microscopy (TPM). An analysis of the average fluorescence intensity profiles as a function of skin depth, obtained from the TPM images, revealed that SRB and RBHE penetrated beyond the stratum corneum and into the viable epidermis only in the LTRs of US-treated and of US/SLS-treated skin. Further analysis of the average fluorescence intensity profiles and of the enhancements in the vehicle-skin partition coefficient, the intensity gradient, and the effective diffusion path length confirmed that a chemical enhancer was required in the coupling medium during US-treatment to obtain two significant levels of increased penetration of SRB and RBHE into the skin.
(cont.) Finally, by comparing the heights and the widths of the fluorescence intensity peaks obtained from the dual-channel TPM images, the existence of transcellular pathways was confirmed in the LTRs of US-treated and of US/SLS-treated skin for SRB and RBHE, as well as in SLS-treated skin for SRB. In the final investigation of this thesis, the differences in the hindrance factor, the porosity, and the tortuosity of the aqueous pore channels located in the LTRs and in the non-LTRs were evaluated for the delivery of four hydrophilic permeants (urea, mannitol, raffinose, and inulin) using the transport model developed in the initial investigation of this thesis combined with dual radiolabeled diffusion masking experiments. In this analysis, three different idealized cases were examined. In the first case, where the porosity and the tortuosity were assumed to be independent of the permeant radius, the hindrance factor, and, therefore, the average pore radius, was found to be statistically larger in the LTRs than in the non-LTRs. In the second case, where a distribution of pore radii was assumed to exist in the skin, no meaningful results could be obtained due to the large variation in the shape of the distribution of pore radii used in the analysis.
(cont.) In the final case, where infinitely large aqueous pores were assumed to exist in the skin, the value of the porosity of the LTRs was found to be 3- to 8-fold larger than that of the non-LTRs, while there little difference was found in the values of the tortuosity of the LTRs and of the non-LTRs.
by Joseph Kushner, IV.
Ph.D.

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Gerayeli, Faezeh. "Stimulated delivery of therapeutic molecules from hydrogels using ultrasound". Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAS019/document.

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Le doctorant n'a pas fourni de résumé en français
The research described in this thesis is directed to study an externally stimulated DDS that incorporates a hydrogel as the matrix for the therapeutic agent. The research does not investigate a particular site for the delivery of the therapeutic agent. However, the aim of this research program is to develop various hydrogel formulations with desirable characteristics and structures from which the drug release can be controlled with applied external energy in the form of low-frequency ultrasound. To accomplish this, two types of natural hydrogels from agarose and chitosan and one type of synthetic hydrogel from PVA were fabricated. Parameters that affect the structure were varied for each type of hydrogel in order to study the effect of structural changes on drug loading and release capacity of hydrogels. Next, the obtained hydrogels were assessed for the delivery of Theophylline as the model drug.Among the three types of hydrogels, chitosan was found to have the fastest swelling rates and the higher water uptakes while the least swelling was found with PVA hydrogels and then agarose hydrogels crosslinked at pH 12. Regarding the mechanical stability of hydrogels, the ranking of the elastic modulus was PVA hydrogels (highest), then agarose hydrogels and chitosan copolymers (lowest). It seemed that the more mechanically stable structure of the PVA hydrogels correlated with a reduced mobility of water, in comparison to the greater mobility of water in the mechanically weaker chitosan copolymers.The stimulated and passive release of Theophylline from those hydrogel carriers showed how ultrasound, as an external energy, stimulates and controls the release of the drug. The measurements confirmed that it is only the energy imparted by the longitudinal ultrasonic waves that act on the polymeric network. The mechanism by which the ultrasound affects the release is considered as a form of a ratchet motor. The polymer chains play the role of the “ratchet” steps and the ultrasonic waves accelerate the particle movement in the release media. Hence, once the ultrasound is applied, the particles descend chain-to-chain (i.e. step-by-step) driven down their concentration gradient by the applied energy until they reach the surface of the hydrogel and hence are released into the surrounding media.Increasing the ultrasound intensity vastly accelerates the drug release. Indeed a higher intensity equals a higher energy transferred from the ultrasonic waves to the drug particles, resulting in faster and less controlled release. This also depends on the type of drug carrier structure. If the hydrogel carrier is mechanically stable, such as the PVA samples or the agarose hydrogels crosslinked at pH 12, the effect of high ultrasound intensity is much less compared to a less mechanically stable carrier such as the chitosan blends. Ultrasound applied for a longer period of time increases the amount of drug released, with the consequent effect of increasing the amount of heat generated in the hydrogel. Generally, a longer duration of the applied energy results in a greater amount of energy absorption, and an increase in friction and heat generation. These effects are important considerations in relation to the heat sensitivity of the drug to be delivered and the thermal characteristics of the polymeric carrier.This PhD research has demonstrated that both natural and synthetic hydrogels coupled to an ultrasonic energy source provides a controllable DDS, which provide some novel outcomes and contributions to the body of knowledge in the field of controlled drug delivery

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Errico, Claudia. "Ultrasound sensitive agents for transcranial functional imaging, super-resolution microscopy and drug delivery". Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCC013.

