Défense de thèse de doctorat - sciences biologiques

Hybrid gold nanoparticles coated with organic polymers and antibodies as platform for cancer theranostics: Investigation of the cytotoxicity mechanisms and feasibility study of radioactive labeling

Jury:

 

Abstract:

 Thanks to their unique optical and physicochemical properties, gold nanoparticles (AuNPs) have emerged as promising radiosensitizers, which can enhance the efficacy of external and internal radiotherapy. In this thesis, we investigated the toxicity mechanism of antibody-functionalized AuNPs in normal liver, kidney and microvascular endothelial cells. Furthermore, we evaluated the pharmacokinetics, biodistribution and toxicity of the AuNPs after a single intravenous injection in healthy mice. Finally, the antibody-functionalized AuNPs were radiolabeled with the radionuclide, 177Lu, using bifunctional chelators and were tested for their stability, specificity, and internalization in human cancer cells.
The results demonstrated that the antibody-functionalized AuNPs were internalized in normal cells, causing oxidative stress, mitochondrial dysfunction and inhibition of the antioxidant defense system. In vivo, the antibody-functionalized AuNPs were rapidly cleared from the blood circulation and accumulated mainly in the liver and spleen, followed by a long-term retention. Nevertheless, cytokine serum levels showed no significant increase and there was only a slight and transient increase of the liver aminotransferase enzymes. Furthermore, normal kidney, liver, spleen and lung morphology was observed up to 4 weeks post-injection. Finally, the bifunctional chelator diethylenetriaminepentaacetic acid (DTPA) was coupled to the antibody-functionalized AuNPs and rapidly achieved a high radiolabeling efficiency and yield (90%) under mild reaction conditions. The obtained 177Lu-radiolabeled AuNPs showed an enhanced binding and internalization in receptor-overexpressing cancer cells when compared to receptor-negative cancer cells.
In conclusion, together with the biological inhibition, radiolabeled antibody-functionalized AuNPs could have the potential to increase the efficacy of targeted radionuclide therapy compared to a radiolabeled antibody. However, the rapid sequestration and long-term retention of the AuNPs in the liver and spleen after intravenous administration might restrict the tumor accumulation and thus its therapeutic potential.

Contact : Alexia Petit - 081/725476 - alexia.petit@unamur.be
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