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Caractérisations physico-chimiques et évaluations biologiques de nanoparticules polymères chargées pour des applications en thérapie photodynamique et en théranostique / Physico-chemical characterization and biological evaluation of polymer-based loaded nanoparticles for applications in photodynamic therapy and theranosticBoeuf, Gaëlle 06 November 2014 (has links)
La thérapie photodynamique (PDT) est utilisée actuellement pour traiter certains cancers accessibles par irradiation laser. Son principe repose sur l'action combinée de la lumière et d'un principe actif nommé photosensibilisant (PS). La molécule photosensible génère des espèces réactives de l'oxygène sous l'action d'un rayonnement spécifique. Ces espèces sont fortement réactives et entrainent la mort des cellules alentour. Plusieurs facteurs limitent cependant l'efficacité de ce traitement. Dans cette optique, l'encapsulation d'un PS de seconde génération, le Foscan®, a conduit à la formation de nanoparticules qui ont été caractérisées et dont l'effet PDT a été étudié sur des cellules gliomales C6. Les nanoparticules présentent l'avantage de contrôler la solubilité du système, d'affiner le ciblage des traitements et de pouvoir adapter les doses de traitement. Le confinement du PS au sein de la nanoparticule peut permettre de réduire des effets secondaires et d'augmenter la concentration en principe actif au sein des tissus tumoraux. Par la suite, des nanoparticules chargées en complexes de ruthénium(II) ont été caractérisées. Ces complexes présentent des propriétés optiques adéquates pour de telles applications. De plus, une excitation biphotonique est réalisable, permettant d'augmenter la sélectivité et la profondeur du traitement. Des études préliminaires de l'effet PDT par excitation biphotonique ont été effectuées. / Photodynamic therapy (PDT) is currently used to treat certain cancers accessible by laser irradiation. Its principle is based on the combined action of light and a drug called photosensitizer (PS). The photosensitive molecule generates reactive oxygen species through the action of a specific radiation. These species are highly reactive, entailing the death of surrounding cells. However, several factors limit the effectiveness of this treatment. In this context, the encapsulation of a second-generation PS, Foscan®, led to the formation of nanoparticles that have been characterized and whose PDT effect was studied on C6 glioma cells. The nanoparticles have the advantage of controlling the solubility of the system, better targeting of treatment and to adjust the dose of treatment. Containment of the PS inside nanoparticles can reduce side effects and increase the concentration of active drug in tumor tissues. Thereafter, the nanoparticles loaded with ruthenium(II) complexes have been characterized. These complexes show optical properties suitable for such applications. In addition, a two-photon excitation is possible, improving the selectivity and increasing the depth of treatment. Preliminary studies of the effect of PDT photon excitation were performed.
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Étude de l'effet radiosensibilisant de nanoparticules théranostiques / Evaluation of the radiosensitizing effect of theranostic nanoparticlesMiladi, Imen 27 June 2012 (has links)
Le cancer est une des premières causes de mortalité dans le monde. Avec la chirurgie, la radiothérapie est une des thérapies curatrices essentielles en cancérologie. Elle consiste à utiliser les propriétés des rayonnements ionisants pour induire la mort des cellules cancéreuses. Néanmoins, du fait de la radiorésistance d’un certain nombre de tumeurs, nécessitant des doses délivrées intolérables pour les tissus sains environnants, de nombreux développements sont en cours pour limiter la dose délivrée et augmenter la radiosensibilité des tumeurs actuellement radio-résistantes. Parmi les stratégies envisagées, l’utilisation de nanoparticules théranostiques inorganiques ouvre des perspectives très intéressantes car il deviendrait possible de