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1
Roberts, Fiona L. « Cancer therapy : origin and application ». Thesis, University of Strathclyde, 2012. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=16930.
Texte intégralRésumé :
In this thesis we use mathematical techniques to model two biological systems. First, we examine the growth dynamics of the antibiotic producing bacteria Streptomyces coelicolor and present a system of PDEs. We study the system both numerically and analytically. Due to oscillations in the numerical solution when solved using NAG, which uses a finite difference discretization, we change to a finite element discretization which corrects the oscillations. S. coelicolor also produces anticancer drugs, these can be encapsulated during the self-assembly of nanometre-sized vesicles, BPVs (biomimetic polymer vesicles) which are used as a novel targeted cancer therapy. We present a system of ODEs that focuses on the binding kinetics between cell-surface receptors and targeting molecules (ligands) on the BPV. We solve the system numerically, showing there is an optimal number of ligands per BPV for optimal uptake by tumour cells. We extend the model to allow for the infiltration of BPVs into tumour spheroids. Numerical solutions show that the growth of the spheroid is linear if the therapeutic BPVs are absent, and slows in the other case (for some parameter values). Using large time asymptotics we explore regions of parameter space where either steady states or travelling waves will occur.
2
Roslan, Nuruliza. « Inhibiting Tumor Protein D52 function for anti-cancer therapy application ». Thesis, The University of Sydney, 2013. http://hdl.handle.net/2123/9437.
Texte intégralRésumé :
Tumor protein D52 (TPD52) is amplified and/or overexpressed in many cancer types. Previously, TPD52 expression has been associated with ERBB2, suggesting these oncogenes may co-operate in cancer pathogenesis. Furthermore, as ERBB2 is known to promote lipogenesis, this led us to hypothesize that TPD52 expression may be associated with lipogenic phenotypes. RNA interference approaches investigated the effects of depleting TPD52 and ERBB2 in breast cancer cell lines with differing TPD52 and ERBB2 gene amplification and/or expression status. Transient TPD52 knock-down in the ERBB2-amplified breast cancer cell lines SK-BR-3 and BT-474 produced significant apoptosis. Unlike ERBB2 knock-down, transient TPD52 knock-down produced no reduction in pAKT levels. Multiple SK-BR-3 cell lines were generated in which TPD52 levels were stably reduced, showed significant inverse correlations between pERBB2 and TPD52 levels in viable TPD52-depleted and control cell lines. Fluorescent staining (BODIPY 493/503) showed increased lipid droplet numbers and sizes in TPD52- but not TPD52L1-transfected 3T3 cell lines relative to controls, as measured by fluorescent intensity. This study therefore identified TPD52 as a survival factor in ERBB2-amplified breast cancer cell lines, and provided the first direct evidence for TPD52 involvement in regulating cellular lipid storage.
3
Cheng, Wing-Shing. « TARP Promoter-Based Prostate Cancer Gene Therapy : From Development to Application ». Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5736.
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4
Hobson, N. J. « Nanoparticle theranostics for applications in cancer diagnostics and cancer therapy ». Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1546610/.
Texte intégralRésumé :
Traditionally, medicine has been conducted using a diagnostic procedure followed by an appropriate therapy and monitored were possible. On the whole, these steps have happened independently of each other. In recent years however many have started to question this independent approach and have asked whether technologies that seek to combine diagnostics and therapies would be more beneficial at treating diseases. This new medical discipline has been termed theranostics. The aim of this project was to design and synthesise a novel theranostic nanoparticle, using a micelle forming amphiphilic carbohydrate, with the overall hypothesis of determining whether using a nanomedicine that can simultaneously image and treat would improve the effectiveness of a cancer treatment. Super paramagnetic iron oxide nanoparticles (IONPs) have gained considerable attention as an MRI contrast agent due to their unique magnetic properties and relatively inoffensive toxicity profile. Before IONPs may be used in a biological environment they must overcome several challenges, including being stable to aggregation and organ targeting. In this project a modified chitosan amphiphilic polymer was used to successfully formulate IONPs into colloidal stable aqueous dispersions using two different methods which produced blackberry nanoparticles and raspberry nanoparticles. The raspberry nanoparticles were extensively characterised in vitro and in vivo and were found to be highly effective as an MRI imaging probe for the liver and spleen. Following this, they were tested for their cancer imaging properties in an in vivo mouse tumour model. The drug loading capacity of the raspberry nanoparticles was investigated using lomustine, paclitaxel and methotrexate, however no effective drug encapsulation was determined in this project. Overall, a highly effective MRI probe was engineered and characterised, although its future success will be determined by its activity towards a disease target.
5
Hawwa, Ahmed Fayeq. « Application of pharmacokinetics and pharmacogenomics to tailor anti-cancer and immunosuppressive therapy ». Thesis, Queen's University Belfast, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486218.
Texte intégralRésumé :
In the research presented in this thesis, the application of pharmacokinetic principles and pharmacogenetic tools to enhance therapeutic drug monitoring of the anti-cancer and immunosuppressive medications (6-MP and AZA) in two patient populations (paediatric patients with ALL and adults with IBD) was investigated. Before a pharmacokinetic analysis was conducted, a valid and reliable microanalytical method for the rapid, simultaneous and accurate determination of 6-MP and four of its metabolites from small volumes (200JlL) of plasma and erythrocytes was developed (Chapter 2). The developed method was successfully applied to the analysis of 75 samples from 19 paediatric patients with ALL and 44 samples from 35 adult patients with IBD. The association between the measured metabolite levels and the ·allelic variations of 3 enzymes involved in 6-MP metabolism (XO, TPMT and ITPA) was examined (Chapter 3). In addition, the association between the studied variants and the occurrence of myelotoxicity and haematological parameters was evaluated. This contributed to a clearer understanding of 6-MP metabolism and showed important pharmacogenetic associations. Furthermore, it threw light on potential genetic. characteristics that may contribute to higher risk of adverse events. In Chapter 4, the individual relationships between 6-MP and its metabolites and the correlations between these metabolites and dose, haematological parameters or the incidence of various forms of myelotoxicity in ALL and IBD patients were evaluated. The intra- and inter-patient variability in 6~MP metabolite concentrations were utilised to investigate the different factors that could lead to this variation via constructing a population pharmacokinetic model from the metabolite concentrations measured. The model offered a more rational dosing approach than the traditional empirical method since it combin~d the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype. In Chapter 5, adherence to 6-MP/AZA in ALL and IBD patients was evaluated via examining red blood cell and plasma levels of drug and metabolites. In addition, adherence questionnaires completed by patients or their parents (in case of children) and therapeutic outcome measures (as assessed by haematological parameters, myelotoxicity or activity indices) were used to assess adherence in the same cohort of patients. The study demonstrated non-adherence to medication in both ALL and IBD populations and highlighted the need for programmes to help these patients better !lndefstand their disease and for the implementation of disease-specific interventions to improve medication adherence.
6
Silva, Ana Sofia Matias da. « Design and production of new nanodevices for future application in cancer therapy ». Master's thesis, Universidade da Beira Interior, 2011. http://hdl.handle.net/10400.6/1054.
Texte intégralRésumé :
Nanotechnology is a multidisciplinary area of research that involves different knowledgements from, like life sciences, engineering and medicine. It has been used for different applications such as molecular imaging, molecular diagnosis and also targeted therapy. So far, ddifferent nanoscale devices have been produced, among them, inorganic nanoparticles, dendrimes, lipossomes, polymeric micelles, polymeric nanoparticles, nanotubes and nanofibers are some of the examples. Some of these particles exhibit unique optical and electrical properties allowing their course identification and precise location in the body. Gold nanoparticles are an example of inorganic particles with exceptional physico-chemical properties that demonstrate a huge potential for biomedicine applications.
The present study aimed to produce gold nanoparticles by two different methods: the citrate reduction method developed by Frens in 1973 (method 1), and its functionalization with oligoaziridine, developed by the colleagues from Universidade Nova de Lisboa, as a capping agent (method 2). This second method relies on the fact that gold nanoparticles can be prepared in water directly by the complexation of the alkylamine molecules that act as reducing agents and consequently stabilizes gold nanoparticles.
Moreover, gold nanoparticles produced by method 1 were also grafted with homofunctional maleimide poly(ethylene glycol) and then capped with oligoaziridine and the same parameters mentioned above were also evaluated.
The cytotoxicity and cell internalization of the different nanoparticles herein produced, was evaluated through in vitro studies.
The use of this new biosensor allow us to confirm the entry of the produced nanoparticles into cells opening new sights for the use of these particles as drug/gene delivery agents and/or as a new method for optimal imaging when methodologies like X-ray computed tomography or magnetic resonance cannot be used.A nanotecnologia é uma área de investigação multidisciplinar que abrange conhecimentos das ciências da vida, da engenharia e da medicina. Esta área do conheciemnto tem contribuido para melhorar as tecnologias de imagiologia, diagnóstico molecular e na terapia direccionada. Nos últimos anos têm sido produzidos diferentes dispositivos à nanoescala, entre eles destacam-se as nanopartículas inorgânicas, dendrímeros, lipossomas, micelas poliméricas, nanopartículas poliméricas, nanotubos e nanofibras. As nanopartículas de ouro são um exemplo de partículas inorgânicas, e apresentam propriedades físicas e químicas excepcionais que lhe conferem um elevado potencial para aplicações biomédicas. O presente estudo teve como objectivo produzir nanopartículas de ouro por dois métodos diferentes: o método de redução de citrato desenvolvido por Frens em 1973 (método 1); e o da funcionalização das aminas através da adição de oligoaziridina, um biosensor desenvolvido pelos colegas da Universidade Nova de Lisboa, como agente de revestimento (método 2). Este segundo método envolve a preparação das nanopartículas de ouro directamente em água através da complexação com moléculas acilaminas, que actuam como agentes redutores, estabilizando as nanopartículas de ouro. Numa segunda fase, as nanopartículas de ouro produzidas pelo método 1 foram revestidas com polietilenoglicol maleimida homofuncional e, em seguida, adiciounou-se oligoaziridine. A citoxicidade e a capacidade de entrarem nas células foi tambem avaliada para estas nanopartículas. Os resultados obtidos demonstram que o polimero polietilenoglicol maleimida homofuncional se liga de uma forma efectiva às nanopartículas de ouro. Por outro lado, provou-se que o oligoaziridine se liga tanto ao polietilenoglicol como às nanopartículas isoladas. Após a sintese das nanopartículas pelos dois métodos foi avaliada a sua toxicidade e a capacidade de entrarem nas células eucarióticas. A utilização deste novo biosensor permite confirmar a entrada das nanopartículas nas células, o que possibilitará o uso destas partículas como agentes de entrega direccionada de fármacos, genes ou como um novo método para a obtenção de imagens quando metodologias como Tomografia Computadorizada por raios X ou Ressonância Magnética não poderem ser usadas.
7
Tsedev, Uyanga. « Engineering M13 bacteriophage platforms for cancer therapy applications ». Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/103838.
Texte intégralRésumé :
Thesis: S.M., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2015.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 46-48).
Two novel schemes for engineering M13 bacteriophage for application in the diagnosis, imaging and treatment of human tumors are proposed. Firstly, by exploiting the uniquely malleable biology of the M13 filamentous phage, we have engineered filamentous phages of shorter lengths by constructing our own set of small viral ssDNA that are packaged by M13 capsid proteins. These 'inho' phages can be sized to ~50nm and above in length. The small phage retains the M13 major and minor coat proteins which have previously been manipulated to serve as tethers to carry various therapy and imaging agents and target specific cancer sites. Now with the ability to control the aspect ratio of these rigid, rod-like phages we can further improve on M13 based cancer detection by optimizing for phage blood circulation and tumor extravasation. Secondly, we have added to our cancer targeting M13 platform collection by cloning for chlorotoxin display on the tail p3 capsid protein of M13. Chlorotoxin can induce passage across blood-brain barrier, targets for cancer cells, and specifically internalizes to glioma cells. Expression of chlorotoxin on M13 will allow us to capitalize on its strong affinity for tumors of neuroectodermal origin and expand the M13 therapy and imaging platform to tumor masses in the brain.
by Uyanga Tsedev.
S.M.
8
Hauser, Anastasia K. « PEPTIDE-FUNCTIONALIZED MAGNETIC NANOPARTICLES FOR CANCER THERAPY APPLICATIONS ». UKnowledge, 2016. http://uknowledge.uky.edu/cme_etds/59.