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Cette thèse porte sur deux branches majeures de l'utilisation d'agents sensibles aux ultrasons: l'échographie ultrarapide du cerveau assistée par microbulles et la délivrance par ultrasons de médicaments pour la thérapie du cancer. Dans la première approche, des microbulles remplies de gaz fluoré ont été utilisés pour observer l'activation du cerveau à travers le crâne des rongeurs. Nous avons été en mesure de reconstituer de manière non invasive le réseau vasculaire du cerveau, puis de récupérer sa réponse hémodynamique avec une résolution spatio-temporelle élevée. La validation de cette approche d'imagerie fonctionnelle par échographie (FUS) a été facilitée par la grande sensibilité de la technique du Doppler ultrarapide ultrasensible. En effet, cette modalité d'imagerie permet de détecter les changements hémodynamiques dus au couplage neurovasculaire avec une grande résolution (1ms, 100pm). Ces résultats suggèrent que la combinaison des agents de contraste et l'imagerie ultrarapide peut aider à compenser entièrement l'atténuation par le crâne, et ce en préservant la résolution et en augmentant la profondeur de pénétration. L'injection d'agents de contraste ultrasonore a également conduit à des résultats remarquables en imagerie ultrasonore ultrarapide. La barrière de la diffraction a été contournée pour aller au-delà de la limite de demi-longueur d'onde de résolution. Nous avons démontré que des microvaisseaux cérébraux de 9pm de diamètre peuvent être distingués par microscopie échographie ultrarapide de localisation (uULM). Des millions de sources «clignotantes» sont localisées dans l'espace et dans le temps, conduisant à des images super-résolues (cartographie de densité de microbulles) de l'ensemble du réseau vasculaire du cerveau du rat avec une résolution spatiale de À / 10. En outre, les trajets des microbulles au cours du temps ont pu être relevés et ainsi permettre d'extraire les vitesses des flux sanguins avec une grande dynamique. Dans la seconde approche, nous avons exploité la manière dont nous pouvons contrôler, spatialement et temporellement, la vaporisation de micro gouttes composites de perfluorocarbone (PFC) lorsque leur activation est déclenchée par de courtes impulsions ultrasonore. Le concept de "chimie in-situ" est introduit dès lors que nous avons été en mesure de contrôler une réaction chimique spontanée in vitro. En outre, dans le cadre des applications in vivo de la chimie in situ, un nouveau dispositif microfluidique en verre a été proposé afin de permettre une production stable et rapide de gouttes monodisperses. Ce nouveau dispositif présente 128 générateurs en parallèles avec deux canaux sous pression. Finalement, de nouvelles séquences d'échographie de contrôle ultra-rapides ont été développées dans le but de contrôler et de surveiller la libération des gouttelettes composites
This thesis focuses on two main branches of the application of ultrasound contrast agents: microbubbles-aided ultrafast ultrasound imaging of the brain and ultrasound-triggered drug delivery for cancer therapy. At first, gas-filled microbubbles have been used to retrieve the brain activation through the skull in large animais. With this approach we have been able to non-invasively reconstruct the cerebral network of the brain, as well as retrieve its hemodynamic response to specific evoked tasks with high spatiotemporal resolution. The validation of this novel functional ultrasound (fUS) imaging approach was facilitated by the high sensitivity of the ultrasensitive Doppler technique able to detect subtle hemodynamic changes due to the neurovascular coupling. These resuits suggested that combining microbubbles injections with ultrafast imaging may help to fully compensate for the attenuation from the skull. Indeed, by combining both, we preserved resolution and increased penetration depth. The injection of ultrasound contrast agents has also lead to outstanding resuits in ultrafast ultrasound imaging by breaking the diffraction barrier and move beyond the half-wavelength limit in resolution. We have demonstrated that cerebral microvessels of 9pm in diameter can me distinguished via ultrafast ultrasound localization microscopy (uULM). Millions of blinking sources were localized in space and in time in few seconds in a higher dimensional space, leading to super-resolved images (microbubble density map) of the whole rat brain with a spatial resolution of À/10. Moreover, a displacement vector allowed microbubbles-tracking within frames yielding to in-plane velocity measurements retrieving a large dynamic of cerebral blood velocities. Next, we have exploited how we can spatiotemporally control the vaporization of composite perfluorocarbon (PFC) microdroplets when their activation is triggered by short ultrasound pulses. The concept 'chemistry in-situ' is introduced as we have been able to control a spontaneous chemical reaction in-vitro. Moreover, a new microfluidic device in glass has been proposed to robustly produce monodisperse droplets for future in-vivo applications of the chemistry in situ. This new device presents 128-parallel generators with two pressurized rivers. Eventually, new ultrafast ultrasound monitoring sequences have been developed in order to control and monitor the release of composite droplets

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Lattin, James R. "Ultrasound-Induced Phase Change of Emulsion Droplets for Targeted Gene and Drug Delivery". BYU ScholarsArchive, 2012. https://scholarsarchive.byu.edu/etd/3377.

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This dissertation explores the potential of using perfluorocarbon emulsion droplets to add an ultrasound-sensitive element to drug delivery systems. These emulsion droplets may be induced to vaporize with ultrasound; during the rarefactional phase of an ultrasound wave, the pressure around the droplets may fall below the vapor pressure of the liquid forming the emulsion, providing a thermodynamic potential for vaporization. This ultrasound-induced phase change of the emulsion droplet could release therapeutics attached to the droplet surface or aid in drug delivery due to mechanical effects associated with vaporization and expansion, similar to the ability of cavitating bubbles to aid in drug delivery. In contrast to bubbles, stable emulsions can be formed at nano-scale sizes, allowing them to extravasate into tissues and potentially be endocytosed into cells. Perfluorohexane and perfluoropentane were selected to form the emulsions due to their relatively high vapor pressure, low water solubility, and biocompatibility. Acoustic droplet vaporization was explored for its potential to increase ultrasound-induced drug release from liposomes. Liposomes have proven to be versatile and effective drug carriers, but are not inherently responsive to ultrasound. eLiposomes, defined as a liposome with encapsulated emulsion droplets, were developed due to the potential of the expanding vapor phase to disrupt bilayer membranes. The resulting vesicle retains the advantages of liposomes for drug delivery, while adding an ultrasound-sensitive element. eLiposomes were loaded with calcein, a fluorescent molecule, as a model drug in order to quantify ultrasound-mediated drug release compared to release from conventional liposomes. Upon exposure to ultrasound, eLiposomes typically released 3 to 5 times as much of the encapsulated load compared to conventional liposomes, with some eLiposome samples approaching 100% release. Emulsion droplets were also added to the outside of conventional liposomes, but resulted in little to no increase compared to control samples without emulsions. Lastly, in vitro experiments were performed with HeLa cells to explore the ability of emulsion droplets and eLiposomes to deliver calcein inside of cells. Calcein delivery to the cytosol was accomplished, and the emulsion-containing samples demonstrated the ability to aid in endosomal escape.

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Lyon, P. C. "Targeted release from lyso-thermosensitive liposomal doxorubicin (ThermoDox®) using focused ultrasound in patients with liver tumours". Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:4817361a-e7f8-4773-ac81-8445ace05301.

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Hartley, Jonathan Michael. "Surface Modification of Liposomes Containing Nanoemulsions". BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/2846.