faire parvenir en quantité suffisante ces nanoparticules dans une tumeur après injection intraveineuse. Au sein du Laboratoire de Physico-Chimie des Matériaux Luminescents, les physico-chimistes ont développé des nanoparticules inorganiques d’un diamètre inférieur à 5 nm, permettant leur injection intraveineuse et leur élimination urinaire. Notre travail de thèse a porté sur la validation préclinique de deux types de nanoparticules (1- à coeur d’oxyde de gadolinium ; 2- nanoparticules d’or) en tant qu’agents radiosensibilisants permettant d’augmenter l’effet de la radiothérapie externe par rayons X sur divers types de tumeurs radio-résistantes : le gliosarcome, le carcinome épidermoïde du larynx et l’ostéosarcome. Les résultats obtenus aussi bien pour les nanoparticules d’oxyde de gadolinium que pour les nanoparticules d’or sont très prometteurs et laissent entrevoir un potentiel d’application en tant qu’agents de thérapie guidée par l’imagerie. / Cancer is a leading cause of death worldwide. With surgery, radiation therapy is an essential to cure tumors. Radiotherapy consists in using the properties of ionizing radiations to induce cancer cell death. However, because of the radioresistance of some tumors, requiring unacceptable dose delivered to surrounding healthy tissue, many developments are underway to limit the dose and increase the radiosensitivity of radio-resistant tumors. Among the proposed strategies, the use of inorganic theranostic nanoparticles opens very interesting perspectives since it should be possible to target sufficient nanoparticles into the tumor of interest following an intravenous injection. In the Laboratoire de Physico-Chimie des Matériaux Luminescents, chemists have developed inorganic nanoparticles with diameters below 5 nm, allowing their intravenous injection and urinary excretion. Our thesis has focused on the preclinical validation of two types of nanoparticles (1- based on gadolinium oxide, 2- based on gold) as radiosensitizing agents to increase the effect of external beam X-ray radiation on various types of radioresistant tumors : gliosarcoma, squamous cell carcinoma of the larynx and osteosarcoma. The results for both gadolinium oxide nanoparticles and gold nanoparticles are very promising and open the way for potential applications for imaging-guided therapy.
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Využití nanofluidního směšování pro přípravu liposomálních nosičů značených gadoliniem pro kontrastní zobrazování magnetickou resonancí (MRI) / Use of nanofluidic mixing for preparation of liposome carriers stained by gadolinium for contrast imaging by magnetic resonance (MRI)Velínská, Kamila January 2017 (has links)
This diploma thesis focuses on the preparation of the liposomes, containing lipids with gadolinium, which are used for a contrast magnetic resonance imaging. The liposomes were prepared by the lipid film hydration followed by an extrusion and also by a new nanofluid mixing method on the NanoAssemblr Benchtop. The preparation technology has been optimized for parameters such as the composition of lipids, the flow rate ratio and total flow rate. The method of modification of the liposomes surface by gadolinium complexes has been developed. This method is using a conjugation reaction between the lipids containing cyanuric acid and Gd-DOTA. Prepared Gd-liposomes, which contain gadolinium, were complexly defined by the characterization techniques of DLS and NTA. The morphology of liposomes was observed by TEM and cryo-TEM. Methods for the determination of phospholipid content (Stewart test) and residual water in the lyophylisates of liposomes (Karl-Fischer titration) were used. Gadolinium in liposomal preparations was determined by ICP-OES. Using MR, the concept of gadolinium liposomes was verified and designed for MRI imaging of thrombi. The concept describing the mechanism of liposomes formation based on the experimentally proven existence of a phospholipid bilayer fragment has been developed. This concept is based on the experimentally proven existence of a phospholipid bilayer fragment.
