Дисертації з теми "Drug imaging"
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1
Blazek, Almira. "NMR imaging investigations of swelling-controlled drug delivery." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ34513.pdf.
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Trim, Paul James. "MALDI-MS imaging for direct drug distribution analysis." Thesis, Sheffield Hallam University, 2009. http://shura.shu.ac.uk/20455/.
Повний текст джерелаАнотація:
MALDI Imaging has gained huge interest in the past few years with an ever increasing population of specialists choosing to investigate samples using MALDI imaging, including growing interest and financial backing from pharma and contract research organisations. Presented within this thesis is the development and application of MALDI imaging techniques for a variety of analytical problems. The use of various software packages have been employed in the interpretation of the data acquired from MALDI experiments including, the use of statistical analysis for the identification of ion of interest from 6 distinct brain regions and also for the identification of ions of interest associated with small molecule tumour markers. The advantages of MALDI-IMS-MSI as a further separation stage within MALDI-MSI have been shown. Demonstrated is a method for MALDI-IMS-MS imaging of endogenous lipids in healthy tissue and tumours, also demonstrated is the application of MALDI-IMS-MS to xenobiotic distribution studies, it has been clearly shown that ion mobility separation within MALDI-MSI experiments can improve the analysis of xenobiotics by removing any interfering ions. With instrumentation development for MALDI a high repetition rate Nd:YVO4 laser has been assessed as a possible method for decreasing acquisition time.
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Chen, Chen. "Quantitative magnetic resonance imaging studies of extended drug release systems." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708155.
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Gade, Terence Peter Ferrante. "Integrated imaging of drug delivery : a molecular imaging approach to the optimization of cancer therapy /." Access full-text from WCMC:, 2007. http://proquest.umi.com/pqdweb?did=1432803381&sid=12&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Sauer, Anna Magdalena. "Live-cell imaging of drug delivery by mesoporous silica nanoparticles." Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-138222.
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6
Septiadi, Dedy. "Optical imaging and drug delivery using soft- and hard- nanomaterials." Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAF036/document.
Повний текст джерелаАнотація:
Le travail décrit dans cette thèse se concentre sur le développement de matériaux « durs et mous » ainsi que leur interaction avec les cellules biologiques pour une application finale dans le domaine de la théranostique couvrant l'imagerie, la détection, la thérapie génique et la thérapie du cancer. Dans ce contexte, nous avons tout d'abord étudié l'utilisation de complexes (II) de platine phosphorescents auto-assemblés comme sonde cellulaire. Nous avons étendu l'idée de bio-imagerie en introduisant un concept d’imagerie basée sur l’émission stimulée où nous étions en mesure de générer un laser provenant d'une cellule biologique unique sans utiliser de cavité optique conventionnelle. En outre, des nano-transporteurs multifonctionnels à base de matières poreuses dures à savoir des zéolithes L et des nanoparticules de silice mésoporeuse pour de la « drug delivery » (relargage de médicaments et d’oligonucléotides) in vitro ide ont été développés avec succès et testés pour le traitement du glioblastome. Un autre nano-vecteur, qui est construit à partir de silice biodégradable, a également été synthétisé et sa capacité d'encapsuler des protéines et de les libérer dans les cellules vivantes lors de la dégradation de la structure dans un environnement réducteur a été démontrée. Enfin, l'utilisation de nouveaux matériaux plasmonique sur la base de nanoparticules d'argent enrobées de silice cassable pour la détection d'agents réducteurs a été mise en valeurThe work described in this thesis focuses on the development of soft- and hard-materials as well as their interaction with biological cells for applications in the field of theranostics covering imaging, sensing, and gene, and cancer therapy. In this context, we first investigated the use of phosphorescent self-assembled platinum(II) complexes as cellular probes. We extended the concept stimulated emission-based bioimaging by generating a laser-like emission coming from a single biological cell without using any conventional optical cavity. In addition, we successfully developed multifunctional nanocarriers based on porous hard materials, namely zeolites-L and mesoporous silica nanoparticles for drug and oligonucleotide delivery in vitro and they were tested to treat glioblastoma. Another nanovector, which is constructed from biodegradable silica, was also synthesized and its ability to encapsulate proteins and release them in living cells upon degradation of the structure in reductive environment was demonstrated. Finally, the use of novel plasmonic structures based on breakable silica-coated silver nanoparticles for detection of reducing agents was successfully investigated
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Tang, Jingjie. "Innovative imaging systems and novel drug candidates for cancer therapy." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4021.
Повний текст джерелаАнотація:
Le cancer est l'une des principales causes de décès dans le monde et reste une maladie difficile à traiter du fait des difficultés de pronostic, du développement rapide de métastases et de la résistance aux médicaments. Il en résulte une forte demande en méthodologies d'imagerie innovantes pour le diagnostic précoce et précis ainsi qu’en nouveaux agents anticancéreux possédant de nouveaux mécanismes pour surmonter la résistance aux médicaments. Le but de mon projet de recherche de doctorat était donc de contribuer à cet objectif.La première partie de ma thèse de doctorat a porté sur la création de systèmes sensibles et précis d'imagerie pour la détection de tumeurs cancéreuses en utilisant une nanotechnologie novatrice permettant la délivrance des agents d'imagerie spécifiquement dans les lésions tumorales. Nous avons conçu de nouveaux dendrimères amphiphiles pour assurer le transport de différents agents d'imagerie pour les imageries PET/SPECT, par résonance magnétique et par fluorescence optique. Ces systèmes d'imagerie ont été préparés soit par encapsulation de petites sondes d'imagerie à l'intérieur de nanomicelles dendritiques ou par fonctionnalisation de la surface hydrophile ou de la queue hydrophobe du dendrimère. La deuxième partie a eu pour objectif de développer de nouveaux agents anticancéreux possédant nouveaux mécanismes d’action et une meilleure activité antitumorale. A cet effet, nous avons conçu une série de nucléosides arylvinyltriazoles par réaction oxydante de Heck, ce qui nous a permis d'obtenir les composés désirés pourtant difficiles à synthétiser avec un très large éventail de substrats et une stéréosélectivité uniqueCancer is one of the leading causes of death in the world, and remains a difficult disease to treat because of poor prognosis, rapid tumor metastasis and drug resistance. Therefore, innovative imaging modalities for early and precise diagnosis as well as new anticancer drug candidates with novel mechanisms to overcome drug resistance are in high demand. The aim of my PhD research project was to contribute to this goal.The first part of my PhD thesis was focused on establishing sensitive and precise imaging systems for cancer detection using innovative nanotechnology to deliver imaging agents specifically into tumor lesions. We designed and constructed novel amphiphilic dendrimers to carry different imaging agents for PET/SPECT imaging, magnetic resonance imaging and optical fluorescence imaging. These innovative imaging systems were prepared by either encapsulation of small imaging probes within the dendrimer nanomicelles, or functionalization of the dendrimer hydrophilic surface or hydrophobic tail. The second part of my PhD program aimed to develop new anticancer drug candidates with novel mechanisms for better anticancer activity. Therefore, we designed and synthesized a series of challenging arylvinyltriazole nucleosides via the oxidative Heck reaction, which allowed us to obtain the desired compounds with excellent substrate scope and unique stereoselectivity
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Varela, Aramburu Silvia [Verfasser]. "Carbohydrate-based Nanomaterials for Imaging and Drug Delivery / Silvia Varela Aramburu." Berlin : Freie Universität Berlin, 2018. http://d-nb.info/117663254X/34.
