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Vasculature targeting for the treatment of cancer and inflammatory diseases : looking for ligands of E selection and endoglin

Aline Savarin
Abstract : My work concerned tumor vasculature targeting. Compounds targeting the tumor endothelium were investigated in order to redirect drugs and induce, specifically, the destruction of the tumor endothelium and therefore the tumor. According to the literature, two targets have been identified for the present study: E selectin and endoglin. E selectin is a glycoprotein surexpressed on endothelial cells during inflammation and angiogenesis. Classically, antagonists of its natural ligand, the SleX, are researched. Based on the key interaction groups between E selectin and SleX, three mimics' families have been designed. The ability of these analogs to block the interaction of the SleX expressed on HL-60 cells with the E selectin protein was evaluated in an adhesion assay. However, none of the analogs had a sufficient affinity for a use as a targeting agent. In a second strategy, a phage library was selected on activated HUVECs to find peptide ligands of the E selectin. Some of the selected phages-peptides showed a better affinity for E selectin and / or P selectin in an ELISA assay than the insert-less phage. Their specificity for the target will soon be evaluated in competition assays with the corresponding synthetic peptides. In a second part, phage display was used to identify peptide ligands of the endoglin. First, the endoglin was cloned and expressed in mammalian cells in order to select the phage library on the cellular protein. Selection on the recombinant endoglin was also carried out to reduce the background linked to the cells. Some of the selected peptides showed sequence homologies with known endoglin ligands. The corresponding phages-peptides gave a strong signal in an ELISA assay on the recombinant protein by comparison with an insert-less peptide. Those peptides will be soon characterized. In conclusion, potential peptide ligands of E and P selectin and of endoglin were identified. This work also led us to set up the phage display technology in the laboratory and to optimize the selection procedure.
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Aline Savarin. Vasculature targeting for the treatment of cancer and inflammatory diseases : looking for ligands of E selection and endoglin. Life Sciences [q-bio]. AgroParisTech, 2005. English. ⟨NNT : 2005INAP0018⟩. ⟨pastel-00005017⟩

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