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TARGETABLE MULTI-DRUG NANOPARTICLES FOR TREATMENT OF GLIOBLASTOMA WITH NEUROIMAGING ASSESSMENTShelby Brentyn Smiley (8786417) 01 May 2020 (has links)
Glioblastoma (GBM) is a deadly, malignant brain tumor with a poor long-term prognosis. The current median survival is approximately fifteen to seventeen months with the standard of care therapy which includes surgery, radiation, and chemotherapy. An important factor contributing to recurrence of GBM is high resistance of GBM cancer stem cells (CSCs), for which a systematically delivered single drug approach will be unlikely to produce a viable cure. Therefore, multi-drug therapies are needed. Currently, only temozolomide (TMZ), which is a DNA alkylator, affects overall survival in GBM patients. CSCs regenerate rapidly and over-express a methyl transferase which overrides the DNA-alkylating mechanism of TMZ, leading to drug resistance. Idasanutlin (RG7388, R05503781) is a potent, selective MDM2 antagonist that additively kills GBM CSCs when combined with diagnostics in a truly theranostic manner for enhancing personalized medicine against GBM. The goal of this thesis was to develop a multi-drug therapy using mutli-functional nanoparticles (NPs) that preferentially target the GBM CSC subpopulation and provide in vivo preclinical imaging capability. Polymer-micellar NPs composed of poly(styrene-<i>b</i>-ethylene oxide) (PS-<i>b</i>-PEO) and poly(lactic-<i>co</i>-glycolic) acid (PLGA) were developed investigating both single and double emulsion fabrication techniques as well as combinatinos of TMZ and RG7388. The NPs were covalently bound to a 15 base-pair CD133 aptamer in order to target a specific epitope on the CD133 antigen expressed on the surface of GBM CSC subpopulation. For theranostic functionality, the NPs were also labelled with a positron emission tomography (PET) radiotracer, zirconium-89 (<sup>89</sup>Zr). The NPs maintained a small size of less than 100 nm, a relatively neutral charge and exhibited the ability to produce a cytotoxic effect on CSCs. There was a slight increase in killing with the aptamer-bound NPs compared to those without a targeting agent. This work has provided a potentially therapeutic option for GBM specific for CSC targeting and future in vivo biodistribution
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Proton irradiation of gold targets for 197(m)Hg productionWalther, Martin, Preusche, Stephan, Pietzsch, Hans-Jürgen, Bartel, Stig, Steinbach, Jörg January 2015 (has links)
Introduction
Irradiation of gold with protons provides access to no-carrier-added 197mHg and 197Hg. Interests in these radionuclides were awakened by the unique chemical and physical properties of mercury and its compounds combined with convenient nuclear properties like suitable half life (197mHg: T1/2 = 23.8 h, 197Hg: T1/2 = 64.14 h), low energy gamma radiations for imaging, Auger – and conversion electrons for therapy. The high thermal conductivity of gold enables high current irradiations and the monoisotopic natural abundance of 197Au supersedes expensive enrichment of the target material. The 197Au(p,n)197(m)Hg reaction was applied until now only for beam monitoring1, stacked foil meas-urements2 or very small scale tracer production.
Material and Methods
The irradiations were performed at a Cyclone 18/9 (IBA, Louvain la Neuve, Belgium). Its beam-line was sealed with a 1.0 mm vacuum foil (high purity aluminum, 99.999 %) from Goodfellow (Huntingdon, England). High purity gold disks (23 mm diameter, 2 mm thickness, 99.999% pure, 1 ppm Cu) as target material were purchased from ESPI (Ashland, USA). Gold foils as alternative gold targets (12.5×12.5 mm, 0.25 mm thickness, 99.99+ %, 1 ppm Cu) between an aluminum disk (22 mm diameter, 1 mm thickness, 99.0 %, hard) and an aluminum lid (23 mm diameter, 99.0 %, hard) were purchased from Goodfellow (Huntingdon, England). Hydrochloric acid (30%) and nitric acid (65%) were purchased from Roth (Karlsruhe, Germany) in Rotipuran® Ultra quality. Deionized water with > 18 MΩcm resistivity was prepared by a Milli-Q® system (Millipore, Molsheim, France). For separation of target material and side products a liquid-liquid extraction method (Gold was extracted with methyl isobutyl ketone (MIBK) from 2 M HCl target solution) and an ion exchange method (cation exchange resin (Dowex50W-x8, 100–200 mesh, H+ form) were applied.