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Ewing, Andrew. "ATR-FTIR spectroscopic imaging to study drug release and tablet dissolution." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/51556.
Повний текст джерелаАнотація:
The active pharmaceutical ingredient (API) and excipients are vital for determining the behaviour of drug release from tablet compacts. Macro attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic imaging can be employed for in situ studies of dissolving tablets. This thesis describes new developments that applied macro ATR-FTIR spectroscopic imaging to investigate the stability and dissolution of amorphous APIs, the effect of carriers for improving drug release, the stability of ionised drug candidates and the behaviour of multiple formulations in microfluidic devices. Solid dispersions containing an amorphous drug formulated with different polymers were investigated using ATR-FTIR spectroscopy and spectroscopic imaging. Crystallisation of the amorphous drug was detected during stability and tablet dissolution experiments. The implications of this form change inhibited dissolution of the drug into solution. ATR-FTIR spectroscopic imaging was also used in combination with ultraviolet detection to study the release of a drug formulated with selected carriers. Hydrogen bonded interactions between the drug and carrier were characterised and resulted in an increased rate of drug release. When these interactions were not present in the tablet, a slower rate of dissolution was observed. Disproportionation of an ionised drug was investigated by ATR-FTIR spectroscopic imaging and Raman mapping. During dissolution experiments in acidic solution, chemical changes of the ionised API were detected in real time that resulted in the formation of the less soluble form of the drug. Exciting results were obtained by simultaneously screening the behaviour of multiple formulations in microfluidic channels using macro ATR-FTIR spectroscopic imaging. Moreover, the precipitation of a dissolved drug that crystallised upon contact with an acidic solution was investigated. Overall, the research in this thesis has demonstrated that macro ATR-FTIR spectroscopic imaging can address the challenges of studying a range of innovative delivery systems that can ultimately lead to the development of more efficient pharmaceutical formulations.
10
Zhang, Rui. "Ionic Copolymer-Magnetite Complexes for Magnetic Resonance Imaging and Drug Delivery." Thesis, Virginia Tech, 2015. http://hdl.handle.net/10919/73648.
Повний текст джерелаАнотація:
This thesis is focused on the design, synthesis and characterization of magnetite-ionic copolymer complexes as nanocarriers for drug delivery and magnetic resonance imaging. The polymers included phosphonate and carboxylate-containing graft and block copolymers. Oleic-acid coated magnetite nanoparticles (8-nm and 16-nm diameters) were investigated. Cisplatin and carboplatin were used as sample drugs. The potentials of the magnetite-ionomer complexes as dual drug delivery carriers and magnetic resonance imaging agents were evaluated.
An acrylate-functional poly(ethylene oxide) macromonomer and hexyl (and propyl) ammonium bisphosphonate methacrylate monomers were synthesized. Conventional free radical copolymerizations were conducted to synthesize the graft copolymers. The acrylate-functional poly(ethylene oxide) macromonomer was also used to form graft copolymers with tert-butyl acrylate. Block ionomers containing poly(tert-butyl acrylate) were synthesized via atom transfer radical polymerization, then the tert-butyl groups were removed to afford anions. All the monomers and polymers were characterized by 1H NMR to confirm their structures and assess their compositions. Phosphonate-containing polymers were also characterized by 31P NMR. Magnetite nanoparticles (8-nm diameter) were synthesized by reducing Fe(acac)3 with benzyl alcohol. The 16-nm diameter magnetite was synthesized by thermal decomposition of an iron oleate precursor in trioctylamine as a high-boiling solvent. The iron-oleate precursor was synthesized with iron (III) chloride hexahydrate and sodium oleate with mixed solvents. TEM images of the magnetite were obtained.
Magnetite-ionomer complexes were synthesized by binding a portion of the anions (carboxylate or phosphonate) on the copolymers onto the surfaces the magnetite. The remainder of the anions was used to bind with cisplatin and carboplatin via chelation. Physicochemical properties of the complexes were measured by dynamic light scattering. All the complexes with different polymers and magnetite nanoparticles displayed relatively uniform sizes and good size distributions. The magnetite-ionomer complexes displayed good colloidal stabilities in simulated physiological conditions for at least 24 hours. Those graft and block copolymer-magnetite complexes may be good candidates as drug carriers for delivery applications.
After cisplatin and carboplatin loading, the sizes of the complexes increased slightly and the zeta potential decreased slightly, which indicated that the loadings were successful. Minimal loss of iron was found, signaling that the binding strengths between the magnetite and the anions of the graft copolymers were strong. 8.7 wt% of platinum was found in the cisplatin loaded complexes and 6.9% in the carboplatin loaded complexes. The results indicated that the magnetite-graft ionomer complexes were capable of loading drugs. Drug release studies were performed at pH 4.6 and 7.4 to mimick endosomal conditions and the physiological environment. Sustained release of drugs was observed. This further indicated the potential for using the magnetite-ionomer complexes as drug carriers.
Transverse relaxivities of the magnetite-ionomer complexes with and without drugs were measured and compared to a commercial T2-weighted iron MRI contrast agent-Feridex®. All the complexes had higher relaxivities compared to Feridex®. Thus, the magnetite-ionomer complexes are promising candidates for dual magnetic resonance imaging and drug delivery.Moreover, the aqueous dispersion of the complexes was found to heat upon exposure to an AC magnetic field, thus potentially allowing heat-induced drug release.Master of Science
11
Kim, Heekyong Stephanie. "Analysis of drug delivery in the eye using magnetic resonance imaging." College Park, Md.: University of Maryland, 2007. http://hdl.handle.net/1903/7650.
Повний текст джерелаАнотація:
Thesis (Ph. D.) -- University of Maryland, College Park, 2007.Thesis research directed by: Dept. of Chemical and Biomolecular Engineering. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Johnston, Alexander Henderson. "Novel approaches to dendrimer based radiopharmaceutical imaging agents and drug delivery systems." Thesis, University of Southampton, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.582662.
Повний текст джерелаАнотація:
The work reported in this thesis details two novel approaches towards the use of poly(amidoamine) (PAMAM) dendrimers for medicinal applications. The introduction contains a brief overview on the synthesis and properties of dendrimers, focusing in particular on PAMAM dendrimers and the growing interest in their use as polymer therapeutics. The second part of the introduction contains an overview of the role of Tc99m in nuclear medicine. The final part of the introduction gives an explanation of the genetic disorder, cystic fibrosis, concentrating on the degenerative lung disease associated with the disease and the role neutrophil elastase has in the degeneration of the lung. The next chapter then proceeds to describe the preparation of 4th and 5th generation PAMAM dendrimers with dioctylamine surface groups. These surface modified dendrimers are reported as potential NaTc99m04 complexation systems for potential application as radiopharmaceutical agents for use in lung imaging. The next chapter describes the preparation of PAMAM dendrimers with p-lactam and saccharine-based inhibitors linked to the surface. These modified dendrimers are shown to inhibit intracellular neutrophil elastase in samples of human blood. The results indicate that the modified dendrimers could potentially be used to reduce the extent of lung damage in a cystic fibrosis patient and improve both their quality of life and life expectancy.
13
Pothayee, Nipon. "Development of Polymeric Nanocarriers for Dual Magnetic Resonance Imaging and Drug Delivery." Diss., Virginia Tech, 2013. http://hdl.handle.net/10919/24355.