Texte intégralRésumé :
Lung cancer is one of the leading causes of cancer deaths in the United States. Radiation and chemotherapy are conventional treatments, but they result in serious side effects and the probability of tumor recurrence remains high. Therefore, there is an increasing need to enhance the efficacy of conventional treatments. Magnetic nanoparticles have been previously studied for a variety of applications such as magnetic resonance imaging contrast agents, anemia treatment, magnetic cell sorting and magnetically mediated hyperthermia (MMH). In this work, dextran coated iron oxide nanoparticles were developed and functionalized with peptides to target the nanoparticles to either the extracellular matrix (ECM) of tumor tissue or to localize the nanoparticles in subcellular regions after cell uptake.
The magnetic nanoparticles were utilized for a variety of applications. First, heating properties of the nanoparticles were utilized to administer hyperthermia treatments combined with chemotherapy. The nanoparticles were functionalized with peptides to target fibrinogen in the ECM and extensively characterized for their physicochemical properties, and MMH combined with chemotherapy was able to enhance the toxicity of chemotherapy.
The second application of the nanoparticles was magnetically mediated energy delivery. This treatment does not result in a bulk temperature rise upon actuation of the nanoparticles by an alternating magnetic field (AMF) but rather results in intracellular damage via friction from Brownian rotation or nanoscale heating effects from Neél relaxations. The nanoparticles were functionalized with a cell penetrating peptide to facilitate cell uptake and lysosomal escape. The intracellular effects of the internalized nanoparticles alone and with activation by an AMF were evaluated.
Iron concentrations in vivo are highly regulated as excess iron can catalyze the formation of the hydroxyl radical through Fenton chemistry. Although often a concern of using iron oxide nanoparticles for therapeutic applications, these inherent toxicities were harnessed and utilized to enhance radiation therapy. Therefore, the third application of magnetic nanoparticles was their ability to catalyze reactive oxygen species formation and increase efficacy of radiation. Overall, iron oxide nanoparticles have a variety of cancer therapy applications and are a promising class of materials for increasing efficacy and reducing the side effects of conventional cancer treatments.
9
Huth, Christopher. « Development of Multifunctional Nanoparticles for Cancer Therapy Applications ». University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1352401861.
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10
JAFER, RASHIDA. « Laser plasma protons and applications in cancer therapy and proton radiography ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2009. http://hdl.handle.net/10281/7457.
Texte intégralRésumé :
Recent developments in high power, ultrashort pulse laser systems enable laser intensities beyond 10^21 W/cm^2 to be achieved. When focused onto thin foil targets, plasmas with extremely high electrostatic fields (>10^12V/m) are produced, resulting in the acceleration of protons/ions to very high energies (~60MeV). During my PhD, I have worked on experimental investigations into proton acceleration driven by high power laser pulses. Key to successful deployment of laser proton sources one one side is getting higher proton energies through to achieve the ultimate goal of realising table top machines for the treatment of cancer and on the other side, optimising the beam quality, an objective that was of the main motivation for my PhD work. My two main achievements were:
1. The production of bright, ultrashort and radially smooth pulsed proton beams using laser heating of pre-plasmas formed with long (nanosecond) pulses with ultrahigh intensity picosecond pulses.
2. Use of these beams to study the ultrafast dynamics of target implosion under intense laser irradiation
The experiments on proton acceleration with the specific goal of controlling the proton beam quality by optical tool design, were performed at RAL. This scheme involves the use of multiple laser pulses to enhance and control the properties of beams of protons accelerated in ultra-intense laser irradiation of planar foil targets. Specifically, one laser pulse produces and controls the expansion of the target to enhance the energy coupling to the main (delayed) laser and/or drives shock deformation of the target to change the direction of the proton beam. The preplasma formed by this low intensity nanosecond beam (~ 0.5-5x10^12 W/cm^2) was used to enhance the laser absorption of the main (delayed) CPA (Chirped pulse amplified). The main CPA picosecond beam was used at high intensity (~ 4x 10^20 W /cm^2) to produce intense proton beams from the hydrogen rich target. The optimum intensity of the nanosecond beam was investigated and optimised to yield a very smooth and circular distribution of the proton beam achieved using a second long pulse laser at 5x10^12w/cm^2.
The second achievement concerns an experiment also performed at RAL on proton radiography. As the laser based protons are characterised by small source size, high degree of collimation and short duration, they can be used in point projection backlighting schemes to perform radiography. In particular, I used this idea to perform radiography of a cylindrical target ~ 200µm long imploding under irradiation by long laser pulses of nanosecond duration. This allows measuring the degree of compression of the target as well as the stagnation time in the dynamic regime. The experiment took place in the framework of the HiPER project (the European High Power laser Energy Research facility Project). The final goal of the experiment was to study the transport of fast electron in cylindrical compressed target a subject of interest for fast ignition. In parallel to proton radiography x-ray radiography was used to compare the results. One of the specific advantages of using laser generated protons is that their spectrum is continuous upto a high energy cutoff. Because of their different time of flights protons proved to be very effective in revealing the implosion history of the target. In principle, the obtained implosion can be followed in time with a single shot sensitivity. Instead x-ray radiograph gives one image per laser shot at one fixed time and one has to make several shots in order to reveal the complete history of implosion. Another advantage of using proton radiography is a simpler experimental setup keeping imploding cylinder between proton target and proton detector on the same axis. Simulations of formation of proton images were made with the Monte Carlo MCNPX Code using the density profiles of the imploded cylinder obtained with the 2D-hydro CHIC code. A detailed study of Multiple Coulomb Scattering and Stopping Powers of the protons in low energy regimes for cold and warm matter was done to interpret the experimental results.
Finally, I’m taking part in the analysis of experimental results obtained at the University of Rochester (USA) on the Omega-EP laser, and concerning magnetic field effect on the proton radiographs of a wired cone.
11
Theeranaew, Wanchat. « A SURFACE-BASED DEFORMABLE IMAGE REGISTRATION WITH APPLICATION TO BREAST CANCER RADIATION THERAPY ». Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1200427318.
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12
Little, Sarah Ann. « Hepatic malignancy neo-adjuvant therapy and surgical management : clinical and in vivo studies / ». Available from the University of Aberdeen Library and Historic Collections Digital Resources. Restricted : no access, contains 3rd party material and therfore cannot be made available electronically, 2008. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=26220.
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Thesis (M.Phil.)--Aberdeen University, 2008.Title from web page (Viewed on July 29, 2009). With: Improvement in perioperative outcome after hepatic resection : analysis of 1,803 consecutive cases over the past decade / W. R. Jarnagan ... et al Ann. Surg. 2002: 236(4), 397-407. With: Diabetes is associated with increased perioperative mortality but equivalent long-term outcome after hepatic resection for colorectal cancer / Sarah A. Little ... et al. J. Gastrointest. Surg. 2002: 6, 88-94. With: Tumours of the ampulla and bile ducts / S. A. Little ... et al. in: Current diagnosis and management in gastroenterology / S. L. Friedman, K. R. McQuaid, J. H. Grendell (eds). With: Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholanagiocarcinona : implications for adjuvant therapeutic strategies / S. A. Little ... et al. Cancer: 2003: 15, 98(8) 1689-700. With: Hepatocellular carcinoma : current surgical management / S. A. Little Y. Fong. Seminars in oncology 2001: 28, 5 474-486. With: Neoadjuvant treatment of hepatic malignancy : an oncolytic herpes simplex virus expressing 1L-12 effectively treats the parent tumor and protects against recurrence after resection /W.R. Jarnagin ... et al. Cancer gene therapy. 2003: 10: 215-223. With: The neo-adjuvant combination of an oncolytic HSV-1 with external beam radiation has potent additive effects against a nude mouse model of human cholangiocarcinoma / J. S. Zagwer ... et al. Wangelsteen Surgical Forum. 2001: LII, 252-255. With: Treatment of cholangiocarcinoma with oncolytic herpes simplex virus combined with external beam radiation therapy / W.R. Jarnagin Cancer gene therapy. 2006: 13, 3, 326-34. Includes bibliographical references.
13
Cui, Xiaoming. « Discontinuous finite/boundary element method for radiative heat transfer with application in laser cancer therapy ». Online access for everyone, 2005. http://www.dissertations.wsu.edu/Dissertations/Fall2005/x%5Fcui%5F121805.pdf.
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Baillie-Hamilton, Paula. « Applications of magnetic resonance in cancer diagnosis and therapy ». Thesis, University of Oxford, 1995. http://ora.ox.ac.uk/objects/uuid:72d25d7c-4f5a-4bc4-9fb0-45f758c09d7b.
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Johnson, Charles Alan 1957. « A CONTROL SYSTEM FOR THE APPLICATION OF SCANNED, FOCUSSED ULTRASOUND IN HYPERTHERMIA CANCER THERAPY ». Thesis, The University of Arizona, 1987. http://hdl.handle.net/10150/276438.
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Vera, Gomis Pablo de. « Charged particle interaction with biological materials : modelling and application to ion beam cancer therapy ». Doctoral thesis, Universidad de Alicante, 2016. http://hdl.handle.net/10045/56995.
Texte intégralRésumé :
En esta tesis se presenta un estudio teórico sobre la interacción de partículas cargadas aceleradas con materiales de interés radioterapéutico, con miras a su posible aplicación en el tratamiento del cáncer mediante haces de iones. El trabajo se centra en el cálculo de las probabilidades de interacción electrónica (secciones eficaces de excitación y de ionización) de partículas cargadas (haces de iones y de electrones) con materia condensada, incluyendo materiales inorgánicos y orgánicos de interés para el problema estudiado, así como su uso en programas de simulación de la interacción de la radiación con materiales biológicos. Tras una introducción general (capítulo 1), la primera parte de la tesis (capítulos 2-4) trata sobre el cálculo de las secciones eficaces. El formalismo dieléctrico se ha utilizado para obtener las magnitudes básicas de frenado, tales como el poder de frenado, el straggling en la pérdida de energía, o el recorrido libre medio, para haces de iones y electrones. También se ha desarrollado un método para aplicar el formalismo dieléctrico al cálculo de secciones eficaces de ionización, incluyendo el cálculo de las distribuciones energéticas y angulares de electrones secundarios. Además, se ha implementado una metodología para extender estos cálculos a materiales biológicos arbitrarios, incluyendo blancos complejos, tales como el hueso, el ADN y sus componentes moleculares, proteínas, o compartimentos celulares. Las secciones eficaces obtenidas se han utilizado como dato de entrada en el código de simulación SEICS para la propagación de haces de iones en materia condensada (capítulos 5 y 6). Este programa se ha ampliado para tener en cuenta los efectos específicos sufridos por protones relativistas (correcciones relativistas y reacciones nucleares de fragmentación nuclear) y se ha utilizado para simular situaciones de interés en la terapia del cáncer mediante haces de iones. Mediante el programa de simulación SEICS se ha reproducido una serie de experimentos de irradiación de blancos cilíndricos micrométricos, para poner a prueba el programa, así como para evaluar el poder de frenado de protones en agua líquida (el principal componente de los tejidos vivos). Además, se ha utilizado SEICS para obtener cantidades tales como la dosis en función de la profundidad, los perfiles de dosis lateral, y otras cantidades relacionadas, útiles en terapia. Por último, se han desarrollado técnicas analíticas, en contraste con la técnica de simulación (capítulo 7). Se ha implementado un algoritmo de haces tipo pincel para el cálculo rápido de la dosis, aprovechando los resultados obtenidos con el programa SEICS. Además, se ha desarrollado un modelo analítico para describir la interacción de haces de iones con compartimentos subcelulares realistas. Este modelo es muy útil para evaluar el depósito de energía y el número de ionizaciones producidas en el núcleo y el citoplasma celular, cantidades que son relevantes en radiobiología, ya que la energía depositada en el núcleo puede relacionarse con la probabilidad de muerte celular, mientras que existen otros efectos biológicos relacionados con el depósito de energía fuera del núcleo. Los resultados presentados en esta tesis exploran diferentes procesos físicos implicados en los mecanismos que subyacen a la terapia del cáncer mediante haces de iones.
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Mackey, Megan A. « Gold nanoparticles in some chemical and photothermal applications of cancer therapy ». Diss., Georgia Institute of Technology, 2013. http://hdl.handle.net/1853/52934.
Texte intégralRésumé :
Gold nanoparticles exhibit an array of properties, both intrinsic (chemical) and extrinsic (photothermal), that can be exploited for their use in cancer therapeutics. Owing to their size and ease with which they can be functionalized with various ligands, gold nanoparticles represent a class of highly functional biomedically relevant nanostructures. Here, we explore the use of gold nanoparticles as intrinsic (chemical) antineoplastic agents, with their ability to cause DNA damage and cytokinesis arrest, to induce apoptosis in a metallic composition-dependent manner, as well as their ability to enhance sensitivity to chemotherapy by regulation of the cell cycle. The extrinsic (photothermal) properties of gold nanoparticles are also examined, in detail, through both theoretical and experimental assessment, for their use as photothermal contrast agents in vitro. Based on this assessment, the gold nanoparticles are tested in the plasmonic photothermal therapy of head and neck cancer in a mouse model.
