Groupe du prof. Zhu
Copolymères Amphiphiles à Base d’Acide Biliaire et de Sucre pour le transport d’ARN
Résumé: Gene delivery may be used in the treatment of genetic diseases and cancers while gene vaccine stimulates our immunity and prevents diseases propagation. Nucleic acid sequences need to penetrate into the cytoplasm without being degraded in vivo. Polymer and lipid nanoparticles are chemical carriers that can protect and transport the genes to the targeted cells. They have lower transfection capacity than viruses but are considered to be safer (non-immunogenic) and are easier to produce. Polymers may be less efficient than lipid carriers but are easier and cheaper to produce. They may become as efficient as lipids if they are designed and prepared to fulfill their role as RNA delivery system. Requirements for the nano carriers include complexation with RNA (usually through ionic interactions), protection of RNA from in-vivo degradation through antifouling properties by the use of a hydrophilic polymer such as poly(ethylene glycol) (PEG), reaching the targeted cells, and allowing the escape of RNA from the endosome (acidic vacuole that traps foreign matter to protect the cell) to the cytoplasm of the cell. Polymers made of natural compounds may have improved bio-acceptance. Bile acids are amphiphilic compounds in the digestive system for the dissolution and digestion of fat, lipids, and vitamins, while carbohydrates can bind to lectins on cells surfaces, favoring cell recognition and targeting. Histidine is an amino acid with imidazole group that may facilitate complexation with RNA and attract protons in the endosome to build up osmotic pressure for the release of RNA. We have already prepared star-shaped block copolymers via anionic polymerization for the encapsulation of hydrophobic drugs as well as the complexation of siRNA sequences. The thermosensitivity of the PEG block caused the aggregation of the copolymers under physiological conditions. Therefore, we seek to replace the PEG block by a glycopolymer block. We choose to use RAFT polymerization for the preparation of a series of copolymers made of monomers containing bile acids, mannose, and amines by varying the chemical composition and morphology of the copolymers. Their aggregation behavior in water, complexation with RNA and model compounds, cytotoxicity and transfection efficiency are evaluated in vitro and in vivo with the aim to be used as safe and effective gene delivery system.