Повний текст джерелаАнотація:
Two types of (polymer-imaging agent-drug) complexes were prepared and characterized. These included block and graft copolymer complexes with magnetite nanoparticles and manganese ions.
Magnetite block ionomer complexes (MBICs) were formed through binding of a portion of the anionic segment of poly(ethylene oxide)-b-poly(acrylic acid) (PEO-b-PAA) block copolymers with the magnetite nanoparticle surfaces. The remainder of the carboxylic acids were utilized to bind with high concentrations of the cationic antibiotic gentamicin (31 wt%). A near zero-order release of gentamicin (pH 7.4 in PBS) that reached ~35 wt% of the initial gentamicin within 10 hours was observed, and this was followed by slower release of another 7 % by 18 hours. These nanoparticles were efficiently taken up by macrophages and appeared to enhance intracellular antimicrobial activities of gentamicin. To increase the complex sizes and NMR T2 relaxivities, amine functional MBICs (MBICs-NH2) were first assembled by adsorbing the polyacrylate block of an aminofunctional poly(ethylene oxide)-b-poly(acrylic acid)) (H2N-PEO-b-PAA) copolymer onto magnetite nanoparticles. Amines at the tips of the H2N-PEO corona were then linked through reaction with a PEO diacrylate oligomer to yield MBIClusters where the metal oxides in the precursor nanoparticles were distinctly separated by the hydrophilic polymer. These MBIClusters with hydrophilic intra-cluster space had transverse relaxivities (r2's) that increased from 190 to 604 s-1 mM Fe-1 measured at 1.4 T and 37°C as their average sizes increased. The clusters were loaded with up to ~38 wt% of the multi-cationic drug gentamicin. MRI scans focused on the livers of mice demonstrated that these MBIClusters are very sensitive contrast agents. These results indicate that these complexes could be potential theranostic agents for dual imaging and drug delivery.
Manganese graft ionomer complexes (MaGICs) comprised of Mn ions and a novel polyaminobisphosphonate-g-PEO copolymer were developed for use as T1 weighted MRI positive contrast agents. The graft copolymers were prepared by free radical copolymerization of ammonium bisphosphonate methacrylate monomers with PEO-acrylate macromonomers. The complexes exhibited good colloidal stability without release of free manganese and did not show any in vitro toxicity against mouse hepatocytes. The T1 relaxivities of the MaGICs were 2-10 times higher than that of a commercial manganese based contrast agent MnDPDP. These MaGICs with encapsulated anticancer drugs including doxorubicin, cisplatin and carboplatin have encapsulation efficiencies of 80-100 %. Drug release was sustained and depended on environmental pH, drug structure and drug concentration in the MaGICs. Moreover, these drug-loaded complexes exhibited high anticancer efficacy against MCF-7 breast cancer cells. The prominent MRI relaxivities and high anticancer efficacy suggest that these MaGICs have potential as effective dual imaging and chemotherapeutic agents.Ph. D.
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Wen, Amy M. "Engineering Virus-Based Nanoparticles for Applications in Drug Delivery, Imaging, and Biotechnology." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1452954511.
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Perumal, Meg. "Positron emission tomography imaging of platinum resistant ovarian cancer and drug modulation." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/10532.
Повний текст джерелаАнотація:
Epithelial ovarian cancer is the commonest cause of death from gynaecological malignancy. Platinum based chemotherapy remains the cornerstone of first-line therapy for ovarian cancer, however relapse is common and acquired resistance is frequently observed on subsequent lines of platinum based treatment. Because activation of the PI3K/AKT pathway has been shown to play a role in acquired platinum resistance phenotype of ovarian cancer, combination of platinum with AKT pathway inhibitors holds promise for resensitising tumours to platinum. The aims of this thesis were i) to evaluate the effect of pharmacological AKT inhibitors AKT on the resensitisation of clinically-derived platinum resistant ovarian cancer cells to platinum, and ii) establish molecular imaging approaches for monitoring resensitisation to platinum in vivo combined with biochemical profiling of pathway activity. Treatment of platinum sensitive PEO1 ovarian cancer cells with cisplatin induced growth inhibition and apoptosis. The AKT inhibitor, API-2, resensitised paired platinum resistant PEO4 cells to cisplatin. These in vitro studies established 1h pre-treatment time point with API-2 followed by cisplatin as the most appropriate schedule for further studies. Resensitisation to platinum appeared to be a pathway effect rather than a specific effect of API-2. In order to establish the utility of PET imaging for therapy response, a bilateral tumour xenograft model comprising of platinum sensitive PEO1 and the platinum resistant cell line PEO4 was developed. Both [18F]fluorothymidine ([18F]FLT)-PET, which measures proliferation, and [18F]fluorodeoxyglucose ([18F]FDG)-PET, which measures glucose metabolism detected responses to cisplatin alone in PEO1 tumours and the combination of cisplatin and API-2 in both PEO1 and PEO4 tumours. Correlative reduction in phosphorylated PRAS40, a direct downstream marker of AKT activity indicated that in vivo changes in imaging variables of the combination treatment resulted from AKT inhibition. The imaging changes were also linked to histological reductions in Ki67 labelling index. AKT Biochemical profiling of tumours obtained after imaging confirmed that the changes in tumour [18F]FDG and [18F]FLT uptake were due, at least in part, to reductions in the expression of glucose transporter Glut-1 and hexokinase activity, as well as decreases in TK1 expression, respectively. These studies demonstrated that [18F]FDG-and [18F]FLT-PET hold promise for clinical evaluation of platinum resensitisation in patients with platinum resistant ovarian cancer. Given also that combination treatment with cisplatin and API-2 induced apoptosis in PEO4 cells in vitro, further studies were conducted with the aim of establishing [18F]ICMT11 PET, a specific cleaved caspase-3/7 radiotracer, for monitoring re-sensitisation to platinum in PEO4 tumours. [18F]ICMT11 uptake detected by PET increased after combination treatment but not with cisplatin alone. Parallel increases in TUNEL and cleaved caspase-3 staining by immunohistochemistry were observed consistent with the PET outcome. Thus, [18F]ICMT11 PET could also find utility in monitoring early responses to platinum therapy in combination with AKT inhibition. In addition to the 3 imaging agents described above, analysis of baseline levels of integrin αvβ3/5 expression, an index of angiogenesis, as well as myo-inositol uptake were investigated as potential discriminators of platinum resistant phenotype. These preliminary experiments were inconclusive. In summary PET imaging of proliferation, glucose metabolism and apoptosis were shown to be promising techniques for early detection of resensitisation to platinum therapy in platinum resistant ovarian cancer and warrant further investigation.
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Sauer, Anna Magdalena [Verfasser], and CHRISTOPH [Akademischer Betreuer] BRAEUCHLE. "Live-cell imaging of drug delivery by mesoporous silica nanoparticles : Drug loading, pore sealing, cellular uptake and controlled drug release / Anna Magdalena Sauer. Betreuer: Christoph Bräuchle." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2011. http://d-nb.info/1018847219/34.
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Mezzanotte, Laura <1982>. "Bioanalytical applications of multicolour bioluminescence imaging: new tools for drug discovery and development." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2011. http://amsdottorato.unibo.it/3536/.