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Evans, J. P. « Development of a murine model of colorectal cancer : application to the optimisation of irinotecan therapy ». Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3010630/.
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Musazzi, U. M. « TRANSDERMAL AND TRANSMUCOSAL PHARMACEUTICAL DOSAGE FORMS FOR PALLIATIVE CARE IN CANCER THERAPY ». Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/232411.
Texte intégralRésumé :
Pain is recognized as one of the most distressing cancer-related syndromes and treatment side effects and is linked to decreased quality of life among patients. Despite the improvements of pain management guidelines proposed in the last decades, therapeutic issues are still unsolved, above all in the treatment of loco-regional painful symptoms. For example, a proper pharmacological therapy to treat cisplatin-induced ototoxicity is not currently available. Pain associated to cutaneous wounds is treated by an off-label use of systemic analgesics with high incidence of related side effects. Conventional dosage forms applied in the buccal cavity are unable to achieve suitable efficacy in the case of oral mucositis.
Hence, there is a need to design novel drug delivery systems, which can be easily used in the clinical practice for an effective treatment of loco-regional painful syndromes.
This doctoral thesis aimed to investigate the critical aspects of drug delivery correlated to three loco-regional syndromes and propose technological solutions to rationalize drug delivery. In particular, the experimental work focused on:
(1) the development of a mucoadhesive microparticle suspension intended for treating oral mucositis and designed to combine the peculiarities of prolonged release mucoadhesive systems with those of an immediate release oromucosal solution;
(2) the optimization of a biodegradable nanoparticle system intended to deliver resveratrol to cochlea in the therapy of cisplatin-induced ototoxicity;
(3) the rationalization of the use of morphine derivatives, according to their chemical structure, in the management of cutaneous painful syndromes.
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Meenach, Samantha Ann. « SYNTHESIS AND CHARACTERIZATION OF MAGNETIC HYDROGEL NANOCOMPOSITES FOR CANCER THERAPY APPLICATIONS ». UKnowledge, 2010. http://uknowledge.uky.edu/gradschool_diss/108.
Texte intégralRésumé :
Currently, cancer is the second leading cause of death in the United States. Conventional cancer treatment includes chemotherapy, radiation, and surgical resection, but unfortunately, all of these methods have significant drawbacks. Hyperthermia, the heating of cancerous tissues to between 41 and 45°C, has been shown to improve the efficacy of cancer therapy when used in conjunction with irradiation and/or chemotherapy. In this work, a novel method for remotely administering heat is presented. This method involves heating of tumor tissue using hydrogel nanocomposites containing magnetic nanoparticles which can be remotely heated upon exposure to an external alternating magnetic field (AMF). The iron oxide nanoparticles contained in the hydrogel nanocomposites are able to heat via an AMF due to Brownian and Neel relaxation processes. The administration of hyperthermia via hydrogel nanocomposites allows for local delivery of heat to tumor tissue while also providing a drug depot to deliver chemotherapeutic agents. Both in vivo and in vitro studies have demonstrated that numerous chemotherapeutic agents, when used in conjunction with hyperthermia, show improved efficacy in treating cancer
Various magnetic hydrogel nanocomposites were synthesized and characterized for this work including poly(ethylene glycol) (PEG)-based hydrogels, which were studied due to their inherent biocompatibility and “stealth” properties, as well as, poly(β-amino ester) (PBAE)-based hydrogels which have tailorable degradation properties. The PEG hydrogels were investigated for their temperature-responsiveness swelling, mechanical strength, heating capabilities, biocompatibility, ability to kill M059K glioblastoma cells via thermoablation, and the ability to deliver paclitaxel, a chemotherapeutic agent. PBAE hydrogels were also characterized for their degradation and swelling properties, ability to heat upon exposure to an AMF, biocompatibility, mechanical strength, and ability to deliver paclitaxel in a controlled fashion. Additionally, multiple cancer cell lines were exposed to a combination of paclitaxel and heat (at 42.5 °C) in vitro and it was shown that A539 lung carcinoma cells exhibit higher cytotoxicity when exposed to both heat and paclitaxel than either treatment alone. Overall, magnetic hydrogel nanocomposites are promising materials that can be utilized for the multi-modality treatment of cancer through the synergistic delivery of both heat and chemotherapeutic agents.
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Dhami, Archana. « Approaches to new DNA-repair inhibitors for applications in cancer therapy ». Thesis, University of Bath, 2008. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.512320.
Texte intégralRésumé :
5-Aminoisoquinolin-1(2H)-one hydrochloride (5-AIQ.HCI) is a potent, water-soluble PARP-1 inhibitor that exhibits outstanding activity in a wide range of disease models in vivo. The aim of this project is the design and synthesis of derivatives with substituents at the 4-positoin of 5-AIQ. The modes of cyclisation of methyl 2-(substituted)alkynyl-3-nitrobenzoates with different electrophiles (ICI, PhSeCI, HgSO4) were studied. The exclusive formation of isocoumarins demonstrates the influence of the nitro group in directing electrophile-driven cyclisations towards the 6-endo-dig mode. The crystal structure of 5-nitro-3-phenyl-4-phenylselenylisocoumarin showed intermolecular and intramolecular ?-stacking. Attempted synthesis of 4-benzyl-5-nitroisoquinolin-1-one by selective reduction of the nitrile of methyl 2-(1-cyano-2-phenylethyl)-3-nitrobenzamide failed. Bromination of 5-nitro-isoquinolin-1-one gave 4-bromo-5-nitroisoquinolin-1-one but Pd(0)-catalysed cross-couplings (Stille, Sonogashira, Suzuki-Miyaura) of this and of 4-bromo-5-AIQ failed. An alternative approach was Pd-catalysed cyclisation of N-(2-alkenyl)-2-iodo-3-nitrobenzamides. Reaction of N,N-diallyl-2-iodo-3-nitrobenzamide with Pd(PPh₃)₄ gave 2-allyl-4-methyl-5-nitroisoquinolin-1-one and 2-allyl-4-methylene-5-nitro-3,4-dihydro-isoquinolin-1-one. N-Benzhydryl-N-cinnamyl-2-iodo-3-nitrobenzamide gave 2-benz-hydryl-4-benzyl-5-nitroisoquinolin-1-one and 2-benzhydryl-4-benzylidene-5-nitro-3,4-dihydroisoquinolin-1-one. These products are not interconvertible. The secondary amides N-allyl-2-iodo-3-nitrobenzamide and N N-((substituted)-cinnamyl)-2-iodo-3-nitrobenzamide gave good yields of the required 4-methyl- and 4-((substituted)-benzyl)-5-nitroisoquinolin-1-ones, respectively, under optimised conditions (Pd(PPh₃)₄, Et₃N, Bu₄NCI, 150°C, rapid heating). Hydrogen gave 4-methyl- and 4-benzyl-5-amino-isoquinolin-1-ones. The 4-substituted 5-AIQs were evaluated for inhibition of recombinant human PARP-1 activity. Three were more potent than 5-AIQ; 5-amino-4-methylisoquinolin-1-one (IC₅₀ = 0.25 μM), 5-amino-4-benzylisoquinolin-1-one (IC₅₀ = 0.5 μM) and 5-amino-4-bromoisoquinolin-1-one (IC₅₀ = 1.0 μM).
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Vile, Douglas J. « Statistical modeling of interfractional tissue deformation and its application in radiation therapy planning ». VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3675.
Texte intégralRésumé :
In radiation therapy, interfraction organ motion introduces a level of geometric uncertainty into the planning process. Plans, which are typically based upon a single instance of anatomy, must be robust against daily anatomical variations. For this problem, a model of the magnitude, direction, and likelihood of deformation is useful. In this thesis, principal component analysis (PCA) is used to statistically model the 3D organ motion for 19 prostate cancer patients, each with 8-13 fractional computed tomography (CT) images. Deformable image registration and the resultant displacement vector fields (DVFs) are used to quantify the interfraction systematic and random motion. By applying the PCA technique to the random DVFs, principal modes of random tissue deformation were determined for each patient, and a method for sampling synthetic random DVFs was developed.
The PCA model was then extended to describe the principal modes of systematic and random organ motion for the population of patients. A leave-one-out study tested both the systematic and random motion model’s ability to represent PCA training set DVFs. The random and systematic DVF PCA models allowed the reconstruction of these data with absolute mean errors between 0.5-0.9 mm and 1-2 mm, respectively. To the best of the author’s knowledge, this study is the first successful effort to build a fully 3D statistical PCA model of systematic tissue deformation in a population of patients.
By sampling synthetic systematic and random errors, organ occupancy maps were created for bony and prostate-centroid patient setup processes. By thresholding these maps, PCA-based planning target volume (PTV) was created and tested against conventional margin recipes (van Herk for bony alignment and 5 mm fixed [3 mm posterior] margin for centroid alignment) in a virtual clinical trial for low-risk prostate cancer. Deformably accumulated delivered dose served as a surrogate for clinical outcome. For the bony landmark setup subtrial, the PCA PTV significantly (p30, D20, and D5 to bladder and D50 to rectum, while increasing rectal D20 and D5. For the centroid-aligned setup, the PCA PTV significantly reduced all bladder DVH metrics and trended to lower rectal toxicity metrics. All PTVs covered the prostate with the prescription dose.
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Luo, Phoebe Lihong. « Development of improved expression vectors and their applications in cancer gene therapy ». Diss., The University of Arizona, 2003. http://hdl.handle.net/10150/280431.
Texte intégralRésumé :
Recombinant DNA vectors are fundamental tools in gene therapy research. A novel cloning system, pLinus, was made to facilitate vector construction by providing 32 unique restriction sites to adapt DNA fragments in a single step. To compensate the low delivery efficiency of the non-viral vector systems, we have constructed two high expression plasmid vectors, pHi1/2, by incorporating a transcriptional amplifier strategy into a single construct. In both pHi1/2 vectors, the amplifier expression cassettes contained two independent transcriptional units. One transcriptional unit contained a transcriptional factor, the tat gene, driven by a strong constitutive CMV promoter. The second transcriptional unit contained either an HIV1 LTR or HIV2 LTR driving the gene of interest. Using the human IL-2 cytokine as a reporter and therapeutic gene, the pHi1/2 amplifier vectors could achieve significantly higher IL-2 expression levels than that observed when using the CMV promoter alone. In vivo injection of the stable pHi2-IL-2 gene modified Lewis Lung (LL/2) tumor clones resulted in slower tumor growth and longer survival as compared to those mice injected with either CMV-driven IL-2 transfected clones or the parental tumor cells. To solve the safety concern, we constructed a novel plasmid vector, pHi-Hot, by combining inducible and amplifier strategies in a single vector. In pHi-Hot, the first transcriptional unit contained an inducible heat shock protein (hsp70B) promoter controlling the expression of a transcriptional factor, Tat, which transactivates a second promoter, the HIV2 LTR, located downstream on the same construct. The second promoter drives the gene of interest. Using the human IL-2 cytokine gene as a reporter gene, we demonstrated that, heat shock at 42°C for 30 min, the pHi-Hot vector could achieve high gene expression levels while maintaining its inducibility. The induced IL-2 levels were significantly higher than achieved by using the hsp promoter or CMV promoter directly. And repeated heat shock at 42°C for 30 min of mice injected with a pHi-Hot-IL-2 gene modified LL/2 clone led to tumor regression. In this study, three major approaches towards facilitating vector construction and improving vector expression cassette design are described.
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Abada, Zahra. « Synthèse de porphyrines chirales : application en oxydation asymétrique et application antiparasitaire et anticancéreuse ». Thesis, Paris 11, 2012. http://www.theses.fr/2012PA114806.