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Many attempts have been made to make cancer therapy more selective and less detrimental to the health of the patients. Nanoparticles have emerged as a way to solve some of the problems of traditional chemotherapy. Nanoparticles can provide protection for the therapeutic from degradation or clearance, as well as protection to healthy tissue from the damaging effects of chemotherapy drugs. Researchers are pursuing different strategies but all have the same goals of improving the outcomes of cancer patients. The field of controlled release of drugs has increased significantly in hopes of better treating diseases like cancer. Improved control of drug release has great potential for improving patient outcomes. Still there exist certain barriers such as circulation time, cell specificity, and endosomal escape.In this study a novel drug delivery vehicle was studied in vitro. The novel construct consisted of a liposome containing perfluorocarbon emulsions—an eLiposome—that was activated by ultrasound to break open on demand. Two targeting moieties were attached to the eLiposome to increase cell specificity and induce endocytosis. These studies determined the localization of eLiposomes in vitro using flow cytometry and confocal microscopy. Results indicated that eLiposomes modified with a targeting moiety attached to HeLa cells to a greater extent than non-targeting eLiposomes. Confocal images indicated localization of eLiposomes around the membrane of cells. Flow cytometer results indicated that ultrasound does in fact disrupt the eLiposomes but evidence of significant delivery to the cytoplasm was not obtained. However cells that were incubated with eLiposomes for 24 hours showed over 60% of the cells had green color association indicating eLiposome uptake.

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Han, Tao. "Ultrasound and insertion force effects on microneedles based drug delivery : experiments and numerical simulation". Thesis, Loughborough University, 2015. https://dspace.lboro.ac.uk/2134/19591.

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Transdermal drug delivery (TDD) is limited by high resistance of the outer layer of the skin, namely stratum corneum which blocks any molecule that is larger than 500 Da. Research on TDD has become very active in recent years and various technologies have been developed to overcome the resistance of the stratum corneum. In particular, researchers have started to consider the possibility of combining the TDD technologies in order to achieve further increment for drug permeability. Microneedles (MNs) and sonophoresis are both promising technologies that can perform notable enhancement in drug permeation via different mechanisms and therefore give a good potential for combining with each other. We discuss the possible ways to achieve this combination as well as how this combination would increase the permeability. Some of the undeveloped (weaker) research areas of MNs and sonophoresis are also discussed in order to understand the true potential of combining the two technologies when they are developed further in the future. We propose several hypothetical combinations based on the possible mechanisms of MNs and sonophoresis.

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THACKER, JAMES H. "SONOFLUIDIC MICRO-SYSTEMS FOR PRECISION-CONTROLLED IN-VIVO DRUG DELIVERY". University of Cincinnati / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1196178160.

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Liu, Ying. "The impact of physical and biological factors on intracellular uptake, trafficking and gene transfection after ultrasound exposure". Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/43626.

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We used megahertz pulsed ultrasound and studied gene transfection with a human prostate cancer cell line. We first studied the compromise of cell viability and uptake efficiency and found out that increasing sonication temperature or changing US contrast agents could improve drug/gene delivery mediated by US exposure. We also found that accounting for cell debris after sonication was important to correctly determine cell viability. Next, we verified the capability of US to deliver DNA into the cell nuclei, which is necessary for successful gene transfection. Under the optimal sonication conditions, ~ 30% of cells showed DNA uptake right after US exposure and most had a portion of DNA already localized in the cell nuclei. The maximum transfection efficiency was ~ 12% at 8 h post US exposure. From the DNA perspective, ~ 30% of DNA was localized in the cell nuclei immediately after US exposure and ~ 30% was in the autophagosomes/ autophagolysosomes with the rest ¡°free¡± in the cytoplasm. At later time up to 24 h, DNA continued to be distributed ~ 30% in the nuclei and most or all of the rest in autophagosomes/autophagolysosomes. Our results showed that US was able to deliver DNA into the cell nuclei shortly after the treatment and that the rest of DNA was mostly cleared by autophagosomes/autophagolysosomes. To further increase transfection efficiency, we then studied the differences between live cells with DNA uptake and those with successful gene transfection post US exposure using cell sorting, cell cycle and microarray analysis. Cells with gene transfection were found to accumulate at the G1 phase of cell cycle and associate with the up-regulation of 32 genes (e.g., GADD45¦Á) and the down-regulation of 46 genes (e.g., TOP2¦Á). Drugs that regulate the expression levels of GADD45¦Á and TOP2¦Á were found to further enhance the transfection mediated by US. A maximun increase of ~ 2 fold in transfection efficiency was observed when cells were sonicated with 0.6 mg/mL ethyl methanesulfonate to up-regulate GADD45¦Á. These results suggestted that using drugs that regulate certain introcellular processes could further enhance US-mediated gene transfection. Over a broad range of US conditions, the integrity of three common gene delivery vectors, plasmid DNA, siRNA and adeno-associated virus, were not affected by US exposure. This thesis verified that US was able to delivery DNA into the cell nuclei to facilitate rapid gene transfection, and provided a proof of princible that by modulating certain intracellular processes, the efficiency of US-mediated gene transfection could be further increased. US could potentially be a safe and efficient method for gene therapy.

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Hallow, Daniel Martin. "Measurement and Correlation of Acoustic Cavitation with Cellular and Tissue Bioeffects". Diss., Georgia Institute of Technology, 2006. http://hdl.handle.net/1853/19741.

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Targeted intracellular delivery is a goal of many novel drug delivery systems to treat site-specific diseases thereby increasing the effectiveness of drugs and reducing side effects associated with current drug administration. The development of ultrasound-enhanced delivery is aimed at providing a targeted means to deliver drugs and genes intracellularly by utilizing ultrasound s ability to non-invasively focus energy into the body and generate cavitation, which has been found to cause transient poration of cells. To address some of the current issues in this field, the goals of this study were (i) to develop a measurement of cavitation to correlate with cellular bioeffects and (ii) to evaluate the ability of ultrasound to target delivery into cells in viable tissue. In addition, this study sought to exploit the shear-based mechanism of cavitation by (iii) developing a simplified device to expose cells to shear stress and cause intracellular uptake of molecules. This study has shown that broadband noise levels of frequency spectra processed from cavitation sound emissions can be used to quantify the kinetic activity of cavitation and provide a unifying parameter to correlate with the cellular bioeffects. We further demonstrated that ultrasound can target delivery of molecules into endothelial and smooth muscle cells in viable arterial tissue and determined approximate acoustic energies relevant to drug delivery applications. Lastly, we developed a novel device to expose cells to high-magnitude shear stress for short durations by using microfluidics and demonstrated the ability of this method to cause delivery of small and macromolecules into cells. In conclusion, this work has advanced the field of ultrasound-enhanced delivery in two major areas: (i) developing a real-time non-invasive measurement to correlate with intracellular uptake and viability that can be used as means to predict and control bioeffects in the lab and potentially the clinic and (ii) quantitatively evaluating the intracellular uptake into viable cells in tissue due to ultrasound that suggest applications to treat cardiovascular diseases and dysfunctions. Finally, by using shear forces generated in microchannels, we have fabricated a simple and inexpensive device to cause intracellular uptake of small and large molecules, which may have applications in biotechnology.