Повний текст джерелаАнотація:
The subject of this thesis is multicolour bioluminescence analysis and how it can provide new tools for drug discovery and development.The mechanism of color tuning in bioluminescent reactions is not fully understood yet but it is object of intense research and several hypothesis have been generated. In the past decade key residues of the active site of the enzyme or in the surface surrounding the active site have been identified as responsible of different color emission. Anyway since bioluminescence reaction is strictly dependent from the interaction between the enzyme and its substrate D-luciferin, modification of the substrate can lead to a different emission spectrum too. In the recent years firefly luciferase and other luciferases underwent mutagenesis in order to obtain mutants with different emission characteristics. Thanks to these new discoveries in the bioluminescence field multicolour luciferases can be nowadays employed in bioanalysis for assay developments and imaging purposes. The use of multicolor bioluminescent enzymes expanded the potential of a range of application in vitro and in vivo. Multiple analysis and more information can be obtained from the same analytical session saving cost and time. This thesis focuses on several application of multicolour bioluminescence for high-throughput screening and in vivo imaging. Multicolor luciferases can be employed as new tools for drug discovery and developments and some examples are provided in the different chapters. New red codon optimized luciferase have been demonstrated to be improved tools for bioluminescence imaging in small animal and the possibility to combine red and green luciferases for BLI has been achieved even if some aspects of the methodology remain challenging and need further improvement. In vivo Bioluminescence imaging has known a rapid progress since its first application no more than 15 years ago. It is becoming an indispensable tool in pharmacological research. At the same time the development of more sensitive and implemented microscopes and low-light imager for a better visualization and quantification of multicolor signals would boost the research and the discoveries in life sciences in general and in drug discovery and development in particular.
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Balderstone, Lucy Anne. "Use of fluorescent imaging to monitor drug responses in mouse models of tumourigenesis." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17859.
Повний текст джерелаАнотація:
As our understanding of the complexities of cancer biology has increased, the ability to exploit unique features of tumour cells with molecularly targeted therapies has become a reality. However, despite unprecedented volumes of new molecules in clinical trials, the number of highly effective drugs approved by the regulatory authorities remains disappointingly low. Moreover, oncology drug development is plagued by high levels of attrition in late phase clinical development. Failure due to poor efficacy and toxicity issues are not believed to be a result of the development of molecules with inadequate pharmaceutical properties, but rather due to a lack of understanding of their full mechanism of action. All of this points to imprecise analysis of the drugs during the preclinical phase, highlighting the need for better preclinical drug development tools. Animal models provide a key preclinical tool, and as a therapeutic area, oncology is characterised by models which are not predictive of the true human pathology. Overexpression of the human epidermal growth factor receptor two (HER2) oncogene, and inactivation of the phosphatase and tensin (PTEN) tumour suppressor, are two important events in human breast cancer. A novel conditional mouse model driven by overexpression of HER2 coupled with / without the loss of PTEN has been characterised to interrogate the importance of these two cellular perturbations. Multifocal tumours arose in mice from both lines, while luminal tumour characteristics were shown to be reduced and basal characteristics increased with a reduction in PTEN expression. Disruption of PTEN rapidly accelerated tumour onset (from 138 to 82 days) and tumour growth (with the time from tumour onset to maximum tumour size reduced from 38 to 21 days), significantly reducing overall survival (from 165 to 102 days). The ability of tumour cells to colonize the lungs was not significantly affected by the loss of PTEN. Tumours arising in both mice genotypes were utilized to generate cell lines. These failed to provide an in vitro representation of the tumours, and found little utility in drug efficacy studies with HER family targeted agents, a situation which could be improved by the use of different culture methods. Since suppression of apoptosis is a hallmark of human cancer, and a desired endpoint of many anticancer therapies is the induction of cell death, the generation of cell lines inherently capable of sensing caspase-mediated apoptotic cell death would be a valuable drug development tool. Given that fluorescence imaging is also emerging as a potentially powerful modality for preclinical drug development, a novel fluorescent in house apoptosis reporter construct was generated (pCasFSwitch). Initial validation of pCasFSwitch by transient transfection into murine mammary carcinoma cells proved difficult due to transfection associated toxicity, yet proof-of-principle was indicated. Transfer of pCasFSwitch into a retroviral backbone vector enabled the generation of stably transfected squamous carcinoma cells more suitable for further analysis. Incubation of lysates from these cells with recombinant enzymes revealed the construct could be cleaved by caspase-3, but not by other members of the cysteine protease family. Furthermore, assessment of apoptosis levels in the cells upon staurosporine treatment proved the utility of the construct to quantify cell death, and was validated against data generated with a commercial competitor, NucView. Further comparison of the specificity of the imaging agents using caspase inhibitors was limited by the functionality of currently available inhibitors, but did reveal that in common with NucView, construct quantified levels of apoptosis were affected by inhibition. This thesis details the development of two preclinical drug development tools. A novel mouse model enables biological interrogation of two key events in human breast carcinogenesis. Since PTEN loss is associated with resistance to HER2 targeted therapies, it is ideally suited for efficacy testing to overcome such resistance. The in house fluorescent apoptosis imaging agent allows a temporal read-out of drug effects in live single cells. While the use of intravital imaging of stable cell lines implanted under imaging windows would allow in vivo validation of in vitro data. Taken together, such facilitation of thorough evaluation of therapies at the preclinical stage, will reduce the adverse effects felt by the pharmaceutical industry of failure late in the drug development pipeline.
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Flinders, Bryn. "The use of MALDI-MS for imaging drug disposition in respiratory disease models." Thesis, Sheffield Hallam University, 2013. http://shura.shu.ac.uk/19652/.
Повний текст джерелаАнотація:
Matrix-assisted laser desorption/ionisation-mass spectrometry imaging (MALDI-MSI) has been extensively applied to monitoring the distribution of pharmaceutical compounds in tissues. The main aim of the work reported in this thesis is to monitor the distribution of respiratory compounds in the lungs following inhaled delivery. Glucocorticoids that contain multiple carbonyl functionalities are not easily protonated/de-protonated to form charged species due to the poor ionisation efficiencies of the carbonyl functionalities. Derivatisation with hydrazine based reagents has been proposed as a solution to this problem. These reagents have been employed for the in-solution and on-tissue derivatisation of a range of glucocorticoids to form their respective hydrazones improving their mass spectral ionisation efficiency and detection. MALDI-MSI has been used to screen a set of respiratory compounds in order to determine their on-tissue limit of detection. The distribution of a Tiotropium Bromide was monitored throughout the lungs following inhaled delivery. High spatial resolution imaging enabled a detailed view of the distribution of Tiotropium in the trachea and major airways. Quantitative mass spectrometry imaging is a new field that has recently gained a lot of attention especially in pharmaceutical research. The ability to obtain quantitative information as well as the distribution of pharmaceutical compounds and associated metabolites offers a distinct advantage over traditional quantitative methods such as LC-MS/MS and QWBA. The current methods of generating quantification information from MALDI-MS images has been evaluated, which let development of a method for the preparation of standards for use in the quantification of drugs in tissue sections. MALDI-MSI has been used to acquire data from serial sections obtained at equal intervals through control mouse lung tissue, homogenate registration markers were incorporated in order to aid the final 3D image construction. Using two 3D imaging software packages were used to reconstruct the images were stacked together to enable the 3D distribution of a particular endogenous species throughout the lungs to be displayed.
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Guduru, Rakesh. "Bionano Electronics: Magneto-Electric Nanoparticles for Drug Delivery, Brain Stimulation and Imaging Applications." FIU Digital Commons, 2013. http://digitalcommons.fiu.edu/etd/979.