Texte intégralRésumé :
Les molécules chirales représentent environ 60% des médicaments présents sur le marché pharmaceutique et plus de 80% des médicaments en développement avec plus de 150 milliards de dollars de chiffre d’affaire pour l’année 2002. Les intermédiaires chiraux sont fortement demandés dans l’industrie pharmaceutique atteignant 15 milliards de dollars de chiffre d’affaire en 2009. D’autres domaines en sont demandeurs avec une répartition d’environ 15% dans l’agrochimie et 5% pour la parfumerie. L’obtention de composés d’intérêt pharmaceutique de façon asymétrique est un réel défi et une réelle nécessité. Ces molécules possèdent une architecture spatiale qui entraîne des interactions spécifiques et des affinités particulières avec les enzymes ou des récepteurs biologiques chiraux. L’utilisation de catalyseurs pour accéder à des composés organiques chiraux et plus précisément l’oxydation d’alcanes prochiraux ou d’oléfines constitue un domaine en essor ces dernières décennies. Pour parvenir à synthétiser des molécules chirales, l’industrie pharmaceutique s’est tournée vers l’utilisation de biocatalyseurs en partie pour réaliser différentes réactions stéréo-contrôlées avec la nécessité de séparer les mélanges racémiques par résolution enzymatique. Cependant, les biocatalyseurs présentent un inconvénient majeur qui est généralement le faible rendement en composé chiral recherché et nécessite un savoir faire pour la manipulation de ces enzymes. Les métalloporphyrines sont des catalyseurs comportant un macrocycle tétrapyrrolique et différentes fonctionnalisations en positions méso. Ces molécules ont fait l’objet de nombreuses études qui ont conduit à la synthèse de métalloporphyrines chirales très complexes. Malheureusement, leur synthèse est souvent longue avec de faibles rendements et leur application à un nombre limité de substrats ne permet pas leur généralisation. Ce travail de thèse, développé pour la première fois au laboratoire, s’inscrit dans le cadre d'un contrat CIFRE, dans le but de parvenir à la synthèse de porphyrines chirales facilement accessibles, applicables dans des réactions d’oxydation énantiosélectives efficacement (stabilité). Le premier objectif visé est la synthèse de porphyrines chirales dont la structure ciblée comporte des groupements hétérocycliques azotés chiraux en position méso, reliés par une liaison carbone-hétéroatome (C-N). Nous avons pu atteindre 4 séries de porphyrines qui ont été évaluées dans des réactions d’oxydation énantiosélectives (époxydation, hydroxylation). Le deuxième objectif visé est d’exploiter les propriétés électroniques particulières des porphyrines permettant l’application des porphyrines en tant que photosensibilisant après photoactivation en thérapie anticancéreuse. L’étude des paramètres physiques est primordiale pour déterminer la longueur d’onde d’activation et le rendement quantique. Nous avons souhaité utiliser nos porphyrines et leurs précurseurs en tant qu’agents antiparasitaires, sans photoactivation dans un premier temps, conduisant à la découverte d’activités très intéressantes sur certaines espèce de leishmanies. Enfin, leur application sur P. falciparum nous a permis d’isoler une molécule avec une activité très intéressante. Dans les deux cas, des manipulations avec photoactivation sont en coursChiral molecules represent about 60% of drugs in pharmaceutical market and over 80% of drugs in development with more than 150 billion dollars in 2002. Chiral intermediates are in high demand in the pharmaceutical industry producing a turnover of 15 billion dollars in 2009. Other areas are seekers of chiral molecules with a distribution of about 15% in agrochemicals and 5% for the perfume. Asymmetrically production of compounds of pharmaceutical interest is a real challenge. These molecules have a spatial architecture that results in specific interactions and affinity with the enzymes or biological chiral receptors. The use of catalysts to synthesis chiral organic compounds, and more specifically to oxidize alkenes and alkanes having prochiral positions, is a very important area extensively studied in recent decades with few positive results. To achieve the synthesis of chiral molecules, the pharmaceutical industry has turned to the use of biocatalysts, in part, to perform various stereo-controlled reactions with systematically followed by separation of the different isomers by different methodes. However, biocatalysts have a major disadvantage relative to low yields of chiral compound and requires expertise for handling these enzymes. Metalloporphyrins are tetrapyrrolic macrocyle substituted in meso position with various functional groups and incorporating metals (Fe, Mn, Co, Ru). These molecules have been extensively studied and led to the synthesis of many complex chiral metalloporphyrins. Unfortunately, their synthesis is often long with low yields and their application to a limited number of substrates is a major drawback. The first objective of this work is the synthesis of original chiral porphyrins. The targeted structure contains chiral heterocyclic nitrogen groups in two meso positions, connected by a carbon-heteoatom bond (C-N). We were able to reach 4 porphyrins-series that have been evaluated as catalyst in oxidation reactions (epoxidation, hydroxylation). The second objective is to take advantage of specific electronic properties of porphyrins for applications as photosensitizer after photoactivation for cancer by photodynamic therapy. The use of this therapy increased during last decades but poor specificity and solubility of the different porphyrins used in clinic against many cancers prompt us to investigate this area. The study of the physical parameters is essential to determine wavelength activation and quantum yield of a photosensitizer. We wanted to use our porphyrins and their precursors as antiparasitic agents, with and without photoactivation against L. donovani, L. major, T. brucei brucei. Malaria is caused by a protist of the genus of Plasmodium. This parasite has an iron deficiency on one hand and cannot biosynthesize certain amino acids. Strucure analogy of porphyrins with heme led us to evaluate antimalarial activity of several porphyrins against P. falciparum
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Nofriyanti, Lisa. « Physico chemistry analysis radionuclide praseodymium-143 for theraphy cancer application ». Thesis, Видавництво СумДУ, 2011. http://essuir.sumdu.edu.ua/handle/123456789/10113.
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Maietta, Antonio. « Assessing the efficiency of In Vivo electroporation as a nonviral gene transfer technique and studying its application in antiangiogenic cancer gene therapy and cancer immunotherapy ». Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=31267.
Texte intégralRésumé :
Electroporation refers to a technique that makes use of electrical pulses to create transient and reversible pores into cellular membranes which allows the passage of drugs and macromolecules, such as plasmid DNA, into the cell's interior. It is a widely used laboratory procedure for the transfection of cultured mammalian cells, plant cells and bacteria. Only recently has in vivo electroporation been used for the transfer of genetic material into living tissue, such as muscle, hepatocytes, and tumors of experimental animals. Using a luciferase assay, we have shown that electroporation-mediated luciferase gene transfer into solid, subcutaneous tumors in mice resulted in a 103 fold increase in tumor luciferase activity compared to naked DNA injections. Using this technique, we succeeded in inhibiting the growth of LLC tumors in mice by delivering plasmid DNA encoding mouse Endostatin and mouse single-chain IL-12 directly into the tumor site. Lastly, in vivo electroporation was used to enhance DNA vaccination with the tumor associated antigen CEA and IL-12 gene adjuvant, which protected mice from a tumor challenge with LLC/CEA+ tumor cells. Our results suggest that in vivo electroporation is an efficient nonviral, gene transfer vehicle that can be used in the fields of antiangiogenic cancer gene therapy as well as cancer immunotherapy.
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Mott, Landon Alexander. « TOWARDS THE RATIONAL DESIGN AND APPLICATION OF POLYMERS FOR GENE THERAPY : INTERNALIZATION AND INTRACELLULAR FATE ». UKnowledge, 2019. https://uknowledge.uky.edu/cme_etds/99.
Texte intégralRésumé :
Gene therapy is an approach for the treatment of acquired cancers, infectious disease, degenerative disease, and inherited genetic indications. Developments in the fields of immunotherapies and CRISPR/Cas9 genome editing are revitalizing the efforts to move gene therapy to the forefront of modern medicine. However, slow progress and poor clinical outcomes have plagued the field due to regulatory and safety concerns associated with the flagship delivery vector, the recombinant virus. Immunogenicity and poor transduction in certain cell types severely limits the utility of viruses as a delivery agent of nucleic acids. As a result, significant efforts are being made to develop non-viral delivery systems that perform mechanistically similarly to viral delivery but lack immunogenic factors. Though safer, existing agents lack the efficacy inherent in the natural design of viral vectors. Clinical relevance of non-viral vectors will therefore depend on the ability to engineer optimized systems for cellular delivery in physiological environments.
Progress in non-viral vector design for gene delivery requires a deep understanding of the various barriers associated with nucleic acid delivery, including cell surface interaction, internalization, endosomal escape, cytosolic transport, nuclear localization, unpackaging, etc. Further, it requires a knowledge of vector design properties (surface chemistry, charge, size, shape, etc.) and how these physical parameters affect interactions with the cellular environment. Of these interactions, charge is shown to govern how particles are internalized and subsequently processed, thereby affecting the intracellular fate and efficacy of delivery. Charge also affects the in-serum stability where negative zeta potential improves stability and circulation time. Therefore, it is important to understand the effects of polyplex charge and other parameters on the internalization and intracellular fate of polyplexes for gene therapy.
In chapter 2, studies are performed to delineate the effects of polyplex charge on the cellular internalization and intracellular processing of polymer-mediated gene delivery. Charge is shown to affect the endocytic pathway involved in internalization, and the caveolin-dependent and macropinocytosis pathways lead to higher gene delivery efficacy, likely due to avoidance of acidified compartments such as late endosomes and lysosomes. In chapters 3-4, novel nanoparticles carrying DNA, RNA, and antioxidants are assessed for therapeutic effect with an emphasis on studying the internalization mechanisms and resulting effect on efficacy. Novel RNA delivery agents are shown to benefit from EGFR-targeting aptamer and nanoceria/PEI hybrids are demonstrated to provide simultaneous antioxidant and gene therapy. Finally, chapter 5 demonstrates the use of silencing RNA and CRISPR/Cas9 genome editing to study the prevalence of gene targets in vivo.
The overall goal of this work is to contribute to the design and application of novel nanoparticles for gene delivery and offer insight into the engineering of novel polyplexes. It remains clear that route of internalization is key to successful gene delivery, and designing polyplexes to enter through non-acidified endocytic pathways is highly beneficial to transgene expression. This can be achieved through incorporation of surface chemistries that trigger internalization through targeted pathways and is the source of further work in the lab.
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Souchon, Rémi Chapelon Jean-Yves. « Application de l'élastographie à l'imagerie du cancer de la prostate et à sa thérapie par ultrasons focalisés rostate cancer detection and HIFU therapy monitoring using elastography / ». Villeurbanne : Doc'INSA, 2005. http://docinsa.insa-lyon.fr/these/pont.php?id=souchon.
Texte intégralRésumé :
Thèse doctorat : Images et Systèmes : Villeurbanne, INSA : 2004.Thèse rédigée en anglais. Introduction et conclusion en français et en anglais. Titre provenant de l'écran-titre. Bibliogr. p. 113-118. Publications de l'auteur, 3 p.
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Mooney, Marie R. « Precision Medicine Approaches to Integrating Genomics with Cancer Therapy| Applications in Glioblastoma and Lymphoma ». Thesis, Van Andel Research Institute, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10275288.
Texte intégralRésumé :
The word "cancer" rarely stands alone, usually prefaced with its anatomical location: lung cancer, prostate cancer, brain cancer. With the advancement of high-throughput omics approaches, specific oncogenic events are reorganizing the landscape of cancer classification, at once creating commonalities between cancers arising in diverse anatomical locations and dividing organ-centric classifications of cancer into a multitude of subtypes. The term "precision medicine" postulates that these new, data-driven groupings based on molecular characterization are the key to making rational therapeutic choices.
The majority of this dissertation addresses the disconnect between extensive molecular characterization and poor cancer therapy outcomes for patients with glioblastoma multiforme (GBM). Despite clear evidence that hyperproduction of the ligand for PDGFR (platelet-derived growth factor receptor α) is sufficient to generate GBM of the proneural subtype, anti-PDGFRα therapeutics have proven disappointing in clinical trials. Cell adaptation contributes to therapeutic escape. In GBM, proneural tumor cells adopt transcriptional profiles of the mesenchymal subtype. The interconversion between the proneural and mesenchymal transcriptional classes within a tumor population presents both a challenge and an opportunity for therapeutic approaches. The proneural subtype has a proliferation phenotype and presents druggable targets such as PDGFRα. The mesenchymal subtype presents an invasive phenotype, but the targets are more challenging to drug. The typical screening for combination therapies that synergize to induce cell death is not as advantageous here, where the disease management is expected to include cytostatic drugs that act on two different aspects of the phenotype: proneurally mediated proliferation and mesenchymally mediated invasion. This work examines the applicability of a combination approach against a proneural target, PDGFRα, and mesenchymal targets in the STAT3 (signal transducer and activator of transcription 3) pathway, in the context of a proneural model of GBM.
The work is concluded with collection of work applying precision medicine in other disease contexts, most notably canine lymphoma.
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Weinschenk, Toni. « Multi-peptide-based vaccines for personalized cancer therapy analytical fundamentals translated into clinical applications / ». [S.l. : s.n.], 2004. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB10976223.
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Bagley, Alexander Francis. « Optically-Active Nanomaterials for Diagnostic and Therapeutic Applications in Ovarian Cancer ». Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11517.
Texte intégralRésumé :
The clinical management of cancer has principally relied upon surgery, radiation therapy, and chemotherapy for many decades. Despite recent advances in molecularly-targeted diagnostic and therapeutic agents, the long-term survival rates in patients with solid malignancies including ovarian cancer have improved only incrementally. Nanotechnologies designed to locally interrogate and modulate the tumor microenvironment offer a promising opportunity to enhance existing treatment modalities and establish new therapeutic paradigms. By virtue of their elemental composition, geometry, and surface chemistry, nanomaterials can be engineered with optical and pharmacokinetic properties which permit these agents to localize, fluoresce, and deposit energy within tumors. Nanomaterials therefore provide a clear route towards future approaches for sensitive diagnosis and imaging of tumors and targeted therapeutic delivery.