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Rodi, Abdalkader. "Development of novel phospholipids-based ultrasound contrast agents intended for drug delivery and cancer theranostics". 京都大学 (Kyoto University), 2016. http://hdl.handle.net/2433/217148.

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Alexandraki, Alexia. "Epigenetic drug delivery using ultrasound-mediated microbubble destruction as a potential treatment for colorectal cancer". Thesis, University of Leeds, 2018. http://etheses.whiterose.ac.uk/22420/.

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Epigenetic therapy using DNA methyltransferase (DNMT) inhibitors, has attracted a great interest for the treatment of solid tumours including colorectal cancer (CRC). Decitabine (DAC), a DNMT inhibitor, has been FDA-approved for the treatment of haematological malignancies. However, the therapeutic clinical outcome of DAC in solid tumours is limited by its short plasma half-life and degradation by cytidine deaminase, whilst myelosuppression can be induced at high doses. To enhance DAC delivery and improve its therapeutic potential in CRC in vitro and/or in vivo, free DAC delivery combined with ultrasound (US)-mediated microbubble (MB) destruction (UMMD) was tested. In addition, encapsulation of DAC within liposomes was performed. Drug-loaded liposomes can be conjugated to US-triggered MBs, which can be targeted to the vascular endothelial growth factor receptor 2 (VEGFR2) of the tumour endothelial cells. End-point assays using aberrantly-methylated genes that would respond to DAC treatment were identified including the tumour suppressor genes, CDO1 and SPARC. These were tested as potential epigenetic biomarkers of response in human CRC cell lines in vitro and in vivo. In vitro treatment with low dose DAC liposomes induced higher protein levels of SPARC in SW620 metastatic CRC (mCRC) cells compared to DAC in solution. Free DAC treatment followed by UMMD resulted in significantly higher SPARC protein levels in SW620 cells compared to DAC with US or DAC alone in vitro. CDO1 protein levels were increased in response to DAC with US with or without MBs compared to DAC alone in HCT116 cells. Free DAC delivery combined with UMMD reduced the tumour growth and tumour mass of SW620 human CRC xenografts compared to DAC with US. This was associated with significant epigenetic reactivation of SPARC. Upregulation of MAGEA3/6, a cancer-testis antigen, was induced in both cases compared to the vehicle control. It can be concluded that systemic DAC treatment combined with UMMD can enhance the epigenetic potential of DAC in a preclinical model of CRC in vivo.

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Chen, Di. "Applications of Acoustic Techniques to Targeting Drug Delivery and Dust Removal Relevant to NASA Projects". ScholarWorks @ UVM, 2010. http://scholarworks.uvm.edu/graddis/44.

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Sonoporation, enhanced by ultrasound contrast agents has been explored as a promising non-viral technique to achieve gene transfection and targeting drug delivery in recent years. However, the short lifespan of traditional ultrasound contrast agents like Optison® microbubbles under moderate intensity ultrasound exposure limits their application. Liposomes, as drug carriers consisting of curved spherical closed phospholipid bilayer shells, have the following characteristics: 1) The ability to encapsulate and carry hydrophilic or hydrophobic molecules. 2) The biocompatibility with cell membranes. 3) The nanometer size and the relative ease of adding special ligands to their surface to target a specific disease site. 4) The stability in the blood stream. 5) Targeted ultrasound irradiation can induce rupture of liposomes letting the drug encapsulated in them leak out to achieve controlled release of the therapeutic agents at a certain concentration and a delivery rate. In this thesis, several liposome synthesis methods are presented. Liposomes synthesized in our laboratory were characterized acoustically and optically. Anti rabbit IgG conjugated with Alexafluor 647 was delivered into Jurkat cells in a suspension containing liposomes by 10 % duty cycle ultrasound tonebursts of 2.2 MHz (the in situ spatially averged and temporally averaged intensity, ISATA = 80W/cm2) with an efficiency of 13 %. It has been experimentally shown that liposomes may be an alternative stable agent to Optison® to cause sonoporation. Furthermore, a type of nanometer-sized liposome (<300nm) was synthesized to explore the feasibility of ultrasound-triggered release from drug encapsulated lipsomes. It has been demonstrated encapsulated fluorescence materials (FITC) can be released from liposomes with an average diameter of 210 nm when exposed to high intensity focused ultrasound (HIFU) at 1.142MHz (ISPTA= 900 W/cm2). Rupture of relatively large liposomes (>100nm) and porelike defects in the membrane of small liposomes due to the excitation of HIFU were the main causes of the content release. The great enhancement of HIFU-mediated release in the nanometer-sized liposomes may prove useful for clinical applications. The presence of fine particles in Martian and lunar soil poses a significant threat to NASA’s viable long-term exploration and habitation of either the moon or Mars. It has been experimentally shown that the acoustic levitating radiation force produced by a 13.8 kHz 128 dB sound-level standing wave between a 3 cm-aperture acoustic tweeter and a reflector separated by 9 cm is strong enough to overcome the van der Waals adhesive force between the dust-particles and the reflector-surface. The majority of fine particles (> 2μm diameter) on a reflector surface can be dislodged and removed by a technique combining acoustic levitation and airflow methods. This dust removal technique may be used in space-stations or other enclosures for habitation.

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Daftardar, Saloni B. "Ultrasound-mediated Topical Delivery of Econazole nitrate for Treating Raynaud’s Phenomenon". University of Toledo Health Science Campus / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=mco1501501075880616.

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Furdella, Kenneth J., Russell S. Witte e Geest Jonathan P. Vande. "Tracking delivery of a drug surrogate in the porcine heart using photoacoustic imaging and spectroscopy". SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS, 2017. http://hdl.handle.net/10150/624370.