Повний текст джерелаАнотація:
Nanoparticles are often considered as efficient drug delivery vehicles for precisely dispensing the therapeutic payloads specifically to the diseased sites in the patient’s body, thereby minimizing the toxic side effects of the payloads on the healthy tissue. However, the fundamental physics that underlies the nanoparticles’ intrinsic interaction with the surrounding cells is inadequately elucidated. The ability of the nanoparticles to precisely control the release of its payloads externally (on-demand) without depending on the physiological conditions of the target sites has the potential to enable patient- and disease-specific nanomedicine, also known as Personalized NanoMedicine (PNM). In this dissertation, magneto-electric nanoparticles (MENs) were utilized for the first time to enable important functions, such as (i) field-controlled high-efficacy dissipation-free targeted drug delivery system and on-demand release at the sub-cellular level, (ii) non-invasive energy-efficient stimulation of deep brain tissue at body temperature, and (iii) a high-sensitivity contrasting agent to map the neuronal activity in the brain non-invasively. First, this dissertation specifically focuses on using MENs as energy-efficient and dissipation-free field-controlled nano-vehicle for targeted delivery and on-demand release of a anti-cancer Paclitaxel (Taxol) drug and a anti-HIV AZT 5’-triphosphate (AZTTP) drug from 30-nm MENs (CoFe2O4-BaTiO3) by applying low-energy DC and low-frequency (below 1000 Hz) AC fields to separate the functions of delivery and release, respectively. Second, this dissertation focuses on the use of MENs to non-invasively stimulate the deep brain neuronal activity via application of a low energy and low frequency external magnetic field to activate intrinsic electric dipoles at the cellular level through numerical simulations. Third, this dissertation describes the use of MENs to track the neuronal activities in the brain (non-invasively) using a magnetic resonance and a magnetic nanoparticle imaging by monitoring the changes in the magnetization of the MENs surrounding the neuronal tissue under different states.
The potential therapeutic and diagnostic impact of this innovative and novel study is highly significant not only in HIV-AIDS, Cancer, Parkinson’s and Alzheimer’s disease but also in many CNS and other diseases, where the ability to remotely control targeted drug delivery/release, and diagnostics is the key.
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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.
Повний текст джерелаАнотація:
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 compositesThis 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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Naik, Sweta. "Design of control release drug delivery system (DDS) for imaging and therapeutic applications." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/2606.
Повний текст джерелаАнотація:
The main challenge in disease treatment is no more the discovery of new therapeutic drugs, but to provide targeted delivery of therapeutic drugs to specific sites without incurring systemic toxicity effects. An efficient way of reducing the toxicity is by encapsulating the drug with a biodegradable matrix that can provide controlled release of the drug along with local heating of the drug. Local heating can be obtained by incorporating magnetic iron oxide particles that heat upon exposure to AC electromagnetic fields. The magnetic iron oxide nanoparticles are also gaining much attention as MRI contrast agents. Thus it would be of potential benefit if a drug delivery system is designed to encapsulate the drug as well as the magnetic iron oxide nanoparticles within a biodegradable matrix, thereby providing a dual modal imaging and therapeutic delivery system. The key step in the design of a dual modal drug delivery system is the encapsulation of the magnetic iron oxide nanoparticles with polymer of choice. The magnetic iron oxide nanoparticles were encapsulated into a robust poly (styrene-co-vinylbenzylchloride-co-divinylbenzene) (PSVBDVB) to study these synthetic variations upon encapsulation with a polymer. The next step to the design of drug delivery system was to replace the PSVBDVB polymer by a biocompatible and biodegradable polymer- Poly (lactide-co-glycolide) (PLGA). The PLGA composites containing the Fe@FeOx core shell nanoparticles and the drug analog [Ru(bpy) dye] was prepared by oil-in water emulsion solvent evaporation technique. The local heating of the PLGA composites was also achieved by irradiating the Fe@FeOx nanoparticles with 2.45 GHz microwave radiations. Higher Ru(bpy) dye release from the composites by locally heating the sample with 2.45 GHz microwave pulse compared to externally heating the composite sample was achieved. The final step was the design of controlled release drug delivery system with dual modal imaging and therapeutic capabilities. To obtain narrow sized PLGA composites the Fe@FeOx nanoparticles were replaced by chloroform based ferrofluid. The ferrofluid was synthesized by novel thermolysis technique. The release of the dye from the PLGA composites when placed in the Rf induction coil was determined by fluorescence spectroscopy and a linear increase in the fluorescent intensity was observed with time. Also, the controlled release of the dye from the composites was achieved by a pulsed Rf treatment. Magnetic resonance imaging was also performed using the PLGA composites which showed enhancement in the T2-weighted image contrast and thus negligible reduction in the contrast capabilities of the iron oxide particles (R2 = 58.7 s-1mM-1). The PLGA composites containing the drug analog and the iron oxide nanoparticles thus constitute a controlled release drug delivery system with dual modal imaging and therapeutic capabilities.
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Rose, Cornelia [Verfasser], and Achim [Akademischer Betreuer] Göpferich. "Particulate systems for fluorescence imaging and drug delivery / Cornelia Rose. Betreuer: Achim Göpferich." Regensburg : Universitätsbibliothek Regensburg, 2010. http://d-nb.info/1023312115/34.
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Li, Zhoulei. "Molecular imaging for characterization of lymphoma biology and monitoring response to cancer drug therapy." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-173181.
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Guduru, Rakesh. "In situ AFM Imaging of Nanoparticle- Cellular Membrane Interaction for a Drug Delivery Study." FIU Digital Commons, 2011. http://digitalcommons.fiu.edu/etd/422.
Повний текст джерелаАнотація:
Nanoparticles (NPs) play a crucial role in delivering therapeutic drugs to cancer cells. Understanding the interaction of NPs with cell surfaces and their internalization is imperative to develop a fully efficient drug delivery vehicle. In this study, atomic force microscopy (AFM) was used to evaluate the dynamic interactions of non-targeted and targeted poly (lactic-co-glycolic acid) (PLGA) NPs with ovarian cancer cells in native environmental conditions. Results demonstrated that the cells incubated in targeted NPs solution for 3 hours showed a 112% increase in cell surface roughness, whereas cells incubated in non-targeted NPs showed only a 38% increase. Cell surface roughness, when incubated for 6 hours, was higher for non-targeted NPs. The changes in cell membrane surface roughness were also monitored for NPs encapsulated with a doxorubicin drug. Based on the results it was concluded that the targeted NPs will attach to the cell membrane and internalize faster than the non-targeted NPs.
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Choi, Sungmoon. "Fluorescent noble metal nanodots for biological applications." Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/37195.
Повний текст джерелаАнотація:
Commercial organic dyes are widely used for cellular staining due to their small size, high brightness, and chemical functionality. However, their blinking and photobleaching are not ideal for studying dynamics inside live cells. An improvement over organics and much larger quantum dots, silver nanodots (Ag NDs) exhibit low cytotoxicity and excellent brightness and photostability, while retaining small size. We have utilized ssDNA hairpin structures to encapsulate Ag NDs with excellent spectral purity, high concentration, and good chemical and photophysical stability in a variety of biological media. Multi-color staining of fixed and live cells has been achieved, suggesting the promise of Ag NDs as good fluorophores for intracellular imaging. The great brightness and photostability of Ag nanodots indicate that they might be outstanding imaging agents for in vivo studies when encapsulated in delivery vehicles. In addition, Ag NDs can be optically modulated, resulting in increased sensitivity within high backgrounds. These good characteristics are combined with delivery vehicles such as PLGA and nanogels. After encapsulation, Ag nanodots still retain their good photophysical properties and modulation. It might be useful for in vivo applications in the near future
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Asem, Heba. "Synthesis of Polymeric Nanocomposites for Drug Delivery and Bioimaging." Licentiate thesis, KTH, Funktionella material, FNM, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-186300.
