IMMUNOTHÉRAPIE ANTITUMORALE PAR TRANSFERT DE L'ARN MESSAGER DE L'ANTIGÈNE MELANA/MART-1

Abstract : An antitumoral response due to the induction of cytotoxic T lymphocytes can be generated after in vitro or directly in vivo transfer of tumor antigens mRNA in dendritic cells (DCs). However, few vectors allow an effective mRNA delivery into the DCs. We developed mRNA nanoparticles with histidylated cationic polymers (polyplexes), histidylated cationic lipids (lipoplexes) or a mixture of both (lipopolyplexes). These vectors become fusiogenic in acidic medium and favor the delivery of mRNA in the cytosol during endocytosis. An mRNA optimization by adding a cap 3'-O-méthyl-m75'GpppS'G (ARCA) in 5' and a tail of 100 adenosines (A100) in 3' led to the synthesis of an ARCA-ARNm-A100 transcript which allows a high antigen expression in DCs.,The histidylated polyethyleneimine was identified as a good transfection reagent for in vitro MART-1 melanoma antigen mRNA transfer in mature DCs. For a vaccination by direct injection of mRNA antigen, we developed news ternary nanoparticles (lipopolyplexes) corresponding to polyplexes of ARCA-MART1-A100 mRNA and a PEGylated derivative of histidylated polylysine encapsulated in histidylated liposomes. Systemic injections of these lipopolyplexes induce a specific and significant protective effect against cutaneous tumour and lung metastasis progression of B16FIO murine melanoma. The induction of Thl immune response with a strong secretion of IFN-y and a T cytotoxic activity, have been prouved showing the interest of histidylated lipopolyplexes
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Submitted on : Wednesday, June 27, 2007 - 4:40:42 PM
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  • HAL Id : tel-00158049, version 1

Citation

Mockey Mickaël. IMMUNOTHÉRAPIE ANTITUMORALE PAR TRANSFERT DE L'ARN MESSAGER DE L'ANTIGÈNE MELANA/MART-1. Biochimie [q-bio.BM]. Université d'Orléans, 2006. Français. ⟨tel-00158049⟩

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