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Although the drug-eluting stent (DES) has dramatically reduced the rate of coronary restenosis, it still occurs in up to 20% of patients with a DES. Monitoring drug delivery could be one way to decrease restenosis rates. We demonstrate real-time photoacoustic imaging and spectroscopy (PAIS) using a wavelength-tunable visible laser and clinical ultrasound scanner to track cardiac drug delivery. The photoacoustic signal was initially calibrated using porcine myocardial samples soaked with a known concentration of a drug surrogate (Dil). Next, an in situ coronary artery was perfused with DiI for 20 min and imaged to monitor dye transport in the tissue. Finally, a partially DiI-coated stent was inserted into the porcine brachiocephalic trunk for imaging. The photoacoustic signal was proportional to the DiI concentration between 2.4 and 120 mu g/ml, and the dye was detected over 1.5 mm from the targeted coronary vessel. Photoacoustic imaging was also able to differentiate the DiI-coated portion of the stent from the uncoated region. These results suggest that PAIS can track drug delivery to cardiac tissue and detect drugs loaded onto a stent with sub-mm precision. Future work using PAIS may help improve DES design and reduce the probability of restenosis. (C) 2017 Society of Photo-Optical Instrumentation Engineers (SPIE)

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36

Hutcheson, Joshua Daniel. "Quantification and control of ultrasound-mediated cell death modes". Thesis, Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/29768.

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Thesis (M. S.)--Chemical Engineering, Georgia Institute of Technology, 2009.
Committee Chair: Prausnitz, Mark; Committee Member: Bommarius, Andreas; Committee Member: Jones, Christopher; Committee Member: Sambanis, Athanassios. Part of the SMARTech Electronic Thesis and Dissertation Collection.

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Aryal, Muna. "Transient disruption of vascular barriers using focused ultrasound and microbubbles for targeted drug delivery in the brain". Thesis, Boston College, 2014. http://hdl.handle.net/2345/bc-ir:104127.

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Thesis advisor: Cyril P. Opeil
The physiology of the vasculature in the central nervous system (CNS) which includes the blood-brain-barrier (BBB) and other factors, prevents the transport of most anticancer agents to the brain and restricts delivery to infiltrating brain tumors. The heterogeneous vascular permeability in tumor vessels (blood-tumor barrier; BTB), along with several other factors, creates additional hurdles for drug treatment of brain tumors. Different methods have been used to bypass the BBB/BTB, but they have their own limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Magnetic Resonance Imaging guided Focused Ultrasound (MRIgFUS), when combined with circulating microbubbles, is an emerging noninvasive method to temporarily permeabilize the BBB and BTB. The purpose of this thesis was to use this alternative approach to deliver chemotherapeutic agents through the BBB/BTB for brain tumor treatment in a rodent model to overcome the hinderances encountered in prior approaches tested for drug delivery in the CNS. The results presented in thesis demonstrate that MRIgFUS can be used to achieve consistent and reproducible BBB/BTB disruption in rats. It enabled us to achieve clinically-relevant concentrations of doxorubicin (~ 4.8±0.5 µg/g) delivered to the brain with the sonication parameters (0.69 MHz; 0.55 MPa; 10 ms bursts; 1 Hz PRF; 60 s duration), microbubble concentration (Definity, 10 µl/kg), and liposomoal doxorubicin (Lipo-DOX) dose (5.67 mg/kg) used. The resulting doxorubicin concentration was reduced by 32% when the agent was injected 10 minute after the last sonication. Three weekly sessions of FUS and Lipo-DOX appeared to be safe in the rat brain, despite some minor tissue damage. Importantly, the severe neurotoxicity seen in earlier works using other approaches does not appear to occur with delivery via FUS-BBB disruption. The resuls from three weekly treatments of FUS and Lipo-DOX in a rat glioma model are highly promising since they demonstrated that the method significantly inhibits tumor growth and improves survival. Animals that received three weekly sessions of FUS + Lipo-DOX (N = 8) had a median survival time that was increased significantly (P<0.001) compared to animals who received Lipo-DOX only (N = 6), FUS only (N = 8), or no treatment (N = 7). Median survival for animals that received FUS + Lipo-DOX was increased by 100% relative to untreated controls, whereas animals who received Lipo-DOX alone had only a 16% improvement. Animals who received only FUS showed no improvement. No tumor cells were found in histology in 4/8 animals in the FUS + Lipo-DOX group, and only a few tumor cells were detected in two animals. Tumor doxorubicin concentrations increased monotonically (823±600, 1817±732 and 2432±448 ng/g) in the control tumors at 9, 14 and 17 days respectively after administration of Lipo-DOX. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P<0.05, P<0.01, and P<0.0001 at days 9, 14, and 17, respectively) and were greater than the control tumors by a factor of two or more (2222±784, 3687±796 and 5658±821 ng/g) regardless of the stage of tumor growth. The transfer coefficient Ktrans was significantly (p<0.05) enhanced compared to control tumors only at day 9 but not at day 14 or 17. These results suggest that FUS-induced enhancements in tumor drug delivery for Lipo-DOX are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da). Overall, this thesis research provides pre-clinical data toward the development of MRIgFUS as a noninvasive method for the delivery of agents such as Lipo-DOX across the BBB/BTB to treat patients with diseases of the central nervous system
Thesis (PhD) — Boston College, 2014
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Physics

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Owen, J. W. "Magnetic microbubbles : investigation and design of new formulations for targeted therapy". Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:47537fb2-76e2-4e84-94bf-1530c57ff25a.

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Targeted therapy is a significant area of research in pharmaceutical and biomedical science. Its overall aim is to achieve maximum impact on malignant cells with minimum side effects to healthy tissue. In this thesis the capabilities of magnetic microbubbles as targeted therapeutic delivery vehicles are explored. New characterisation techniques were developed in order to understand and improve the current magnetic microbubble formulation. Electron microscopy was used to analyse the nanoscale structure of microbubble shells and observe nanoparticles attached to the shell surface. A new flow phantom was developed and the targeting of magnetic microbubbles against flow conditions corresponding to those in the human body was found to be feasible in numerous vessel sizes and flow conditions. Magnetic targeting of microbubbles was also observed in a perfused porcine liver model. Magnetic targeting was then attempted against flowing blood and a decrease in targeting efficiency observed. This was also seen for biochemical targeting and collisions with red blood cells identified as the most likely cause. Importantly, the number of magnetically targeted microbubbles significantly exceeded those targeted via biochemical interactions in both blood and water. In the second part of the thesis new types of magnetic microbubble were developed. The first exploits the fusion of nano-scale magnetic droplets with phospholipid microbubbles. In the second magnetic nanoparticles were incorporated directly into the lipid shell. The new magnetic microbubble formulation could be magnetically targeted, observed via contrast ultrasound and was successfully used to deliver siRNA to neuroblastoma cells.