Повний текст джерелаАнотація:
Nanomaterials have gained great attention for biomedical applications due to their extraordinary physico-chemical and biological properties. The current dissertation presents the design and development of multifunctional nanoparticles for molecular imaging and controlled drug delivery applications which include biodegradable polymeric nanoparticles, superparamagnetic iron oxide nanoparticles (SPION)/polymeric nanocomposite for magnetic resonance imaging (MRI) and drug delivery, manganese-doped zinc sulfide (Mn:ZnS) quantum dots (QDs)/ SPION/ polymeric nanocomposites for fluorescence imaging, MRI and drug delivery.Bioimaging is an important function of multifunctional nanoparticles in this thesis. Imaging probes were made of SPION and Mn:ZnS QDs for in vitro and in vivo imaging. The SPION have been prepared through a high temperature decomposition method to be used as MRI contrast agent. SPION and Mn:ZnS were encapsulated into poly (lactic-co-glycolic) acid (PLGA) nanoparticles during the particles formation. The hydrophobic model drug, busulphan, was loaded in the PLGA vesicles in the composite particles. T2*-weighted MRI of SPION-Mn:ZnS-PLGA phantoms exhibited enhanced negative contrast with r2* relaxivity of 523 mM-1 s-1. SPION-Mn:ZnS-PLGA-NPs have been successfully applied to enhance the contrast of liver in rat model.The biodegradable and biocompatible poly (ethylene glycol)-co-poly (caprolactone) (PEG-PCL) was used as matrix materials for polymeric nanoparticles -based drug delivery system. The PEG-PCL nanoparticles have been constructed to encapsulate SPION and therapeutic agent. The encapsulation efficiency of busulphan was found to be ~ 83 %. PEG-PCL nanoparticles showed a sustained release of the loaded busulphan over a period of 10 h. The SPION-PEG-PCL phantoms showed contrast enhancement in T2*-weighted MRI. Fluorescein-labeled PEG-PCL nanoparticles have been observed in the cytoplasm of the murine macrophage cells (J774A) by fluorescence microscopy. Around 100 % cell viability were noticed for PEG-PCL nanoparticles when incubated with HL60 cell line. The in vivo biodistribution of fluorescent tagged PEG-PCL nanoparticles demonstrated accumulation of PEG-PCL nanoparticles in different tissues including lungs, spleen, liver and kidneys after intravenous administration.QC 20160516
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Khanna, Kunal. "Synthesis and self-assembly of miktoarm polymers and design of a drug-polymer-imaging conjugate." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:8881/R/?func=dbin-jump-full&object_id=92397.
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Holmes, Shannon. "Quantitative magnetic resonance imaging (MRI) assessment of hepatic responses to acute and chronic drug exposure." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0029/MQ47333.pdf.
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Tsvetkova, Yoanna [Verfasser], Fabian [Akademischer Betreuer] Kießling, and Wolfgang [Akademischer Betreuer] Stahl. "Riboflavin-targeted nanomedicines for cancer imaging and drug delivery / Yoanna Tsvetkova ; Fabian Kießling, Wolfgang Stahl." Aachen : Universitätsbibliothek der RWTH Aachen, 2018. http://d-nb.info/118734625X/34.
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Furdella, Kenneth J., Russell S. Witte, and 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.
Повний текст джерелаАнотація:
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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Tayyabi, Ehsen. "Gone Fishing: Synthesis and Design of a Superparamagnetic Nanobait for Trapping Reactive Metabolites In Vivo." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37338.
Повний текст джерелаАнотація:
Adverse drug reactions are common causes of medical injuries. Drug-induced hepatotoxicity remains one of the leading causes of emergency room visits, FDA non-approval, and drug withdrawal from the market. We have investigated the ability of endogenous nucleophilic amino acid residues (K, H, and C) to selectively bind to reactive electrophilic drug metabolites, focusing on acetyl-para-aminophenol (APAP, i.e. Tylenol®), for which hepatotoxicity has recently re- emerged as a major health concern for Canadians. Three peptide sequences were synthesized bearing terminal nucleophilic residues, brominated phenylalanine residues, and c-terminal amides. These peptides were coupled to carboxy methyl dextran coated iron oxide nanoparticles (CMX- IONPs) with a hepatocyte targeting group. IONPs are known for their ability to act as T2-weighted MRI contrast agents, giving us the ability to track them in vivo. This study begins to establish a nanotechnology-based method for the in vivo trapping of NAPQI, the reactive metabolite of APAP, using a cysteine bearing IONP.
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Bobiak, John Peter. "Raman and Infrared Imaging of Dynamic Polymer Systems." Case Western Reserve University School of Graduate Studies / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1133472157.
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Dyke, Stephanie Odette Mary. "Investigating tumour response to the anti-vascular drug combretastatin A₄ using magnetic resonance imaging and spectroscopy." Thesis, University of Cambridge, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598715.
Повний текст джерелаАнотація:
Anti-vascular cancer therapy is based on experimental evidence that the growth of solid tumours relies on the development and continual expansion of a host-derived vascular network to feed the proliferating mass of cancer cells. Combretastatin A4 (CA4) has emerged as a promising anti-vascular drug as it specifically damages tumour vasculature, leading to extensive secondary cancer cell death, without significantly impairing healthy tissue perfusion. The aim of this research was to further our understanding of CA4’s mode of action, and in particular address the hypothesis that CA4 is active upon proliferating (angiogenic) but not quiescent blood vessels in vivo. Two experimental approaches using human tumour models xenografted in mice were adopted for this purpose. In the first, tumour vascular proliferation was limited within a CA4-senstivie tumour model using the anti-angiogenic drug, vascular endothelial growth factor (VEGF) receptor tyrosine-kinase inhibitor\SU. This was shown to significantly reduce the tumour’s vascular response to CA4 treatment as assessed by magnetic resonance imaging and spectroscopy. Secondly, a relatively CA4-resistant tumour model was genetically modified to overexpress VEGF, a major mediator of the angiogenic process. The vasculature of these tumours was shown to be sensitised to the vascular-damaging effects of CA4. The results of this research suggest that CA4 specifically targets angiogenic tumour vessels in vivo. This work provides a biological explanation for the drug’s specificity for tumour versus healthy vessels, and more specifically, can explain the wide variation in tumour response to this anti-vascular drug.
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Murata, Yuki. "Design and Preparation of Gelatin-Based Carriers for Imaging Probes to Visualize Cell Functions." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263622.
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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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Blatherwick, Eleanor Q. "Imaging mass spectrometry approaches for the detection and localisation of drug compounds and small molecules in tissue." Thesis, University of Warwick, 2013. http://wrap.warwick.ac.uk/57257/.