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Böhlen, Till Tobias. « Monte Carlo particle transport codes for ion beam therapy treatment planning : Validation, development and applications ». Doctoral thesis, Stockholms universitet, Fysikum, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-81111.
Texte intégralRésumé :
External radiotherapy with proton and ion beams needs accurate tools for the dosimetric characterization of treatment fields. Monte Carlo (MC) particle transport codes, such as FLUKA and GEANT4, can be a valuable method to increase accuracy of dose calculations and to support various aspects of ion beam therapy (IBT), such as treatment planning and monitoring. One of the prerequisites for such applications is however that the MC codes are able to model reliably and accurately the relevant physics processes. As a first focus of this thesis work, physics models of MC codes with importance for IBT are developed and validated with experimental data. As a result suitable models and code configurations for applications in IBT are established. The accuracy of FLUKA and GEANT4 in describing nuclear fragmentation processes and the production of secondary charged nuclear fragments is investigated for carbon ion therapy. As a complementary approach to evaluate the capability of FLUKA to describe the characteristics of mixed radiation fields created by ion beams, simulated microdosimetric quantities are compared with experimental data. The correct description of microdosimetric quantities is also important when they are used to predict values of relative biological effectiveness (RBE). Furthermore, two models describing Compton scattering and the acollinearity of two-quanta positron annihilation at rest in media were developed, validated and integrated in FLUKA. The detailed description of these processes is important for an accurate simulation of positron emission tomography (PET) and prompt-γ imaging. Both techniques are candidates to be used in clinical routine to monitor dose administration during cancer treatments with IBT. The second objective of this thesis is to contribute to the development of a MC-based treatment planning tool for protons and ions with atomic number Z ≤ 8 using FLUKA. In contrast to previous clinical FLUKA-based MC implementations for IBT which only re-calculate a given treatment plan, the developed prototype features inverse optimization of absorbed dose and RBE-weighted dose for single fields and simultaneous multiple-field optimization for realistic treatment conditions. In a study using this newly-developed tool, the robustness of IBT treatment fields to uncertainties in the prediction of RBE values is investigated, while comparing different optimization strategies.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 5: Submitted. Paper 6: Manuscript.
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Wong, Yuk-na, et 王玉娜. « The potential applications of AMPK activator resveratrol and PAK1 inhibitor IPA-3 in cancer therapy ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45165208.
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Ahmed, Omar. « Contribution of capillary electrophoresis for the therapeutic drug monitoring of patients treated by targeted cancer therapy : application to tyrosine kinase Inhibitors ». Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTS148.
Texte intégralRésumé :
L'objectif de ce travail de thèse était d’évaluer l’apport de l'électrophorèse capillaire (EC) comme technique analytique pour la quantification des inhibiteurs de la tyrosine kinase (ITKs) présents dans des échantillons plasmatiques humains dans le contexte du STP. 4 ITKs ont été sélectionnés pour cette étude: mesylate d’imatinib, chlorhydrate d’erlotinib, ditosylate de lapatinib et sorafenib. Tout d’abord, une méthode simple, rapide et peu couteuse a été développée par électrophorèse capillaire de zone (CZE) avec détection UV. Cette méthode reposait sur l’utilisation d’une méthode de préparation d’échantillon par précipitation des protéines à l’ACN avant l’analyse par CZE-UV. Une étude approfondie a également été réalisée pour comprendre le comportement électrophorétique de l’imatinib en présence de sels et d’ACN dans l’échantillon plasmatique. Ensuite, une seconde étude a été réalisée pour optimiser une méthode de préparation d’échantillon simple, rapide et efficace basée sur le principe d’extraction liquide-liquide en présence de sel (SALLE). Cette méthode SALLE reposait sur l’ajout de sels en grande concentration dans deux solvants immiscibles permettant ainsi d’extraire en une seule étape les ITKs du plasma vers la phase ACN avec des rendements d’extraction élevés. Les extraits étaient ensuite analysés directement par CZE-UV. L’utilisation de l’ACN comme solvant d’extraction permettait d’injecter des volumes d’échantillon allant jusqu’à 80% du volume effectif du capillaire. Les ITKs étaient donc concentrés en tête du capillaire grâce à l’existence de mécanisme de préconcentration électrophorétiques. Dans la perspective d'une utilisation en routine, la méthodologie SALLE-CZE-UV a été entièrement automatisée. Les performances analytiques obtenues pour les quatre ITKs sont parfaitement adaptées aux exigences du STP. Enfin, la méthode SALLE-CZE-UV a été appliquée avec succès pour l'extraction et l'analyse des quatre ITKs directement à partir de sang humain. Tous les développements actuels prouvent que la CE est une technique pertinente pour résoudre de nombreux problèmes rencontrés dans le contexte du STPThe objective of the present work was to evaluate the relevance of capillary electrophoresis (CE) method for the quantification of tyrosine kinase inhibitors (TKIs) in human plasma in the context of TDM. Four TKIs were selected for this study: imatinib mesylate, erlotinib hydrochloride, lapatinib ditosylate and sorafenib.A fast, simple and cost effective CZE-UV methodology for the quantification of imatinib in plasma was first developed using simply ACN precipitation as sample preparation before analysis. A complete study was performed to understand the electrophoretic behavior of imatinib in the presence of salt (from plasma) and ACN in the sample matrix. Then, a thorough study was performed to optimize an easy to use and performing sample pretreatment methodology based on salting-out assisted liquid-liquid extraction (SALLE) for the four TKIs from human plasma. SALLE, which is based on adding high concentration of salt to two miscible liquids, allows to extract in one step TKIs from plasma in an ACN phase with high recovery. The extracted TKIs can then be directly injected for further CZE-UV analysis. The use of ACN as extraction solvent allows to inject up to 80% of the capillary effective volumes. This allows in-line sample concentration through electrophoretic stacking mechanisms. In the perspective of routine use, the SALLE-CZE-UV methodology was fully automated. The analytical performances obtained for the four TKIs are fully suitable with TDM requirements. Finally, the SALLE-CZE-UV was successfully applied for the extraction and analysis of the four TKIs directly from human blood. All the present developments prove that CE is a relevant technique to address many TDM issues
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Lopez, Sara. « Destruction du microenvironnement tumoral par application de forces mécaniques exercées par des nanoparticules magnétiques ». Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30202.
Texte intégralRésumé :
L'efficacité des traitements conventionnels du cancer est en partie limitée par l'acquisition de résistances par les cellules cancéreuses. Ces résistances ont longtemps été considérées comme étant le seul fait du génotype des cellules cancéreuses. Cependant, ces dernières années, les chercheurs ont prouvé que la progression et la résistance du cancer n'étaient pas uniquement déterminées par les caractéristiques inhérentes aux cellules cancéreuses, mais également par leurs interactions avec le microenvironnement tumoral. Les fibroblastes associés au cancer (CAFs), font partie du microenvironnement tumoral, et leur rôle clé dans la modification des autres composants du microenvironnement (vaisseaux sanguins, matrice extracellulaire, acteurs de l'immunité) ainsi, que leurs interactions avec les cellules cancéreuses, participent grandement à la baisse d'efficacité des traitements anti-cancéreux. Il semble donc que la destruction des CAFs soit une stratégie intéressante pour inhiber le développement de la maladie. Tandis que des nanoparticules magnétiques (NPMs) soumises à un champ magnétique hautes fréquences produisent de la chaleur, elles génèrent un couple mécanique en réponse à des champs magnétiques rotatif basse fréquence (RMF). Nous avons choisi d'utiliser les RMF afin de mettre au point une stratégie thérapeutique dirigée contre les CAFs. Le principe de cette stratégie est de cibler les CAFs à l'aide de NPMs vectorisées, puis d'appliquer un RMF permettant de générer suffisamment de stress mécanique pour induire la mort cellulaire. Ainsi, le premier objectif a été de développer des NPMs ciblant les CAFs pancréatiques. Pour cibler les CAF pancréatiques exprimant le récepteur à la cholécystokinine de type 2 (RCCK2), nous avons vectorisé des NPMs avec de la gastrine (NPM@Gastrine), un agoniste du RCCK2. Nous avons montré que les NPM@Gastrine se lient au RCCK2, s'internalisent et s'accumulent dans les lysosomes des CAFs exprimant le RCCK2. Nous avons ensuite testé différentes amplitudes et fréquences de champ magnétiques et mis en évidence qu'une exposition des CAFs après internalisation des NPM@Gastrin dans les lysosomes entraine la mort cellulaire. L'exposition des CAFs à un RMF de fréquence 1Hz et d' amplitude de 40mT a permis d'obtenir l'effet maximal sur la mort des CAFs observé dans cette étude, à savoir environ 40% de mort cellulaire. De plus, nous nous sommes penchés sur le mécanisme de mort cellulaire à l'œuvre et nous avons montré que la mort cellulaire fait intervenir les lysosomes. En effet la membrane des lysosomes se perméabilise, entrainant la fuite de leurs contenus dans le cytoplasme. Les cathepsines B sont impliquées dans le processus de mort. La mort cellulaire à l'œuvre semble être dépendante de la caspase-1. Pour finir nous avons utilisé un générateur de champ magnétique nous permettant d'observer les réactions cellulaires pendant l'application du traitement en microscopie confocale. Nous avons notamment pu observer une rétractation cellulaire, un mouvement général des lysosomes en direction du noyau et une variation de l'adhésion cellulaire. Ces travaux ont permis d'établir une preuve de concept : les NPMs ciblant le microenvironnement peuvent perturber son fonctionnement via l'action de forces mécaniques. Ceci ouvre un nouveau champ des possibles pour les thérapies anti-cancéreusesEfficiency of anti-cancer treatments is limited by development of resistance to treatments, which has long been considered to depend solely on the genotype of cancer cells. However, these past few years, researchers proved that cancer progression and resistance are not only determined by the inherent characteristics of cancer cells, but also by their interactions with tumor microenvironment. Among other components of the tumor microenvironment, cancer-associated fibroblasts (CAFs) promote tumor growth and cancer cell resistance to treatments. CAFs modify the components and properties of tumor microenvironment (blood vessels, extracellular matrix or tumor immunity) and interact with cancer cells; those actions take a great part in the loss of treatment efficacy. Thus, as CAFs seem to be key players in cancer cell resistance to treatment, their eradication is an interesting strategy to inhibit cancer progression. While magnetic nanoparticles (MNPs) under a high frequency magnetic field produce heat, they generate a mechanical torque in response to low frequency rotating magnetic fields (RMF) Here, we chose this last property to elaborate a nano-therapeutic strategy directed against CAFs. The principle of this strategy is to target CAFs using vectorised MNPs and then apply a RMF that generates enough mechanical stress to induce cell death. The first objective was to target pancreatic CAFs that express the type 2 cholecystokinin receptor (CCK2R). For this, we synthesized gastrin-decorated MNPs (MNP@Gastrin). We showed that MNP@Gastrin bind to the CCK2R on the cell membrane of CAF-CCK2R, then internalize and accumulate in the lysosomes. Then, we tested different amplitudes and frequencies of RMF and demonstrated that RMF exposure induces the death of CAFs having accumulated MNP@Gastrin into their lysosomes. The optimal effect on cell death, namely the death of about 40% of CAFs, was obtained with 40mT and 1Hz RMF. Moreover, we investigated the cell death mechanism involved and we showed that cell death occurs through lysosomal damage. Lysosomes undergo membrane permeabilization, releasing their content, including cathepsin B which are involved in the observed cell death process. On top of that, the engaged cell death pathway seems to be caspase-1 dependent. Finally we used a magnetic setup under a confocal microscope in order to observe real-time cell reaction to RMF. We noticed cellular retraction, lysosomal movements towards the nucleus, and changes in cellular adhesion. This study establishes the proof-of-concept that targeted MNPs can disrupt tumor microenvironment through mechanical forces upon RMF exposure, and thus open new opportunities for cancer therapy
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Fernandez-Fernandez, Alicia. « IR820 Nanoconjugates for Theranostic Applications ». FIU Digital Commons, 2013. http://digitalcommons.fiu.edu/etd/819.