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Williams, Jacob Brian. "Nanoemulsions Within Liposomes for Cytosolic Drug Delivery to Multidrug-Resistant Cancer Cells". BYU ScholarsArchive, 2016. https://scholarsarchive.byu.edu/etd/6211.

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Cancer cells that survive chemotherapy treatment often develop resistance to the administered chemotherapeutics, as well as to many other types of drugs, because the cancer cells increase their production of efflux pumps in the cell. This undesired phenomenon of resistance to cancer drugs is known as multidrug resistance. This work uses a novel drug carrier, called an eLiposome, to achieve cytosolic drug delivery to kill multidrug-resistant cancer cells. An eLiposome consists of a perfluoropentane (PFC5) emulsion droplet inside of a liposome. Folate attached to the eLiposome facilitates uptake into the cell. The PFC5 droplet is metastable at body temperature, but will rupture the liposome as the droplet expands during vaporization, and will release any drugs encapsulated inside of the liposome directly to the cell cytosol. Laser and ultrasound were examined as triggers to initiate the vaporization of the PFC5 droplet and actuate the release of doxorubicin (Dox) from folated eLiposomes containing Dox (feLD). Gold nanorods (GNRs) were synthesized and transferred to PFC5 droplets. Although GNRs are efficient at converting irradiated laser light to heat, no vaporization of the PFC5 droplets was observed when irradiated with laser light. Further investigation into the energy required for vaporization of PFC5 droplets revealed that there are currently no portable and wearable lasers available to provide enough energy to vaporize PFC5 droplets. Two seconds of ultrasound can release 78% of encapsulated Dox from feLD. Dox-sensitive KB-3-1 cells and Dox-resistant KB-V1 cells treated with feLD (without ultrasound) had cell viabilities of 33% and 60%, respectively. Ultrasound had negligible additional effect on the cell viability of KB-3-1 and KB-V1 cells treated with feLD (33% and 53%, respectively). We hypothesized that the Dox fiber formed during the loading of Dox into the eLiposome is a site for heterogeneous nucleation once the feLD is endocytosed by the cell, and vaporization and drug release occurs with or without ultrasound. Blocking the efflux pumps with verapamil decreases the rate at which Dox is exported from multidrug-resistant cells. When verapamil is co-delivered with feLD, the cell viability of KB-3-1 and KB-V1 cells decreases to 29% and 25%, respectively; thereby reversing the multidrug resistance possessed by KB-V1 cells. The delivery of doxorubicin inside of folated eLiposomes with an efflux pump blocker is a novel way to kill multidrug-resistant cancer cells as effectively as non-resistant cancer cells independent of lasers or ultrasound.

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40

Appold, Lia [Verfasser], Andrij [Akademischer Betreuer] Pich, Twan [Akademischer Betreuer] Lammers e Lothar [Akademischer Betreuer] Elling. "A polymeric microbubble platform for ultrasound-mediated drug delivery / Lia Appold ; Andrij Pich, Twan Lammers, Lothar Elling". Aachen : Universitätsbibliothek der RWTH Aachen, 2018. http://d-nb.info/1194066518/34.

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41

Solorio, Luis Jr. "Application of Ultrasound Imaging for Noninvasive Characterization of Phase Inverting Implants". Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1332258338.

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42

Wischhusen, Jennifer. "Ultrasound Microbubbles for Molecular Imaging and Drug Delivery : detection of Netrin-1 in Breast Cancer & Immunomodulation in Hepatocellular Carcinoma". Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1317/document.

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Dans l'imagerie moléculaire par ultrasons, des microbulles sont fonctionnalisées avec des ligands. Après injection intraveineuse, ces microbulles ciblées s'accrochent aux marqueurs présents sur l'endothélium tumoral et permettent une détection non-invasive. Dans cette thèse, l'imagerie moléculaire par ultrasons a été développée pour la détection de la nétrine-1, qui est surexprimée dans 70% des cancers du sein et promeut la survie cellulaire. Une nouvelle thérapie moléculaire interférant avec la nétrine-1 a été développée et nécessite l'identification des patientes qui pourront bénéficier de ce traitement. Avec l'imagerie moléculaire de la nétrine-1, il a été possible de discriminer les tumeurs positives pour la nétrine-1 des tumeurs négatives. Par sa capacité à détecter de manière spécifique la nétrine-1 présentée sur l'endothélium des tumeurs, cette technique d'imagerie pourrait donc devenir un test d'accompagnement pour la thérapie d'interférence de la nétrine-1 chez les patientes atteintes de cancer du sein.La destruction ciblée des microbulles par ultrasons induit la cavitation et la sonoporation qui perméabilisent le tissu et facilite la délivrance locale de médicaments. De plus, cette destruction ciblée peut induire l'infiltration de cellules immunitaires et la libération d'antigènes tumoraux, déclenchant une réponse immunitaire anti-tumorale. Dans cette thèse, nous avons quantifié l'activation de la réponse immunitaire dans le carcinome hépatocellulaire, suivant la délivrance de nanoparticules chargés en microARN-122 et anti-microARN-21. Dans les nœuds lymphocytaires tumoraux, une baisse d'expression des cytokines pro-tumorales et une augmentation d'expression des cytokines anti-tumorales ont été observées, suggérant une réponse thérapeutique positive. L'approche thérapeutique de destruction ciblée des microbulles par ultrasons pour la délivrance de micro-ARN s'avère donc être un outil immuno-modulatoire puissant
Ultrasound molecular imaging uses microbubbles as ultrasound contrast agents which are functionalized with targeting ligands. Upon intravenous injection, targeted microbubbles bind to molecular markers presented on the tumor endothelium and enable the non-invasive assessment cancer-related biomarkers. In the present thesis, ultrasound molecular imaging was developed for detection of netrin-1, which is upregulated in 70% of metastatic breast cancer and promotes cell survival. A newly developed netrin-1 interference therapy requires the identification of patients who overexpress the target protein and, could benefit from anti-netrin-1 therapy. In vivo imaging of netrin-1 showed a significantly increased imaging signal in netrin-1-positive breast tumors compared to netrin-1-negative breast tumors and normal mammary glands. The results suggest that ultrasound molecular imaging allows accurate detection of netrin-1 on the endothelium of netrin-1-positive tumors and has the potential to become a companion diagnostic for netrin-1 interference therapy in breast cancer patients.Ultrasound-targeted microbubble destruction triggers cavitation and sonoporation thereby permeabilizing the tissue and facilitating local drug delivery. Further, immune cell infiltration and tumor antigen release are induced and trigger anti-tumor immune responses. In the present thesis, ultrasound-targeted microbubble destruction-mediated delivery of anti-cancer microRNA-122 and anti-microRNA-21 is studied for immune response activation in hepatocellular carcinoma, in which the immune microenvironment is deregulated. Tumor lymph nodes showed pro-tumor cytokine downregulation and anti-tumor cytokine upregulation, suggesting an overall positive therapy response with regard to the tumor immunology. The results identified ultrasound-targeted microbubble destruction-mediated miRNA delivery as a potent immuno-modulatory therapeutic approach

