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Evaluation of the safety and drug delivery efficacy of carbon dots in in vitro and in vivo models

Abstract : Carbon dots (CDs) are the latest member of the family of carbon nanoparticles (NPs) to be discovered. They were isolated for the first time in 2004, during electrophoresis purification of carbon nanotubes. In addition to their nanometric size, these objects are almost spherical and hydrophilic, and are generally presented as biocompatible and very weakly toxic NPs. They are fairly easily accessible by synthesis and can be conveniently modified by reaction of the functional groups present on their surface (amines, carboxylic acids, alcohols, etc.). Finally, they exhibit intrinsic fluorescence properties, are relatively resistant to photobleaching, and can be excited by multi-photon irradiation. Thus, like the other members of the family of carbon NPs (graphene, nanodiamonds, fullerenes, nanotubes), CDs have remarkable properties which are the subject of intense research for applications in fields as different as those of electronics, catalysis, energy storage, imaging, and medicine. In the latter area, CDs can find applications as drug delivery systems, like other NPs successfully developed in this field. The work developed during this thesis had two distinct objectives. The first one was to identify the intrinsic physicochemical properties responsible for the toxicity of NPs. For this, the toxicological profile of a large collection of CDs produced in the laboratory and exhibiting various size, charge, and surface chemistry was characterized using in vitro lung models and mice. We found that although the size of the NPs plays an important role it is not, by itself, a predictive element of the toxicity of the NPs. The charge and the surface chemistry largely effect the interactions between the NPs and the biological medium systems and, therefore, their intrinsic toxicity. The second objective of this thesis was to assess the potential of CDs in the field of drug delivery as synthetic gene carriers. We were able to show the superiority of NPs prepared from citric acid and bPEI600 over all other cationic CDs produced in the laboratory. A systematic evaluation has allowed us, step by step, to improve the efficiency of these transfection agents, to exceed that of bPEI25k, a gold standard for in vitro transfection, without significant toxicity. Overall, this work opens up new horizons in NPs research that may provide 1-a better understanding of the toxicological mechanisms of NPs, especially their determinants, and 2-identification of the relationship between the CDs synthesis methods and the efficiency of these NPs as DNA transfection reagents.
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Jiahui Fan. Evaluation of the safety and drug delivery efficacy of carbon dots in in vitro and in vivo models. Organic chemistry. Université de Strasbourg, 2018. English. ⟨NNT : 2018STRAF045⟩. ⟨tel-02918044⟩

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