Повний текст джерелаАнотація:
A crucial and challenging aspect of the drug development process is the requirement to measure the distribution of a pharmaceutical compound and its metabolites in tissue. Industry-standard methods used to look at total localisation of drug-related material are limited due to their dependence on labels. These labelled techniques can have difficulty in distinguishing between the drug of interest and its metabolites. Imaging mass spectrometry is a technique that has the potential to spatially distinguish between drug and metabolites, due to its high chemical specificity and sensitivity. A number of imaging mass spectrometry approaches have been described for localisation of drug compounds in tissue, most notably matrix-assisted laser desorption/ionisation (MALDI) imaging, which can provide data complementary to existing imaging techniques. Two imaging mass spectrometry approaches have been evaluated and compared for use in the localisation of a range of drug compounds in target tissues. The techniques used were MALDI imaging and a recently described electrospray ionisation-based technique, liquid extraction surface analysis (LESA). Both techniques have been successfully used for the detection of drug compounds in dosed tissue sections. A major challenge associated with imaging techniques is the required selectivity of the experiment for the compound of interest, due to the complex nature of tissue sections. Combining the shape-selective method of ion mobility separation with MS/MS fragmentation has been shown to improve the selectivity of both imaging approaches for the compound of interest. Results obtained using LESA-MS have demonstrated the suitability of this technique as a rapid and sensitive profiling technique for the detection of drugs and metabolites in tissue, but with a lower achievable spatial resolution than MALDI imaging. Higher spatial resolution was achieved with MALDI imaging; however data acquisition times were longer and required higher dosing levels for successful detection of drug compounds in tissue. A biological application of MALDI imaging was also evaluated. Mobility-enabled MALDI imaging was used to assess differences in the localisation of important adenine nucleotides between control and metabolically stressed mouse brain sections. Tissue fixation methods were evaluated to overcome rapid post-mortem degradation of adenine nucleotides such that biologically relevant localisation images can be obtained. These studies highlight the crucial importance of appropriate biological sample preparation in MALDI imaging experiments.
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Karakosta, Eleni. "Soluble drug release from a non-swelling polymer matrix studied by magnetic resonance and other imaging methods." Thesis, University of Surrey, 2006. http://epubs.surrey.ac.uk/844586/.
Повний текст джерелаАнотація:
Research in the area of controlled drug release is increasingly important in the pharmaceutical industry both from quality of life and commercial perspectives. One form of controlled release is of active components incorporated in solid polymer matrices. Understanding the nature and control of drug release is focal to the effective control and targeting of drugs. This will allow the prediction and modelling of new delivery systems. The aim of this thesis is to determine the principal manufacturing parameters affecting the release of a soluble drug from a non-swelling polymer matrix and so to understand better the dissolution mechanism. The matrix chosen for study is Eudragit and the chosen drug is Diltiazem Hydrochloride. Magnetic Resonance Imaging (MRI) experiments on Eudragit tablets with different levels of compression, drug loading and particle size exposed to water were made in order to observe the ingress of the water into the tablets. Nuclear Magnetic Resonance (NMR) spectroscopy was used to assess the amount of drug released. Stimulated-echo pulsed-field-gradient diffusion measurements of drug and water mobility in Diltiazem Hydrochloride solutions were made so as to estimate the self-diffusion coefficient of drug and water. Additional X-ray Computed Microtomography (muCT) and optical microscopy experiments were used to characterise the tablet microstructure. Experimental evidence shows that there is a rapid capillary uptake (≤ 10mins) of water into the initial pore space of a tablet ahead of the primary dissolution. This porosity is very small, less than 4% for pure compact Eudragit and even less for a drug loaded tablet. There is a slow subsequent dissolution characterised by a sharp diffusion front which separates the invaded and un-invaded regions. The water ingress proceeds linearly with the square root of time, t1/2. It is observed that water ingresses faster into tablets with small drug particle size and higher drug loading. Swelling of the whole tablet at intermediate ding loadings is seen as water ingresses into the system. However, no comparable swelling for either 100% polymer or 100% drug tablets is observed. There is evidence that as water ingresses into the tablet, air voids start to accumulate and ripen within the sample. Theoretical models are developed based on the experimental results in terms of diffusion and solubility parameters and the measured microstructure. In particular, a dimensionless time is introduced to best reflect the competition between dissolution and diffusion. This parameter is defined as the ratio of the time required for water to diffuse across the tablet and the time for the drug to dissolve.
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Strindlund, Olle. "Evaluation of Homogeneity in Drug Seizures Using Near-Infrared (NIR) Hyperspectral Imaging and Principal Component Analysis (PCA)." Thesis, Linköpings universitet, Kemi, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-166747.
Повний текст джерелаАнотація:
The selection of a representative sample is a delicate problem when drug seizures comprised of large number of units arrive at the Swedish National Forensic Centre (NFC). If deviating objects in the selected sample size are found, additional analyzes are required to investigate how representative the results are for the entire population. This generates further pressure on operational analysis flow. With the goal to provide a tool which forensic scientists at NFC can base their assessment of the representative nature of the selected sampling of large drug seizures on, this project investigated the possibilities of evaluating the level of homogeneity in drug seizures using near-infrared (NIR) hyperspectral imaging along with principal component analysis (PCA). A total of 27 sample groups (homogeneous, heterogeneous and seized sample groups) were analyzed and different predictive models were developed. The models were either based on quantifying the variation in NIR spectra or in PCA scores plots. It was shown that in the spectral range of 1300-2000 nm, using a pre-processing combination of area normalization, quadratic (second polynomial) detrending and mean centering, promising predictive abilities of the models in their evaluation of the level of homogeneity in drug seizures were achieved. A model where the approximated signal-dependent variation was related to the quotient of significant and noise explained variance given by PCA indicated most promising predictive abilities when quantifying the variation in NIR spectra. Similarly, a model where a rectangular area, defined by the maximum distances along PC1 and PC2, was related to the cumulative explained variance of the two PCs showed most promising predictive abilities when quantifying the variation in PCA scores plots. Different zones for which within sample groups are expected to appear based upon their degree of homogeneity could be established for both models. The two models differed in sensitivity. However, more comprehensive studies are required to evaluate the models applicability from an operational point-of-view.
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Griese, Florian [Verfasser]. "IVOCT catheter tracking and targeted drug delivery using magnetic particle imaging and magnetic particle navigation / Florian Griese." Hamburg : Universitätsbibliothek der Technischen Universität Hamburg-Harburg, 2020. http://d-nb.info/1224966627/34.
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Russell, Lisa Maria. "Dermatopharmacokinetics : an approach to evaluate topical drug bioavailability." Thesis, University of Bath, 2008. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.512306.
Повний текст джерелаАнотація:
Skin, more specifically the outermost skin layer, the stratum corneum (SC), forms an extremely effective barrier, preventing both the loss of heat and water, and the ingress of micro-organisms and chemicals. Assessing the rate and extent of drug permeation into or through the skin is important both to evaluate the usefulness of a drug for topical or transdermal delivery, and to compare different formulations to assess their bioequivalence. Prediction of drug permeation is logistically, ethically and economically preferable to in vivo measurements. The recent progress that has been made with empirical and mechanistic mathematical models, along with in vitro diffusion cell techniques has been reviewed. However, currently, in vivo measurements, in man, are still required. For new chemical entities, the need for clinical trials is clear. In the case of generic products, however, there is considerable effort currently being expended to replace expensive, subjective clinical trials with objective, validated measurements of drug permeation, in vivo, in particular to assess bioequivalence. The tape stripping technique has emerged as a promising technique to objectively measure drug permeation through skin, and is the focus of this thesis. After formulation application and removal, layers of SC are sequentially removed by adhesive tapes. As the SC performs the main barrier function of the skin, measuring the rate and extent of drug permeation through this layer is assumed to be related to overall topical bioavailability. The work in this thesis concentrates on performing tape stripping studies such that all tapes are analysed individually, and drug concentration as a function of SC depth is measured. The concentration depth profiles across the SC may be fitted to an appropriate solution of Fick's second law of diffusion to obtain estimates of the vehicle-SC partition coefficient and the drug's diffusivity in the membrane. These dermato-pharmacokinetic parameters may be compared for different formulations.