Texte intégralRésumé :
Near-infrared dyes can be used as theranostic agents in cancer management based on their optical imaging and localized hyperthermia capabilities. However, their clinical translatability is limited by issues such as photobleaching, short circulation times, and non-specific biodistribution. We studied the applications of IR820 in optical imaging and hyperthermia, and we prepared nanoconjugate formulations to overcome some of the aforementioned limitations. Free IR820 can be used for optical imaging, with a strong signal still present 24 hours after i.v. injection, an elimination plasma half-life in the order of hours, and primary biodistribution to liver, lung, and kidneys. After 808-mn laser exposure, IR820 can also raise in vitro temperatures to the 41-43°C range that can selectively inhibit cancer cell growth. We conjugated IR820 with PEG-diamine via ionic interactions to create nanoconjugates (IR820-PDNCs) with diameters of approximately 50-nm per SEM and a zeta potential of 2.0±0.9 mV. IR820-PDNCs enhanced cellular internalization compared to IR820 for imaging in SKOV-3, MES-SA, and Dx5 cancer cells. The nanoconjugates also significantly enhanced hyperthermia-mediated cytotoxicity in MES-SA and Dx5 compared to the free dye (p
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Beyrath, Julien. « Development and biological characterization of synthetic molecules targeting Death Receptor 5 : potential applications in cancer therapy ». Strasbourg, 2010. http://www.theses.fr/2010STRA6288.
Texte intégralRésumé :
L’échappement à l’apoptose est une caractéristique majeure responsable du développement des cancers. L’apoptose, un mécanisme conduisant à la mort cellulaire et impliqué dans l‘élimination des cellules cancéreuses, peut être induite par la fixation de certains ligands de la famille du TNF (Tumor necrosis Factor) à leur récepteurs de mort. Parmi ces ligands, TRAIL (TNF-related apoptosis- inducing ligand) possède la particularité d’induire la mort des cellules tumorales tout en épargnant les cellules saines. Il existe quatre récepteurs à TRAIL, DR4 et DR5 induisant une signalisation pro-apoptotique, et DcR1 et DcR2 étant des récepteurs leurres n’induisant pas de signalisation et limitant l’efficacité de la protéine TRAIL recombinante comme agent anti-tumoral. Sur la base de séquences peptidiques précédemment décrites pour se lier à DR5, nous avons développé un set de molécules synthétiques multivalentes (nommées TRAIL mim/DR5) afin d’étudier l’effet de la dimérisation et de la trimérisation des peptides sur leur liaison à DR5 et leur efficacité à induire l’apoptose dépendante de DR5. Nos résultats ont montré que la génération des molécules divalentes et trivalentes a permis d’augmenter l’affinité des peptides pour DR5 de l’ordre de plusieurs milliers de fois. Ces molécules multivalentes sont capables d’induire spécifiquement la mort de cellules cancéreuses in vitro et in vivo. Nous avons cependant mis en évidence un rôle antagoniste des TRAIL mim/DR5 dans certaines cellules cancéreuses. Ce travail révèle donc le potentiel mais aussi les limites des TRAIL mim/DR5, des molécules synthétiques ciblant un récepteur spécifique de TRAIL, comme de nouveaux agents ant-cancéreuxEvasion of apoptosis is one of the major hallmarks of cancer. Apoptosis is a physiologic mechanism leading to cell death involved in the clearance of cancer cells. Apoptosis can be triggered extracellularly by pro-apoptotic receptor agonists (PARAs), belonging to the tumor necrosis factor (TNF) family, activating the “extrinsic” pathway. Among PARAs, TRAIL (TNF-related apoptosis- inducing ligand) is of particular interest having the unique characteristic of inducing apoptosis in tumor cells while sparing normal ones. Four membrane-bound TRAIL specific receptors have been described: death receptors 4 and 5 (DR4 and DR5) that mediate the apoptogenic signal and two decoy receptors (DcR1 and DcR2) that do not transduce the apoptogenic signal, limiting the efficiency of recombinant TRAIL as a therapeutic. On the basis of previously reported peptidic sequences that bind to DR5, we have developed a set of synthetic multivalent molecules (named TRAIL mim/DR5) to systematically study the effect of peptide dimerization and trimerization on DR5 binding and selective DR5-mediated death induction. Our results revealed up to several thousand-fold increased affinities of TRAIL imi/DR5-receptor complexes on generation of divalent and trivalent molecules and that multivalent molecules triggered a substantial DR5-dependant apoptotic response in vitro and in vivo. Our results also revealed a cell-specific antagonism role oe the TRAIL mim/DR5 highlighting a limit in their potential use as therapeutics. Our work revealed the potential but also the limits of TRAIL mim/DR5, small molecules specifically targeting one specific receptor of TRAIL, as a new anti-cancer therapeutics
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Kostova, Vesela. « Shiga toxin targeted strategy for chemotherapy and cancer immunotherapy application using copper-free « Click » chemistry ». Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCB144.
Texte intégralRésumé :
Pas de résuméRecently targeted therapies appeared as attractive alternatives to classical antitumoral treatments. The approach, developed on the concept of targeting drug to cancer cells, aims to spear normal tissues and decrease the side effects. This doctoral dissertation focuses on developing new anticancer targeted treatments in the field of chemotherapy and cancer immunotherapy by exploiting an original targeting moiety, the B subunit of Shiga toxin (STxB). Its specific properties, such as, recognition with its receptor Gb3 overexpressed in cancer cells or in antigen-presenting cells, its unconventional intracellular trafficking, guided the choice of this protein as targeting carrier. This project is based in the use of copper-free Huisgen [3+2] cycloaddition as a coupling method, which led to successful preparation of various conjugates for their respective applications. The concept was first validated by STxB-biotin conjugate. The high yield of the reaction and the compatibility between the targeting carrier and the chemical ligation promoted the design of conjugates for chemotherapy and immunotherapy. Two therapeutical optimizations of previously developed strategy in STxB drug targeting delivery were investigated: synthesis of multivalent drug-conjugates and synthesis of conjugates containing a highly potent anticancer agent. Both approaches exploited three anticancer agents: SN38, Doxorubicin and Monomethyl auristatin F. The disulfide spacer, combined with various self-immolative systems, insured drug release. Two cytotoxic conjugates STxB–doxorubicin (STxB-Doxo) and STxB-monomethyl auristatin F (STxB-MMAF) were obtained in very high yield and demonstrated strong tumor inhibition activity in the nanomolar range on Gb3-positive cells. Based on the results the STxB-MMAF conjugate was investigated on a mouse model. The project aimed also to develop STxB bioconjugates for vaccine applications. Previous studies used B subunit as a targeting carrier coupled to an antigenic protein in order to induce a more potent immune response against cancer. The conjugates were prepared using a commercial linker, requiring modifying the antigen at first place, or by oxime ligation, where slightly acidic conditions promoted the coupling. Thus, the work presented herein proposed an alternative ligation via copper-free click chemistry especially for more sensitive antigenic proteins. Various types of conjugates were synthesised and investigated for their immune stimulation properties. The STxB targeting strategy was also applied to the development of a new vaccine based on coupling the targeting carrier to alpha-GalCer, one of the most potent immune stimulating agents known. The work focused on the synthesis of functionalised alpha-Galcer with an azide handle
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Soysouvanh, Frédéric. « Sénescence cellulaire radio-induite : application à l’irradiation pulmonaire en conditions stéréotaxiques ». Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS465.
Texte intégralRésumé :
La radiothérapie constitue l’une des principales modalités de traitement des cancers, mais elle est associée à des atteintes radio-induites aux tissus sains. Les cellules endothéliales (CE) du système vasculaire sont connues pour participer à l’évolution de ces lésions. La sénescence cellulaire est un puissant mécanisme suppresseur de tumeurs mais sa persistance est délétère pour l’homéostasie tissulaire. La présence de cellules sénescentes dans les lésions radio-induites est déjà démontrée mais leur rôle reste encore à élucider. Nous avons cherché à identifier et à comprendre les mécanismes moléculaires impliqués dans la sénescence radio-induite (SRI) ainsi que son rôle dans le développement des lésions après irradiation pulmonaire en conditions stéréotaxiques. In vivo, à l’aide de souris exprimant le gène de la luciférase, placé sous le contrôle de p16, acteur majeur de la sénescence, nous avons détecté des cellules sénescentes au sein de la lésion radio-induite. Nous avons observé par imagerie bioluminescente l’activation de p16 dans le champ d’irradiation et sa persistance jusqu’à 21 mois après irradiation. L’analyse des poumons a révélé une forte hétérogénéité des populations de cellules sénescentes, notamment des pneumocytes, des macrophages et des CE. L’analyse transcriptionnelle de 44 gènes liés à la sénescence, sur 6 types de CE, a montré que les CE de veine ombilicale (HUVEC) sont les plus pertinentes pour étudier la SRI. Le profil moléculaire dynamique des HUVEC a été analysé après 9 doses d’irradiation à différents pas de temps. Une analyse mathématique et bio-informatique approfondie a identifié la voie de l’IL-1 comme acteur clef impactant la sénescenceRadiotherapy is the main modality in cancer treatment but is associated with radiation damages on healthy tissues. Endothelial cells (ECs) play a key role in the evolution of radiation-induced normal tissue injuries. Cellular senescence is a powerful tumor suppressor mechanism but, long-term senescence is deleterious for tissue homeostasis. The presence of senescent cells within the radiation-induced lesions has been shown but their role is not well understood. We aimed to identify and understand the molecular mechanisms involved in radiation-induced senescence (RIS) and its role in radiation-induced lung injuries after stereotactic irradiation. In vivo, using luciferase knock-in mice (p16Ink4-LUC) to detect activation of a senescence player, we explored the presence of senescent cells in radiation-induced pulmonary injury. After high-dose lung irradiation of p16Ink4-LUC mice and using bioluminescence imaging we showed the overexpression of p16 in the irradiation field and its persistence up to 21 months after radiation exposure. Immunostainings revealed a panel of heterogeneous senescent cells including pneumocytes, macrophages and ECs. mRNA expression of 44 genes involved in senescence in 6 human primary irradiated ECs revealed that Human Umbilical Vein Endothelial Cells (HUVECs) are the most relevant in term of gene expression. The dynamic molecular profile associated to RIS in HUVECs was analyzed after 9 doses and 7 time points. Using a deep mathematical/bioinformatics analysis, we deciphered the dynamical transcriptional program involved in RIS and we identified IL1-signaling pathway as a key molecular hub which could modulate the senescence phenotype
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Sadat, Md Ehsan. « Probing the Magnetic Relaxation Dynamics and Optical Properties of Superparamagnetic Iron-Oxide (Fe3O4) Nanoparticles for Biomedical Applications ». University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447689870.
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Hervault, A. M. M. « Development of a doxorubicin-loaded dual pH- and thermo-responsive magnetic nanocarrier for application in magnetic hyperthermia and drug delivery in cancer therapy ». Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1566981/.
Texte intégralRésumé :
Magnetic nanocarriers have attracted increasing attention for multimodal cancer therapy due to the possibility to deliver heat and drugs locally. The enhancement of the anti-cancer effect of chemotherapy with application of concurrent hyperthermia has been noticed more than thirty years ago. However, combining magnetic nanoparticles with drug molecules in the same nanoformulation has only recently emerged as a promising tool for the simultaneous application of hyperthermia and chemotherapy. In this work, initial experimentation was primarily focused on the synthesis of magnetic nanoparticles of high saturation magnetisation to develop efficient mediators of heat based on an iron core and a bismuth shell. However, such nanoparticles could not be obtained due to the impossibility to grow the bismuth shell on the iron nanoparticle surface. The rest of this study reports the development of a novel magnetic nanocomposites (MNCs) made of an iron oxide core and a pH- and thermo-responsive polymer shell, that can be used as both mediators of heat and drug carriers. The conjugation of the anticancer drug doxorubicin to the thermo-responsive MNCs via acid-cleavable imine linkers provides advanced features for the targeted delivery of doxorubicin via the combination of magnetic targeting, and dual pH- and thermo-responsive behaviour, which offers spatial and temporal control over the release of the drug. The nanoparticles exhibit a superparamagnetic behaviour with a saturation magnetization around 78 emu/g and good heating properties in an alternating magnetic field. Almost a complete doxorubicin release was obtained under acidic tumour pH and hyperthermia conditions. Finally, in vitro studies on human glioma and breast cancer cell lines and on a murine prostate carcinoma cell line confirmed that thermo-chemotherapy applied via the developed smart delivery system exhibits a substantial increase in cytotoxicity as compared to standalone therapies, and almost complete cell death was observed while applying low thermal and chemotherapeutic doses.
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Rétif, Paul. « Modélisation, simulation et analyse numériques de l'interaction nanoparticules-rayons X : applications à la radiothérapie augmentée ». Thesis, Université de Lorraine, 2016. http://www.theses.fr/2016LORR0023/document.
