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Développement d’une nouvelle approche combinant la radioimagerie et l’imagerie par spectrométrie de masse pour l’analyse de nanoparticules / Development of a dual imaging strategy combining radio -and mass spectrometry- imaging to study the biodistribution of nanoparticlesCazier, Hélène 08 November 2019 (has links)
La vectorisation de médicaments, qui permet de les acheminer sur les tissus cibles pour accroitre leur activité pharmacologique tout en limitant leur toxicité et effets indésirables, est un axe de recherche en forte expansion dans lequel les nanotechnologies sont un des facteurs clés. L’un des enjeux dans cette thèse a donc été de développer une méthode d’imagerie combinée entre la MSI et l’imagerie β pour l’étude de la biodistribution de nanoparticules de type graphène. Malgré l’étude de nanoparticules hétérogènes, les analyses ont permis de déterminer une signature carbonée répétable de l’oxyde de graphène en analyse LDI - MS et ainsi que des analyses reproductibles de MSI avec de CV inférieur à 30 %. De plus, la combinaison des deux techniques a permis d’obtenir la quantification absolue du GO en radioimagerie après exposition de souris à trois doses d’injection ainsi que la biodistribution à 25 µm de résolution spatiale de ces nanoparticules au sein des tissus grâce à l’apport de la MSI. Lors d’un second projet concernant l’étude de vecteurs micellaires polymériques encapsulant un médicament, une méthode MALDI - TOF a également été développée afin de détecter ces deux molécules simultanément. Cependant, les expérimentations réalisées ont montré le besoin de développer des protocoles de traitements tissulaire compatibles avec la MSI et permettant d’améliorer le seuil de sensibilité de cette technique analytique. / The vectorization of drugs, which allows them to be transported to target tissues to increase their pharmacological activity while limiting their toxicity and adverse effects, is a rapidly expanding research area in which nanotechnologies are one of the key factors. One of the challenges in this thesis was therefore to develop a combined imaging method between MSI and imaging β for the study of the biodistribution of graphene-type nanoparticles. Despite the study of heterogeneous nanoparticles, the analyses determined a repeatable carbon signature of graphene oxide in LDI - MS analysis and reproducible MSI analyses with CVs below 30%. In addition, the combination of the two techniques made it possible to obtain the absolute quantification of GO in radioimaging after exposure of mice to three injection doses as well as the biodistribution at 25 µm of spatial resolution of these nanoparticles within tissues thanks to the contribution of MSI. In a second project to study polymeric micellar vectors encapsulating a drug, a MALDI - TOF method was also developed to detect these two molecules simultaneously. However, the experiments carried out have shown the need to develop tissue treatment protocols compatible with MSI and making it possible to improve the sensitivity threshold of this analytical technique.
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The Synthesis of Dendrimer-based Radioimaging AgentsKnight, Spencer D. 10 1900 (has links)
<p>The synthesis of new macromolecular diagnostic imaging agents has been a growing field in polymeric chemistry research. Dendrimers provide a viable scaffold for such applications due to their unique, defined macromolecular architecture. The precise structural control afforded via the step-wise synthesis of dendrimers yields exceptional and precise macromolecules that can be functionalized to include necessary imaging moieties with the same degree of precision.</p> <p>We have herein contributed to this growing field by attempting the synthesis of a series of PEGylated poly(2,2-bis[hydroxymethyl]propanoic acid) PMPA dendrons using thiol-ene "click" chemistry. The series consisted of three dendritic architectures peripherally functionalized with poly(ethylene glycol) (PEG) chains of varying length (n= 3, 8, 16), with the goal of determining the effect of PEG chain length on blood circulation times. Synthesis of these conjugates began first with functionalization of the dendron periphery to incorporate alkene functionalities using anhydride-mediated esterification chemistry.</p> <p>The core of the alkene PMPA dendrons was then modified to introduce a metal chelating bis-pyridyl functionality, which has been observed to chelate the radionuclide technetium-99m (<sup>99m</sup>Tc) with high binding affinity. <sup>99m</sup>Tc is the most widely used diagnostic radioisotope in diagnostic medicine due to its ideal isotopic properties, widespread availability, low cost, and its ability to be traced, in real time, <em>in vivo</em> using Single Photon Emission Computed Tomography (SPECT).</p> <p>PEGylation at the periphery was performed by thiol-ene “click” chemistry using thiol-terminated PEG chains. Metallation of the core of each PEGylated dendron was then attempted according to literature procedures for <sup>99m</sup>Tc radiolabeling with the bis-pyridyl chelate.</p> / Master of Science (MSc)
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DESIGN, SYNTHESIS, AND PRECLINICAL EVALUATION OF LIGAND-TARGETED CONJUGATES FOR CANCER RADIOTHERANOSTICSSpencer D Lindeman (11205204) 29 July 2021 (has links)
For any drug candidate to be approved by the U.S. Food and Drug Administration, it must meet strict standards for safety and efficacy. While the field of nuclear medicine is over 100 years old, traditional methods such as external beams or systematic administration have rarely met these standards or have limited application. Ligand-targeted therapy and diagnostics, or “theranostics,” has emerged in the past several decades as an exciting field that offers new possibilities to design drugs that are both safe and effective. When applied to nuclear medicine, the field of ligand-targeted radioactive theranostics is younger still, with many critical lessons being discovered and applied currently. This dissertation outlines the necessary principles of radioactive theranostic drug design, then demonstrates the application of several more recent techniques to improve both the efficacy and safety of radioactive theranostics targeting two high priority oncological targets: fibroblast activation protein alpha and folate receptor.
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