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Bentz, Brian Z. "In Vivo Optical Imaging for Targeted Drug Kinetics and Localization for Oral Surgery and Super-Resolution, Facilitated by Printed Phantoms." Thesis, Purdue University, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10274948.
Повний текст джерелаАнотація:
Many human cancer cell types over-express folate receptors, and this provides an opportunity to develop targeted anti-cancer drugs. For these drugs to be effective, their kinetics must be well understood in vivo and in deep tissue where tumors occur. We demonstrate a method for imaging these parameters by incorporating a kinetic compartment model and fluorescence into optical diffusion tomography (ODT). The kinetics were imaged in a live mouse, and found to be in agreement with previous in vitro studies, demonstrating the validity of the method and its feasibility as an effective tool in preclinical drug development studies.
Progress in developing optical imaging for biomedical applications requires customizable and often complex objects known as “phantoms” for testing and evaluation. We present new optical phantoms fabricated using inexpensive 3D printing methods with multiple materials, allowing for the placement of complex inhomogeneities in heterogeneous or anatomically realistic geometries, as opposed to previous phantoms which were limited to simple shapes formed by molds or machining. Furthermore, we show that Mie theory can be used to design the optical properties to match a target tissue. The phantom fabrication methods are versatile, can be applied to optical imaging methods besides diffusive imaging, and can be used in the calibration of live animal imaging data.
Applications of diffuse optical imaging in the operating theater have been limited in part due to computational burden. We present an approach for the fast localization of arteries in the roof of the mouth that has the potential to reduce complications. Furthermore, we use the extracted position information to fabricate a custom surgical guide using 3D printing that could protect the arteries during surgery.
The resolution of ODT is severely limited by the attenuation of high spatial frequencies. We present a super-resolution method achieved through the point localization of fluorescent inhomogeneities in a tissue-like scattering medium, and examine the localization uncertainty numerically and experimentally. Furthermore, we show numerical results for the localization of multiple fluorescent inhomogeneities by distinguishing them based on temporal characteristics. Potential applications include imaging neuron activation in the brain.
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Kampmeier, Florian [Verfasser]. "Site directed modification of recombinant antibody fragments for in vivo fluorescence imaging and targeted drug delivery / Florian Kampmeier." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2011. http://d-nb.info/1014263816/34.
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Foy, Susan Patricia. "Multifunctional Magnetic Nanoparticles for Cancer Imaging and Therapy." Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1319836040.
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Thovhogi, Ntevheleni. "Development of nanotechnology-based drug delivery and imaging system to the white adipose tissue vasculature using Wistar Rat Model." University of the Western Cape, 2013. http://hdl.handle.net/11394/4753.
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Philosophiae Doctor - PhDObesity is a complex metabolic disease of excessive fat accumulation. It is a worldwide epidemic affecting billions of people and its pharmacological management is hampered by drug toxicity and undesirable side effects. Therefore, a need still exists for the development of safe medication for treatment of obesity. Nanotechnology involves the use of small particles at atomic and molecular scale. It has application in medical diagnostics, drug delivery and molecular imaging. Various nanoparticles (NPs) functionalized with different biomolecules have been successfully used in many therapeutic and research applications due to their versatility, ease of chemical synthesis, low toxicity and unique properties. Examples of NPs used in this study are Gold nanoparticles (GNPs) and Quantum dots (QDs). GNPs and QDs are extensively used as drug delivery, labelling and imaging tools in biomedical research. Nanotechnology offers a new potential useful avenue for solving the problem of toxicity of anti-obesity drugs. This could be achieved through targeted drug delivery. In this study, rats were fed a high fed diet (HFD) to induce obesity. The streptavidin conjugated GNPs and QDs were functionalized with biotinylated adipose-homingpeptide (AHP) and/or anti-obesity drug (Gallic acid). Functionalization was characterized using agarose gel electrophoresis, UV-vis spectroscopy and transmission electron microscopy. The binding-specificity and targeting ability of AHP was evaluated in vitro and in vivo. The apoptotic effect of AHP functionalized-drug loaded GNPs (AHP-GA-GNPs) was tested in vitro using APOPercentage TM and Caspase-3 activation assays. The in vitro data indicated that the binding was specific to prohibitin (PHB) expressing cells (MCF-7 and Caco-2), and that the binding was temperature dependent. PHB was confirmed as a target for AHP after overlaying AHP-FITC and anti-prohibitin antibody staining. Cellular uptake was detected on the cells treated with AHP-functionalized NPs as compared to unfunctionalized NPs. The GA and AHP-GA-GNPs reduced cellular viability and induced apoptosis through activation of Caspase-3. The Ex-vivo studies using primary endothelial cells (ECs) isolated from the WAT of lean and obese Wistar rats showed that the binding of AHP was receptor mediated, and specific to receptors differentially expressed in ECs from obese WAT. The in vivo studies showed that, treatment of obese rats with AHP-functionalized NPs resulted in targeted delivery of the NPs to the WAT as compared to those treated with unfunctionalized NPs. Qualitative analysis using fluorescence microscopy and IVIS Luminar XR, live-imaging system showed that the unfunctionalized NPs accumulated mostly in the organs of the reticuloendothelial system, namely: liver, spleen, lungs and kidneys. In contrast, AHP-functionalized NPs accumulated mostly in the WATs as compared to the rest of the organs of the obese rats. Uptake and binding of the NPs to the tissues was quantitatively confirmed by the inductive coupled plasma-optical emission spectroscopy (ICP-OES). In conclusion, this study reports the 1) successful functionalization of GNPs and QDs with AHP, 2) use of AHP-functionalized GNPs and QDs as delivery and imaging agents to the WAT, and 3) potential use of AHP-functionalized drug-loaded GNPs in the treatment of obesity.
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Li, Zhoulei [Verfasser], and Christine [Akademischer Betreuer] Spitzweg. "Molecular imaging for characterization of lymphoma biology and monitoring response to cancer drug therapy / Zhoulei Li. Betreuer: Christine Spitzweg." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1055907866/34.
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Cho, Hoon-Sung. "Design and Development of a multifunctional nano carrier system for imaging, drug delivery, and cell targeting in cancer research." University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1275936260.
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Miyake, Yuka. "Synthesis and Functional Evaluation of Novel Chiral Dendrimer-triamine-coordinated Gd-MRI Contrast Agents That Can Act as Molecular Probes." 京都大学 (Kyoto University), 2016. http://hdl.handle.net/2433/215564.
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Nagura, Kota. "Development of All-Organic Magnetic Mixed Micelles Aiming at Biomedical Application." Kyoto University, 2019. http://hdl.handle.net/2433/242750.
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Kyoto University (京都大学)0048
新制・課程博士
博士(人間・環境学)
甲第21873号
人博第902号
新制||人||215(附属図書館)
2018||人博||902(吉田南総合図書館)
京都大学大学院人間・環境学研究科相関環境学専攻
(主査)教授 小松 直樹, 教授 加藤 立久, 准教授 廣戸 聡
学位規則第4条第1項該当
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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.
Повний текст джерелаАнотація:
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 puissantUltrasound 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