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43

Javadi, Marjan. "Novel Liposomes for Targeted Delivery of Drugs and Plasmids". BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/3879.

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People receiving chemotherapy not only suffer from side effects of therapeutics but also must buy expensive drugs. Targeted drug and gene delivery directed to specific tumor-cells is one way to reduce the side effect of drugs and use less amount of therapeutics. In this research, two novel liposomal nanocarriers were developed. This nanocarrier, called an eLiposome, is basically one or more emulsion droplets inside a liposome. Emulsion droplets are made of perfluorocarbons which usually have a high vapor pressure. Calcein (as a model drug) and Paclitaxel were used to demonstrate drug delivery, and plasmids and siRNA were used to exemplify gene delivery. Drugs or genes were encapsulated inside the interior of the liposomes along with emulsion droplets; targeting moieties were attached to the outside of the phospholipid bilayer. Ultrasound was used to break open the bilayer by changing the liquid emulsion droplets to gas, which released the content of the eLiposomes. Transmission electron microscopy (TEM) was used to prove the formation of eLiposomes and confocal microscopy showed the uptake of drugs and genes in vitro. Cell viability was measured to show the effect of uptake in cancer cells. Results indicate that eLiposomes were successfully made and that they were endocytosed into the cell. It was observed that the emulsion and the targeting moiety in combination with ultrasound are the essential elements required to produce release from eLiposomes.

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44

Wischhusen, Jennifer. "Ultrasound Microbubbles for Molecular Imaging and Drug Delivery : detection of Netrin-1 in Breast Cancer & Immunomodulation in Hepatocellular Carcinoma". Electronic Thesis or Diss., Lyon, 2017. http://www.theses.fr/2017LYSE1317.

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Dans l'imagerie moléculaire par ultrasons, des microbulles sont fonctionnalisées avec des ligands. Après injection intraveineuse, ces microbulles ciblées s'accrochent aux marqueurs présents sur l'endothélium tumoral et permettent une détection non-invasive. Dans cette thèse, l'imagerie moléculaire par ultrasons a été développée pour la détection de la nétrine-1, qui est surexprimée dans 70% des cancers du sein et promeut la survie cellulaire. Une nouvelle thérapie moléculaire interférant avec la nétrine-1 a été développée et nécessite l'identification des patientes qui pourront bénéficier de ce traitement. Avec l'imagerie moléculaire de la nétrine-1, il a été possible de discriminer les tumeurs positives pour la nétrine-1 des tumeurs négatives. Par sa capacité à détecter de manière spécifique la nétrine-1 présentée sur l'endothélium des tumeurs, cette technique d'imagerie pourrait donc devenir un test d'accompagnement pour la thérapie d'interférence de la nétrine-1 chez les patientes atteintes de cancer du sein.La destruction ciblée des microbulles par ultrasons induit la cavitation et la sonoporation qui perméabilisent le tissu et facilite la délivrance locale de médicaments. De plus, cette destruction ciblée peut induire l'infiltration de cellules immunitaires et la libération d'antigènes tumoraux, déclenchant une réponse immunitaire anti-tumorale. Dans cette thèse, nous avons quantifié l'activation de la réponse immunitaire dans le carcinome hépatocellulaire, suivant la délivrance de nanoparticules chargés en microARN-122 et anti-microARN-21. Dans les nœuds lymphocytaires tumoraux, une baisse d'expression des cytokines pro-tumorales et une augmentation d'expression des cytokines anti-tumorales ont été observées, suggérant une réponse thérapeutique positive. L'approche thérapeutique de destruction ciblée des microbulles par ultrasons pour la délivrance de micro-ARN s'avère donc être un outil immuno-modulatoire puissant
Ultrasound molecular imaging uses microbubbles as ultrasound contrast agents which are functionalized with targeting ligands. Upon intravenous injection, targeted microbubbles bind to molecular markers presented on the tumor endothelium and enable the non-invasive assessment cancer-related biomarkers. In the present thesis, ultrasound molecular imaging was developed for detection of netrin-1, which is upregulated in 70% of metastatic breast cancer and promotes cell survival. A newly developed netrin-1 interference therapy requires the identification of patients who overexpress the target protein and, could benefit from anti-netrin-1 therapy. In vivo imaging of netrin-1 showed a significantly increased imaging signal in netrin-1-positive breast tumors compared to netrin-1-negative breast tumors and normal mammary glands. The results suggest that ultrasound molecular imaging allows accurate detection of netrin-1 on the endothelium of netrin-1-positive tumors and has the potential to become a companion diagnostic for netrin-1 interference therapy in breast cancer patients.Ultrasound-targeted microbubble destruction triggers cavitation and sonoporation thereby permeabilizing the tissue and facilitating local drug delivery. Further, immune cell infiltration and tumor antigen release are induced and trigger anti-tumor immune responses. In the present thesis, ultrasound-targeted microbubble destruction-mediated delivery of anti-cancer microRNA-122 and anti-microRNA-21 is studied for immune response activation in hepatocellular carcinoma, in which the immune microenvironment is deregulated. Tumor lymph nodes showed pro-tumor cytokine downregulation and anti-tumor cytokine upregulation, suggesting an overall positive therapy response with regard to the tumor immunology. The results identified ultrasound-targeted microbubble destruction-mediated miRNA delivery as a potent immuno-modulatory therapeutic approach

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45

DATTA, SAURABH. "The Role of Cavitation in Enhancement of rt-PA Thrombolysis". University of Cincinnati / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1196034787.