Texte intégralRésumé :
Les travaux présentés dans le cadre de cette thèse sont divisés en trois grandes parties qui concernent l’utilisation des nanoparticules métalliques pour augmenter les effets de la radiothérapie. Cette utilisation très particulière des nanoparticules n’a fait l’objet, jusqu’à présent, que d’études précliniques sauf un nano-objet qui fait actuellement l’objet de phases cliniques I et II à l’Institut Gustave Roussy de Villejuif, France. La première partie est une recherche bibliographique qui s’est concrétisée par la parution d’un état de l’art dans une revue internationale. Ce dernier identifie les paramètres jouant un rôle clef dans l’augmentation de la radiothérapie par les nanoparticules. Suite à cette étude de la littérature, le constat a été fait que la recherche préclinique en nanomédecine est plus longue et plus onéreuse que celle qui s’intéresse aux objets (macro-molécules) de taille standard. C’est pour améliorer cette prise en charge préclinique qu’une plateforme informatique de simulation Monte-Carlo des interactions nanoparticules – rayons X a été développée. Cette dernière ayant pour objectif de réaliser un classement in silico rapide et fiable des nanoparticules radiosensibilisantes permettant d’identifier de façon efficiente les nanostructures présentant les propriétés les plus prometteuses. La seconde partie de cette thèse consiste en une analyse de robustesse de ce simulateur, visant à identifier les paramètres de variabilité intrinsèques au simulateur et à quantifier leur influence sur la variation des résultats. Trois paramètres ont été identifiés comme paramètres critiques de simulation et doivent être maintenus constants entre les différentes études. Enfin, une troisième partie traite de l’application de cet outil de simulation au screening virtuel de nanoparticules radiosensilisantes. Dans cette partie sont réalisées une analyse de prédiction in silico / in vitro et une analyse de prédiction in silico / in cellulo. Les résultats très encourageants (correspondance acceptable entre les prédictions du simulateur et les résultats in cellulo) obtenus durant cette dernière phase ont également fait l’objet d’une soumission à publication dans une revue internationaleThe work that has been carried out during this PhD thesis is divided into three main parts that are related to the use of metallic nanoparticles to enhance the effects of radiation therapy. Until now, this particular use of nanoparticles has only been limited to preclinical trials apart from a single nano-object which is currently tested in phases I and II clinical trials in the Institut Gustave Roussy of Villejuif, France. The first part of this study is a bibliographic research that has been published as a review article in an international journal. The latter identifies the key parameters responsible for the enhancement of radiation therapy by nanoparticles. Following this part, the observation was made that the preclinical research in nanomedicine is longer and more expensive than for classical macromolecules. That is why, in order to improve this preclinical step, a Monte Carlo simulation platform of nanoparticles – X rays interactions has been developed. The aim of this platform is to perform a quick and reliable in silico ranking of radiosensitizing nanoparticles in order to efficiently identify the nanostructures with the most promising properties. The second part of this thesis consists of a robustness analysis of the latter simulator, aiming to identify its intrinsic variability parameters and to quantify their influence on the variability of the results. Three parameters have been identified as critical simulation parameters and should be kept constant between studies. Finally, a third part deals with the application of the simulation platform to the virtual screening of radiosensitizing nanoparticles. A predictive in silico / in vitro and in silico / in cellulo analysis are carried out in this section. Promising results (acceptable matching between simulator’s predictions and in cellulo results) obtained during this last phase were also submitted for publication in an international journal
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Hillerdal, Victoria. « The Multiple Faces of Genetically-Modified T Cells : Potential Applications in Therapy ». Doctoral thesis, Uppsala universitet, Klinisk immunologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-232850.
Texte intégralRésumé :
In this PhD thesis the potential of T-cells as therapy for disease are explored. The applications of genetically modified T-cells for treatment of cancer and autoimmune disease; the functionality and optimal activation of T-cells are discussed. Successful treatment of cancer with T-cell receptor (TCR)-modified T-cells was first reported in 2006, and is based on recognition of a specific peptide by the TCR in the context of the MHC molecule. As antigen presentation in tumors is often defective and to avoid MHC-restriction, chimeric antigen receptors (CAR) molecules containing an antibody part for recognition of cell surface antigens and TCR and co-receptor signaling domains have been developed. Activated T-cells mount an efficient immune response resulting in the killing of the cancer cell and initiating T-cell proliferation. The rationale for using genetically modified T-cells instead of isolating tumor infiltrating lymphocytes from the tumor and expanding them (TIL therapy) is that it is often very difficult to obtain viable lymphocytes that are able to expand enough in order to use them for therapy. This thesis explores the possibility of using prostate-specific antigens to target T-cells towards prostate cancer. The prostate has many unique tissue antigens but most patients with metastatic prostate cancer have undergone prostatectomy and consequently have “prostate antigen” expression only in cancer cells. We targeted the prostate antigens TARP and PSCA with a HLA-A2 restricted TCR and a CAR respectively. In both cases the tumor-specific T-cells were able to generate potent proliferative and cytotoxic responses in vitro. The PSCA CAR-modified T-cells delayed subcutaneous tumor growth in vivo. It is evident from our in vivo experiments that the PSCA CAR T-cells were unable to completely cure the mice. Therefore, we aimed to improve the quality of the transferred T-cells and their resistance to the immunosuppressive tumor microenvironment. Stimulation with allogeneic lymphocyte-licensed DCs improved the resistance to oxidative stress and antitumor activity of the T-cells. We further investigated the potential of genetically modified regulatory T-cells (Tregs) to suppress effector cells in an antigen-specific manner. Using a strong TCR we hypothesize that the phenotype of the TCR-transduced Tregs may be affected by antigen activation of those cells. We found that the engineered Tregs produced cytokines consistent with Th1, Th2 and Treg phenotypes.
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Ciampa, M. G. « Application of oligosaccharidic gold nanoparticles to the vaccines for the therapy of breast cancer : synthesis of neu5GcLactose antigen starting from a complex ganglioside mixture ». Doctoral thesis, Università degli Studi di Milano, 2008. http://hdl.handle.net/2434/156025.
Texte intégralRésumé :
Gangliosides, sphingolipids containing sialic acid residue(s), are components of the external layer of cell plasma membranes where they are inserted with the hydrophilic head group turned towards the extra cellular environment. In this strategic position, gangliosides contribute to very special cell processes as development, differentiation and oncogenic transformation.
Analysis of the tumour associated ganglioside component profile may aid in the characterization of tumour cells and to establish the degree of malignant transformation.
Furthermore, gangliosides that become prominently exposed on tumour cell during oncogenic dedifferentiation may be used as targets for specific immunohistological identification and possible therapeutic approaches.
In humans the main sialic acid is N-acetyl-neuraminic acid (Neu5Ac), whereas N-glycolyl neuraminic acid (Neu5Gc) is not expressed in normal human tissues because a species-specific genetic mutation abrogate its biosynthesis. However breast cancer cells contain ganglioside GM3 carryng not only Neu5Ac but also Neu5Gc which resulted highly immunogenic and can be considered a good target for immunotherapy development.
Some laboratories produced murine or human monoclonal antibodies (MAbs) against GM3(NeuGc) ganglioside antigen but the low specificity of these monoclonal antibodies made them only partially useful for the cancer diagnosis and therapy.
The aim of this thesis was to synthesize the oligosaccaridic chain of GM3(NeuGc) and obtain an idiotopic antigen that mimic the oligosaccharide of GM3(NeuGc).
The first part of the research involved the synthesis of the oligosaccharide α-Neu5Gc-(2-3)-β-Gal-(1-4)-β-Glc: starting from the natural GM3, which contains the Neu5Ac, we removed the acetyl group from the sialic acid and then synthesized the GM3(NeuGc). Later we removed the ceramide portion in order to obtain the free oligo-saccharide chain of GM3(NeuGc).
Because the it is known that the oligosaccharidic molecules alone are not capable to induce an antibody response enough specific and efficient, we decided to synthesized a complex between the prepared oligosaccharide and gold nanoparticles.
For this purpose we performed a two-phase synthesis: a thiol ligand (thio-acetyl-nonanole) is first tied with the free oligo-saccharide chain of GM3(NeuGc) and then strongly bound to colloidal gold thus obtaining the gold-glyconanoparticles.
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Dolde, Kai [Verfasser], et Joao [Akademischer Betreuer] Seco. « 4D magnetic resonance imaging applications towards MR-guided proton therapy of pancreatic cancer / Kai Dolde ; Betreuer : Joao Seco ». Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1193347327/34.
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Zhang, Chen. « Metal-NHC complexes for anti-cancer applications : gold(I) for antimitochondrial activity and iridium(III) for photodynamic therapy ». Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30129/document.
Texte intégralRésumé :
Dans ce travail de thèse, plusieurs groupes de nouveaux complexes d'or(I) à base de carbènes N-hétérocyclique (NHC)contenant des bras amino-aliphatiques et aromatiques avec un potentiel intéressant dans des applications biomédicales ont été synthétisés et entièrement caractérisés. En outre, une série de complexes d'iridium(III) contenant des ligands NHC avec des activités anticancéreuses prononcées pour une application en thérapie photodynamique, a étépréparée et entièrement caractérisée. Le premier groupe représente une famille de complexes cationiques or(I) bis(NHC) contenant des bras latéraux amino-aliphatiques. Ces complexes ont étésynthétisés et étudiés pour leurs activités antiprolifératives vis-à-vis de quatre lignées cellulaires cancéreuses humaines et de la lignée cellulaire non cancéreuse MDCK. Dans cette série, la lipophilie est directement liée àl'activitécytotoxique contre les cellules cancéreuses. La deuxième famille de composés concerne les complexes cationiques or(I) bis(NHC) contenant des bras latéraux amino-aromatiques. La cytotoxicitéin vitro de ces complexes et de leurs proligands sur les lignées cellulaires représentatives du cancer de la prostate PC-3 et de la vessie T24 a étéévaluée. Tous ces complexes présentent des valeurs de Log P (lipophilie) supérieures àcelles de la première série de complexes en accord avec leur cytotoxicité plus élevée, mais une lipophilie trop élevée peut également conduire àune sélectivitéplus faible. Afin de développer un candidat-médicament avec une activitéet une sélectivité optimisées, nous avons conçu et synthétisé la troisième famille de complexes cationiques or(I) bis(NHC). Les valeurs de log P de cette série se situent entre la première série et la deuxième série. Ces complexes moins lipophiles sont moins cytotoxiques envers les lignées cellulaires saines (NIH3T3) et montre des activités anticancéreuses un peu plus faibles sur les cellules PC-3 que la deuxième série, avec néanmoins des valeurs de GI50 dans la gamme du nanomolaire. Les études mécanistiques sur deux complexes d'or(I) ont été réalisées. Les mesures d'absorption cellulaire ont montré une accumulation cellulaire rapide et une bonne biodisponibilitédes complexes, en accord avec l'activitéantiproliférative de ces deux complexes. De plus, les deux complexes inhibent la thiorédoxine reductase (TrxR), une cible commune pour les complexes d'or(I). La mort cellulaire induite par ces deux complexes est dépendante des espèces réactives de l'oxygène. En plus des activités anticancéreuses, nous avons également testédes complexes d'or(I) mono-NHC pour une autre application biomédicale, la leishmaniose, maladie parsitaire. Ils ont été testés in vitro sur les formes promastigotes et amastigotes axéniques de L. infantum. De plus, leur cytotoxicitéa étéévaluée sur les macrophages murins J774A.1 afin de déterminer leur sélectivitéd'action. Un autre sujet de cette thèse concerne les complexes d'iridium(III)-NHC. Trois familles de complexes ont étépréparées et caractérisées. La cytotoxicitéin vitro de tous les complexes sur les cellules cancéreuses de la prostate PC-3 et de la vessie T24, et les cellules non cancéreuses NIH3T3 a étéévaluée. De plus, tous les complexes sont des agents théranostiques, et les expériences de microscopie confocale d'un complexe ont montréqu'il pouvait être rapidement et efficacement absorbédans les cellules PC-3 et se localiser spécifiquement dans les mitochondries. De manière intéressante, ces complexes peuvent agir comme des photosensibilisateurs efficaces. La cytotoxicitéde ces complexes a étéaugmentée substantiellement après une irradiation lumineuse de 365 nm, ce qui suggère le potentiel élevéde ces agents anticancéreux théranostiques ciblant les mitochondries pour la thérapie photodynamiqueIn this work of thesis, several groups of novel NHC-based gold(I) complexes containing aliphatic and aromatic amino-side arms with interesting potential in biomedical applications have been synthesized and fully characterized. Also, a series of iridium(III) complexes containing NHC ligands with pronounced PDT anticancer activities has been prepared and fully characterized. The first group represents a family of cationic bis(NHC)-gold(I) complexes containing aliphatic amino-side arms. These complexes have been synthesized and investigated for their antiproliferative activities towards four human cancer cell lines and the non-cancerous MDCK cell line. In this series, the lipophilicity correlates directly with the cytotoxic activity against cancer cells. The second family of compounds concerns cationic gold(I) bis(NHC) complexes containing aromatic amino-side arms. The in vitro cytotoxicity of these complexes and proligands on the representative PC-3 prostate and T24 bladder cancer cell lines has been evaluated. All these complexes show higher Log P values (lipophilicity) than the first series of complexes, and in line with this higher cytotoxicity, nevertheless too high lipophilicity can also lead to lower selectivity. In order to develop a drug candidate with optimized activity and selectivity, we designed and synthesized the third family of cationic gold(I) bis(NHC) complexes. The Log P values of this series were between the first series and the second series. The lower cytotoxicity towards non-cancerous NIH3T3 cells was found for this series of complexes whereas they also displayed less activities towards cancer cells than the second series. The mechanistic studies on two gold complexes by monitoring the cellular uptake showed the rapid cellular accumulation of the intact gold bis(NHC) and a good bioavailability, in good agreement with the antiproliferative activity of these two complexes. Moreover, both complexes inhibit TrxR, a common target for gold(I) complexes. The cell death induced by these two complexes was ROS-dependent. Besides anticancer activities, we also tested gold(I) mono-NHC complexes for other biomedical applications in parasite disease Leishmaniasis. They were screened in vitro against both promastigote and axenic amastigote forms of L. infantum. Moreover, their cytotoxicity was evaluated on the murine J774A.1 macrophages in order to determine their selectivity of action. Another topic of this thesis concerns iridium(III)-NHC complexes. Three families of theranostic iridium(III)-NHC complexes were prepared and characterized. The in vitro cytotoxicity of all the complexes against PC-3 prostate, T24 bladder cancer cells and non-cancerous NIH3T3 cells was evaluated. Moreover, all complexes are theranostic agents, and the confocal microscopy experiments of one complex showed that it can be quickly and effectively taken up into PC-3 cells and specifically localize into mitochondria. Interestingly, these complexes can act as efficient photosensitizers. The cytotoxicity of these complexes was increased substantially upon 365 nm light irradiation, which suggested the high potential to be mitochondria-targeting theranostic anticancer agents for photodynamic therapy
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FELICI, ALESSIA. « Development of discoidal polymeric nanoconstructs for the treatment of cancer disease ». Doctoral thesis, Università degli studi di Genova, 2021. http://hdl.handle.net/11567/1046417.