Results and Conclusion
No-carrier-added 197(m)Hg was produced from gold via the 197Au(p,n)197(m)Hg reaction at proton energies of 10 MeV in sufficient quantity and quality for imaging studies.
Two different methods were studied for the separation of Hg radionuclides generated from Au targets. The results demonstrate the possibility to produce 197(m)Hg from gold at low proton energies. Combined with the presented radiochemical separation methods, the 197Au(p,n) reaction could be the basis for repeatable production of 197(m)Hg for imaging and therapy research on sufficient activity level.
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ULTRASOUND-MEDIATED DRUG-LOADED NANOBUBBLES AS A THERANOSTIC AGENT FOR OVARIAN CANCER TREATMENTNittayacharn, Pinunta January 2021 (has links)
No description available.
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Development of Novel Tumor-Targeted Theranostic Nanoparticles Activated by Membrane-Type Matrix Metalloproteinases for Combined Cancer Magnetic Resonance Imaging and TherapyAnsari, C., Tikhomirov, G.A., Hong, S.H., Falconer, Robert A., Loadman, Paul, Gill, Jason H., Castaneda, R., Hazard, F.K., Tong, L., Lenkov, O.D., Felsher, D.W., Rao, J., Daldrup-Link, H.E. 27 August 2013 (has links)
No / A major drawback with current cancer therapy is the prevalence of unrequired doselimiting toxicity to non-cancerous tissues and organs, which is further compounded by a limited ability to rapidly and easily monitor drug delivery, pharmacodynamics and therapeutic response. In this report, the design and characterization of novel multifunctional
“theranostic” nanoparticles (TNPs) is described for enzyme-specifi c drug activation at tumor sites and simultaneous in vivo magnetic resonance imaging (MRI) of drug delivery. TNPs are synthesized by conjugation of FDA-approved iron oxide nanoparticles ferumoxytol to an MMP-activatable peptide conjugate of azademethylcolchicine (ICT), creating CLIOICTs (TNPs). Signifi cant cell death is observed in TNP-treated MMP-14 positive MMTVPyMT breast cancer cells in vitro, but not MMP-14 negative fi broblasts or cells treated with ferumoxytol alone. Intravenous administration of TNPs to MMTV-PyMT tumor-bearing mice and subsequent MRI demonstrates signifi cant tumor selective accumulation of the TNP, an observation confi rmed by histopathology. Treatment with CLIO-ICTs induces a significant antitumor effect and tumor necrosis, a response not observed with ferumoxytol. Furthermore, no toxicity or cell death is observed in normal tissues following treatment with CLIO-ICTs, ICT, or ferumoxytol. These fi ndings demonstrate proof of concept for a new nanotemplate that integrates tumor specifi city, drug delivery and in vivo imaging into a single TNP entity through attachment of enzyme-activated prodrugs onto magnetic nanoparticles. This novel approach holds the potential to signifi cantly improve targeted cancer therapies, and ultimately enable personalized therapy regimens. / Yorkshire Cancer Research
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Síntese e caracterização de nanopartículas emissoras de luz por conversão ascendente de energia (UCNPS) funcionalizadas para uso em aplicações biológicas / Synthesis and Characterization of Upconversion Nanoparticles Functionalized for Biological ApplicationsArai, Marylyn Setsuko 21 September 2018 (has links)
