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Ciblage des protéoglycanes par la fonction ammonium quaternaire. : Développement de nouvelles approches diagnostiques et thérapeutiques pour la prise en charge du chondrosarcome.

Abstract : Our strategy consists in using the quaternary ammonium function, that exhibits a high affinity for proteoglycans of extracellular matrix, as a selective carrier to chondrosarcoma of (i) radioisotopes for a targeted in vivo imaging or (i) cytotoxics for a targeted therapeutic approach. For diagnosis application, a radiotracer radiolabeled with 99m Tc ( 99m Tc-NTP 15-5) was designed and tested in vivo in an orthotopic Swarm chondrosarcoma model. For therapeutic application, a quaternary ammonium derivative of melphalan, Melphalan-AQ, was synthesized and assessed in vitro (cytotoxic activity, cell cycle distribution) and in vivo in the orthotopic Swarm chondrosarcome model (antitumor efficacy, toxicity). Since chondrosarcoma is characterized by hypoxia, research was focused on the vectorization of hypoxia-activated prodrugs. For diagnosis, 99m Tc-NTP 15-5 radiotracer highly accumulated in tumoral tissue at very early stage of pathology while no palpable nor measurable tumor could be assessed. For therapy, chondrosarcoma bearing rats treated with Melphalan-AQ showed a significant tumor growth inhibition with associated heamatological side effects being significantly reduced as compared to Melphalan. Among all phosphoramidate-AQ derivatives synthetised, one was selected on the basis of cytotoxic activity improvement under hypoxia respectively to normoxia. In vivo, this compound demonstrated a significant tumoral growth inhibition in the hypoxic HEMC-SS chondrosarcoma model. This work underlines the potential of the proteoglycans vectorization strategy developed in our lab, for a targeted management of chondrosarcoma including: (i) the first and only radiopharmaceutical able to provide in vivo a specific diagnosis and staging of the tumoral pathology of cartilage and (ii) a promising targeted antineoplastic approach exploiting both the chondrogenic and hypoxic features of chondrosarcoma.
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Caroline Peyrode. Ciblage des protéoglycanes par la fonction ammonium quaternaire. : Développement de nouvelles approches diagnostiques et thérapeutiques pour la prise en charge du chondrosarcome.. Médecine humaine et pathologie. Université d'Auvergne - Clermont-Ferrand I, 2011. Français. ⟨NNT : 2011CLF1MM26⟩. ⟨tel-01875782⟩

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