Texte intégralRésumé :
High loading and specific release of therapeutic agents within the tumor microenvironment are key factors in the development of novel nano-based therapeutic systems against cancer. Although drug availability and preferential tumor accumulation improved with advanced drug delivery system for cancer therapy, they still faces challenge in drug encapsulation and retention. Here, Discoidal Polymeric Nanoconstructs (DPNs) were employed to load and systemically deliver both hydrophilic and hydrophobic therapeutic molecules. DPNs appear as disks, with a diameter of about 1 µm and a height of 400 nm, designed for vascular adhesion in a tortuous and low perfused vasculature as in the case of tumor. Moreover, soft DPNs presenting a stiffness of about few kPa, were shown to circulate longer, more effectively avoid the sequestration by hepatic and splenic immune cells and accumulate at higher doses in the tumor vasculature as compared to rigid DPNs. DPNs were synthetized by mixing together hydrophobic – poly(lactic-co-glycolic acid) (PLGA) and hydrophilic – polyethylene glycol diacrylate (PEG-diacrylate) using a top-down, template-based fabrication process. Improved performance in terms of encapsulation efficiency and drug retention have been achieved following two approaches; first, improving the fabrication process with a multi-passage strategy over the hydrophilic PVA template used for DPN production; Second, modulating the chemical proprieties of the selected drug Docetaxel by lipid or polymeric chains conjugation. In particular, two different prodrugs were realized, namely oleic-Docetaxel (O-DTXL) and PEG-Docetaxel (PEG-DTXL) incorporated in DPN via direct and absorption loading. On one side, the conjugation of Dtxl with PEG chains ensures an improved loading efficiency and retention capability of the drug within the soft polymeric net respect to the Docetaxel alone. In cell-line orthotopic brain cancer model, with only 1 mg/kg of drug administered intravenously every other days for 20 days post resection of the primary mass, DTXL-PEG550-DPNs increase the median overall survival (30 days) as compared also to 10 chemotherapeutic cycles with temozolomide administered at a dose three times higher (3mg/Kg) (27 days).On the other side, multi-passage DTXL-DPNs efficiently accumulated in In orthotopic murine models of Triple negative breast cancer masses with a tumor-to-abdomen ratio of 1.3. With only 2 mg/kg of DTXL, intravenously administered every other day for 13 times, DTXL-DPNs induced tumor regression returning an 80% survival rate at 120 days as compared to 30% with free DTXL. Collectively, these results demonstrate that vascular targeting nanoconstructs with tunable pharmacological properties can be exploited to effectively treat multiples type of tumors.
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Fonseca, Leonor Castro da. « Application of nanotechnological delivery systems in pancreatic cancer therapy ». Master's thesis, 2018. http://hdl.handle.net/10437/10115.
Texte intégralRésumé :
Orientação: Pedro Lopes da Fonte ; co-orientação: Catarina ReisThe aim of this dissertation is to understand the applications of nanotechnology in the delivery of drugs in pancreatic cancer therapy. It was necessary to realize the pathogenesis of pancreatic cancer, as well as the reasons why conventional therapies currently used do not provide a significant increase in patient survival. Pancreatic cancer is one of the most lethal cancers in the world, mainly because of the inability to diagnose it in a timely manner and the lack of effectiveness of existing treatments. In this way, the development of new innovative therapies has become fundamental. In the last decade, nanomedicine has gained increasing prominence as a new approach for the delivery of drugs, since it allows the transport of the drugs to the specific region and in established concentrations, reducing in this way the systemic toxicity. Several studies are related to different types of nanoparticles (lipid, polymer and metal), highlighting the advantages and disadvantages of each of them, as well as some drugs already marketed using nanotechnology. A model administration system was developed for the delivery of Parvifloron D. The characteristics selected were related to the properties of the drug to be encapsulated, with diameters of 200nm, negative zeta potential, IdP of 0.200 and connection efficiency of 97%. The toxicity of the formulation was also evaluated, and it was concluded that the lower concentration nanoparticles (30 μM) provided a growth inhibition of 3.2% Saccharomyces cerevisiae, and at the highest concentration (53 μM) of 15.6%. These results lead us to believe that through further studies it may be possible to use this optimized formulation as a suitable and promising carrier of Parvifloron D, and thus contribute to a therapeutic alternative for pancreatic cancer.
O objetivo desta dissertação prende-se com a compreensão das aplicações da nanotecnologia na vectorização de fármacos na terapia do cancro do pâncreas. Para tal foi necessário perceber a patogénese do cancro do pâncreas, bem como os motivos pelos quais as terapias convencionais atualmente utilizadas não proporcionam um aumento significativo da sobrevivência dos doentes. O cancro do pâncreas representa um dos cancros mais letais no mundo, devido sobretudo à incapacidade de diagnosticá-lo em tempo hábil e à falta de eficácia dos tratamentos existentes. Desta forma, o desenvolvimento de novas terapias inovadoras tornou-se fundamental. Na última década, a nanomedicina tem ganho cada vez mais destaque como uma nova abordagem para a vectorização de fármacos, uma vez que possibilita o transporte dos fármacos até à região específica e em concentrações estabelecidas, reduzindo desta forma a toxicidade sistémica. São abordados diversos estudos relacionados com diferentes tipos de nanopartículas (lipídicas, poliméricas e metálicas), salientando as vantagens e as desvantagens de cada um deles, bem como alguns fármacos já comercializados com recurso à nanotecnologia. Foi desenvolvido um sistema de administração modelo para vectorização de Parviflorona D. As características selecionadas foram de encontro às propriedades do fármaco a encapsular, sendo que obtivemos diâmetros de 200nm, potencial zeta negativo, IdP de 0,200 e eficiência de ligação de 97%. A toxicidade da formulação também foi avaliada, e concluiu-se que as nanopartículas de menor concentração (30 μM) proporcionaram uma inibição de crescimento de 3,2% de Saccharomyces cerevisiae, e na maior concentração (53 μM) de 15,6%. Estes resultados levam-nos a acreditar que mediante mais estudos possa ser possível utilizar esta formulação otimizada como sistema de veiculação adequado e promissor da Parviflorona D, e desta forma contribuir para uma alternativa terapêutica para o cancro do pâncreas.
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Yang, Huei-Jiun, et 楊惠君. « Functional studies of Nampt and its application on cancer therapy ». Thesis, 2008. http://ndltd.ncl.edu.tw/handle/15124156067529613462.
Texte intégralRésumé :
碩士國立成功大學
生物化學研究所
96
Nicotinamide adenine dinucleotide (NAD+) has crucial roles in many cellular processes, such as a coenzyme for redox reactions or as a substrate to donate ADP-ribose units. Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme in the salvage pathway of NAD+ synthesis via nicotinamide and regulates the activity of the NAD-dependent deacetylase Sirt1 in mammalian cells. In previous study, it showed that tumor cells had a high rate of NAD+ turnover owing to elevated ADP-ribosylation activity. In addition, FK866 is a potent small-molecule inhibitor of human Nampt, and the consequent reduction in NAD+ levels can cause apoptosis of tumor cells. On the other hand, Indoleamine 2,3-Dioxygenase (IDO) is the rate-limiting enzyme in the de novo pathway of NAD+ synthesis via tryptophan. IDO inhibitors can potentiate chemotherapy in some cancer models. Hence, We hypothesized that it may enhance cancer therapy by combination of FK866 and L-1MT. We proposed that the significant effect on cancer therapy could be accomplished by one of the following: (1) blocking the NAD+ biosynthesis pathway with FK866 and L-1MT can further inhibit the growth and metabolism of tumor cells. (2) FK866 in combination with L-1MT can achieve better cancer therapy by avoiding tumor cells going to immune escape. In this study, FK866 in combination with L-1MT could significantly delay the tumor growth and elevate the survival of C3H/HeNCrj mice. In contrast, FK866 and L-1MT did not have additive effect on NOD/scid mice. We analyzed the infiltration of immune cell, including CD4, CD8, NK and neutrophil. The result showed a high relationship between neutrophil infiltration and the anti-cancer effect of FK866 in combination with L-1MT. In addition, we analyzed the new blood vessel in the mice tumor by immunohistochemistry. The result suggested that FK866 in combination with L-1MT could significantly reduce tumor angiogenesis up to 45％ when comparing with primary mouse bladder tumor cell line. In conclusion, the therapeutic efficiency may be due to in part from immune enhancement by IDO inhibitor and in part from growth inhibition by Nampt inhibitor.
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Huang, Chun-Kai, et 黃俊凱. « Investigation of Multifunctional Mixed Micelles and Their Application in Cancer Therapy ». Thesis, 2006. http://ndltd.ncl.edu.tw/handle/83181731730010679661.
Texte intégralRésumé :
碩士國立清華大學
化學工程學系
94
The self-assembly of amphiphilic copolymers into micelles in a selective solvent, including diblock copolymers, triblock copolymers and graft copolymers, have attracted much interest. Besides the mono-unimer composition, many investigations dealt with the multicomponent micelles (also called mixed micelles) from the di-diblock copolymer system, the tri-diblock copolymer system or the tri-triblock copolymer system because of their comicellization behavior and their extensive applications in such areas as drug delivery and particle modification. The novel mixed micelle which was composed of graft copolymer and diblock copolymer is successfully prepared. Poly (N-isopropyl- acrylamide-co-methyl acrylic acid)-g-poly (D,L- lactide) (P(NIPAAm-co-MAAc)-g-PLA ) graft copolymer formed the multifunctional inner core of mixed micelle. PNIPAAm have lower critical solution temperature (LCST) at 32℃ which was below the nominal body temperature is unstable in the blood circulation. By the addition of MAAc in PNIPAAm, the LCST not only raise to above the nominal body, but also stabilize in blood circulation and offer the carboxylic group which can generate hydrogen bond interaction and dissociation at pH＞7.4. The micelle can utilized the pH and thermal response to accumulate at tumor tissue. Because the PLA is the side chain of graft copolymer, the mobility is very slowly so that the critical micelle concentration (CMC) is rarely low. By addition the diblock copolymer poly(ethylene glycol)-b-poly (D,L-lactide) (PEG-PLA) in to the micelle system, PEG-PLA can avoid the secondary aggregation of graft copolymer because of the hydrophilicity of PEG.. It’s could not only reduce the secondary aggregation but also prolong the circulation time in the blood. In this study, we investigated the effect of mixed micelle with different hydrophobic length of diblock copolymer on comicellization. The results indicate that the stability of mixed micelles increases with the molecular weight of PLA increasing, and the hydrogen bond interaction of PEG and MAAc only occurred at initial aggregation during comicellization. The particle sizes of mixed micelle were ranged from100 to 200 and exhibited the narrow size distribution (PI < 0.1) in all of these cases.