As nanopartículas emissoras de luz por conversão ascendente de energia (UCNPs) têm atraído grande interesse nos últimos anos devido à sua versatilidade e capacidade de converter radiação menos energética em fótons de maior energia. Quando combinadas com outras moléculas, as UCNPs podem ser empregadas em um grande número de bioaplicações e, apesar de encontrar um de seus maiores usos na terapia fotodinâmica (PDT) de células cancerígenas, os mesmos princípios podem ser empregados na fotoinativação de bactérias (PDI). Nos últimos 20 anos a resistência bacteriana têm se tornado um dos maiores problemas de saúde pública e novas estratégias precisam ser desenvolvidas para superar esse desafio. Nesse trabalho, nós apresentamos a síntese e caracterização de nanopartículas de NaYF4 dopadas com Yb3+ (20%) e Er3+ (2%) e funcionalizadas para uso em PDI. As UCNPs foram sintetizadas utilizando-se o método de co-precipitação e foram revestidas com uma camada de sílica mesoporosa (@mSiO2) visando o aumento da dispersibilidade em água, o incremento da área superficial e a possibilidade de funcionalizações, e a diminuição da citotoxicidade do material. As UCNP@mSiO2 foram decoradas com moléculas orgânicas e com o fotossensibilizador (PS) ftalocianina de silício (SiPc) para estudo de sua interação e efeito bactericida contra cepas bacterianas Gram positivas e negativas. Diferentes abordagens foram utilizadas em busca de nanopartículas com as melhores propriedades: tamanho, forma, geração de oxigênio singleto e estabilidade em solução aquosa. Verificou-se que a transferência de energia entre as UCNPs e as SiPc em sua superfície é muito dependente do tipo de funcionalização realizada e da extensão com que as moléculas de PS adentram os poros da sílica. O material final apresentou toxicidade na ausência de luz contra a bactéria E. coli, enquanto a viabilidade das cepas de S. aureus não foi afetada no escuro. A excitação direta da SiPc nas nanopartículas levou a completa erradicação da E. coli e um drástico decréscimo no número de unidades formadoras de colônia (CFU) da S. aureus de até sete ordens de magnitude. Com esse estudo demonstramos diferentes estratégias para sintetizar e potencializar o uso das UCNPs como agentes teranósticos, principalmente para uso em PDI. / Lanthanide-doped upconverting nanoparticles (UCNPs) that emit high-energy photons upon excitation by low-energy near infrared (NIR) light, have garnered great interest in recent years due to their versatility. These nanoparticles combined to other molecules can be used for a broad range of bio-applications as theranostic agents, for bioimaging, drug and gene delivery and photodynamic therapy (PDT) applications. Although phototherapy is commonly used in the treatment of cancer, the same principles can be applied for the inactivation of bacteria (PDI). In the last twenty years bacterial resistance against antibiotics has become a critical public health issue and new strategies are needed to overcome this challenge. Herein, we describe the synthesis, detailed characterization and application of functionalized NaYF4: Yb (20%), Er (2%) UCNPs for use in PDT and especially for PDI. The UCNPs are produced using the co-precipitation method and covered with a mesoporous silica shell to enhance the dispersibility in water, increase the surface area and grant functionalization possibility and to decrease cytotoxicity. The nanoparticles were decorated with different molecules and functionalized with the photosensitizer (PS) silicon phthalocyanine (SiPc) to study interaction and enhance the bactericidal effect against Gram positive (+) and Gram negative (-) bacteria. Different approaches were used to identify the best particles concerning the shape, size, photophysical properties, generation of singlet oxygen and stability in water. It was verified that the energy transfer (FRET) efficiency from the UCNP towards SiPc depended on the surface functionalization and resulting encapsulation depths of the PS into the mesoporous silica. Functionalized UCNPs displayed dark toxicity towards Gram (-) E. coli while Gram (+) S. aureus viability was not decreased in the dark. Directly exciting the PS on the UNCP led to complete eradication of E. coli and a drastic decrease of colony forming units of S. aureus of up to seven orders of magnitude. Through this study we demonstrate different strategies to synthesize and potentialize the use of UCNPs as theranostic agents, mainly for use in PDI.