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46

Bhargava, Aarushi. "Dynamics of smart materials in high intensity focused ultrasound field". Diss., Virginia Tech, 2020. http://hdl.handle.net/10919/97994.

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Smart materials are intelligent materials that change their structural, chemical, mechanical, or thermal properties in response to an external stimulus such as heat, light, and magnetic and electric fields. With the increase in usage of smart materials in many sensitive applications, the need for a remote, wireless, efficient, and biologically safe stimulus has become crucial. This dissertation addresses this requirement by using high intensity focused ultrasound (HIFU) as the external trigger. HIFU has a unique capability of maintaining both spatial and temporal control and propagating over long distances with reduced losses, to achieve the desired response of the smart material. Two categories of smart materials are investigated in this research; shape memory polymers (SMPs) and piezoelectric materials. SMPs have the ability to store a temporary shape and returning to their permanent or original shape when subjected to an external trigger. On the other hand, piezoelectric materials have the ability to convert mechanical energy to electrical energy and vice versa. Due to these extraordinary properties, these materials are being used in several industries including biomedical, robotic, noise-control, and aerospace. This work introduces two novel concepts: First, HIFU actuation of SMP-based drug delivery capsules as an alternative way of achieving controlled drug delivery. This concept exploits the pre-determined shape changing capabilities of SMPs under localized HIFU exposure to achieve the desired drug delivery rate. Second, solving the existing challenge of low efficiency by focusing the acoustic energy on piezoelectric receivers to transfer power wirelessly. The fundamental physics underlying these two concepts is explored by developing comprehensive mathematical models that provide an in-depth analysis of individual parameters affecting the HIFU-smart material systems, for the first time in literature. Many physical factors such as acoustic, material and dynamical nonlinearities, acoustic standing waves, and mechanical behavior of materials are explored to increase the developed models' accuracy. These mathematical frameworks are designed with the aim of serving as a basic groundwork for building more complex smart material-based systems under HIFU exposure.
Doctor of Philosophy
Smart materials are a type of intelligent materials that have the ability to respond to external stimuli such as heat, light, and magnetic fields. When these materials respond, they can change their structural, thermodynamical, mechanical or chemical nature. Due to this extraordinary property, smart materials are being used in many applications including biomedical, robotic, space, microelectronics, and automobile industry. However, due to increased sensitivity and need for safety in many applications, a biologically safe, wireless, and efficient trigger is required to actuate these materials. In this dissertation, sound is used as an external trigger to actuate two types of smart materials: shape memory polymers (SMPs) and piezoelectric materials. SMPs have an ability to store a temporary (arbitrarily deformed) shape and return to their permanent shape when exposed to a trigger. In this dissertation, focused sound induced thermal energy acts as a trigger for these polymers. A novel concept of focused ultrasound actuation of SMP-based drug delivery capsules is proposed as a means to solve some of the challenges being faced in the field of controlled drug delivery. Piezoelectric materials have an ability to generate electric power when an external mechanical force is applied and vice versa. In this study, sound pressure waves supply the external force required to produce electric current in piezoelectric disks, as a method for achieving power transfer wirelessly. This study aims to solve the current problem of low efficiency in acoustic power transfer systems by focusing sound waves. This dissertation addresses the fundamental physics of high intensity focused ultrasound actuation of smart materials by developing comprehensive mathematical models and systematic experimental investigations, that have not been performed till now. The developed models enable an in-depth analysis of individual parameters including nonlinear material behavior, acoustic nonlinearity and resonance phenomena that affect the functioning of these smart systems. These mathematical frameworks also serve as groundwork for developing more complex systems.

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Mukherjee, Prithiviraj. "Generation of Drug-loaded Echogenic Liposomes using Microfluidic Hydrodynamic Flow Focusing". University of Cincinnati / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460731209.

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SMITH, DENISE ANNE BUSH. "In vitro Characterization of Echogenic Liposomes (ELIP) for Ultrasonic Delivery of Recombinant Tissue-type Plasminogen Activator (rt-PA)". University of Cincinnati / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1214234148.

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Chakravarty, Prerona. "Photoacoustic drug delivery using carbon nanoparticles activated by femtosecond and nanosecond laser pulses". Diss., Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/33842.

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Cellular internalization of large therapeutic agents such as proteins or nucleic acids is a challenging task because of the presence of the plasma membrane. One strategy to facilitate intracellular drug uptake is to induce transient pores in the cell membrane through physical delivery strategies. Physical approaches are attractive as they offer more generic applicability compared with viral or biochemical counterparts. Pulsed laser light can induce the endothermic carbon-steam reaction in carbon-nanoparticle suspensions to produce explosive photoacoustic effects in the surrounding medium. In this study, for the first time, these photoacoustic forces were used to transiently permeabilize the cell membrane to deliver macromolecules into cells. Intracellular delivery using this method was demonstrated in multiple cell types for uptake of small molecules, proteins and DNA. At optimized conditions, uptake was seen in up to 50% of cells with nearly 100% viability and in 90% of cells with ≥90% viability, which compared favorably with other physical methods of drug delivery. Cellular bioeffects were shown to be a consequence of laser-carbon interaction and correlated with properties of the carbon and laser, such as carbon concentration and size, laser pulse duration, wavelength, intensity and exposure time. Similar results were observed using two different lasers, a femtosecond Ti: Sapphire laser and a nanosecond Nd: YAG laser. Uptake was also shown in murine skeletal muscles in vivo with up to 40% efficiency compared to non-irradiated controls. This synergistic use of nanotechnology with advanced laser technology could provide an alternative to viral and chemical-based drug and gene delivery.

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Staples, Bryant J. "Pharmacokinetics of Ultrasonically-Released, Micelle-Encapsulated Doxorubicin in the Rat Model and its Effect on Tumor Growth". Diss., CLICK HERE for online access, 2007. http://contentdm.lib.byu.edu/ETD/image/etd1844.pdf.

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