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Conception de complexes d'or et de titane pour l'imagerie moléculaire, la thérapie et la théranostique / Conception of gold and titanium complexes for molecular imaging, therapy and theranostic.Trommenschlager, Audrey 08 February 2019 (has links)
En vue de contourner les phénomènes de chimiorésistance et l’apparition d’effets secondaires sévères engendrés par les traitements à base de platine, nous avons développé des agents thérapeutiques à base d’autre métaux.Mon premier projet repose sur l’élaboration de complexes d’or(I) traçables possédant des propriétés anticancéreuses et anti-inflammatoires. Afin d’apporter des informations préliminaires sur leur mécanisme d’action, deux sondes imageantes ont été introduites : soit une coumarine, soit un BODIPY. Ainsi, deux séries de complexes d’or(I) ont été synthétisées. Trois d’entre eux présentent cette double activité thérapeutique dont deux pouvant être traçables in vitro.Mon deuxième projet est axé sur le développement de complexes de titane stables et solubles en milieu auqueux. Afin d’améliorer la cytotoxicité de ces titanocènes, notre stratégie a consisté à introduire un second métal thérapeutique au sein de ces structures. Cette étude a mené à deux nouveaux titanocènes possédant une activité anti-proliférative submicromolaire sur différentes lignées de cellules cancéreuses ainsi qu’une activité antitumorale in vivo, sans induire de signe de toxicité chez la souris saine. Afin d’étudier leur mécanisme d’action, l’introduction de deux modalités d’imageries a été envisagée sur ces complexes : l’imagerie optique ou l’imagerie TEP. Un complexe présentant une sonde fluorescente a été synthétisé et une voie de radiomarquage a été développée. / We have developed non-platinum therapeutic agents in order to avoid chemoresistance phenomena and severe side effects caused by treatments based on this metal.My first project relies on the development of trackable gold(I)-complexes displaying both anticancer and anti-inflammatory properties. An imaging probe was introduced on these complexes – either a coumarin or a BODIPY – in order to give preliminary information on their mechanism of action. Thus, two series of gold(I) complexes were synthesized. Three of these compounds presents this double therapeutic activity, two of them can be trackable in vitro.My second project is focused on the development of stable and soluble titanium complexes in water. We decided to introduce a second therapeutic metal into these structures in order to improve the cytotoxicity of these titanocenes. This study led to two new titanocenes displaying submicromolar anti-proliferative activity on different cancer cell lines along with an antitumoral activity in vivo, without inducing any sign of toxicity on healthy mice. We decided to introduce two imaging modalities – optical or PET imaging – into these complexes for investigating their mechanism of action. A complex bearing a fluorescent probe was synthesized and a radiolabeling method was developed.
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Samouspořádané polymerní systémy na bázi poly[(N-2,2-difluorethyl)akrylamidu] jako diagnostické a theranostické tracery pro zobrazování 19F magnetickou rezonancí / Self-Assembled Polymer Systems Based on Poly[(N-2,2-difluoroethyl)acrylamide] as Diagnostic and Theranostic Tracers for 19F Magnetic Resonance ImagingKolouchová, Kristýna January 2020 (has links)
In this doctoral thesis we describe a series of stimuli-responsive polymers which could be used as diagnostic tools or as smart drug delivery systems with simultaneous diagnosis (theranostics). All hereby mentioned polymers are thermoresponsive copolymers of (N-2,2-difluoroethyl)acrylamide exhibiting lower critical solution temperature in aqueous milieu. This means that they are water-soluble at low temperature while when heated above a certain temperature, they self-assemble into nano- or macro- sized assemblies. Because of the high concentration of fluorine atoms, all these polymers could be used as 19 F MRI tracers. We designed multiple different thermoresponsive, thermo- and pH-responsive, thermo-and reactive-oxygen-species-responsive polymers that could find numerous discussed applications in human medicine. We investigated their physico-chemical properties with 1 H and 19 F nuclear magnetic resonance (NMR), size exclusion chromatography (SEC), elemental analysis, dynamic light scattering (DLS), static light scattering (SLS), small angle neutron scattering (SANS), small-angle X-ray scattering (SAXS), and turbidimetry. After the physicochemical optimization of the parameters for the selected applications, their biocompatibility was tested in vitro. Several promising polymers were tested in vivo...
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