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Article Dans Une Revue Advanced Drug Delivery Reviews Année : 1994

Glycoconjugates as carriers for specific delivery of therapeutic drugs and genes

Résumé

Cell surface receptors are good candidates to selectively target drugs, oligonucleotides or even genes by making use of their specific ligands. A large number of mammalian cells express cell surface sugar-binding proteins, also called “membrane lectins”. Therefore, sugars may be used as specific recognition signals to specifically deliver biological active components. Tens of membrane lectins with different sugar specificities have been characterized; some of them actively carry their ligands to intracellular compartments, including endsomes, lysosomes and, in some cases, Golgi apparatus. In this review, we summarize the main properties of neoglycoproteins and glycosylated polymers; they have been developed to study the properties of endogenous lectins and to carry various drugs. Glycoconjugates have been successfully used to carry biological response modifiers such as N-acetylmuramyldipeptide. N-Acetylmuramyldipeptide is, in vitro, hundreds of times more efficient in rendering macrophages tumoricidal when it is bound to this type of carrier. In vivo, the N-acetylmuramyldipeptide bound to glycoconjugates containing mannose in a terminal non-reducing position, induces the eradication of lung metastases, occurring when treatment is started, in 70% of mice; free N-acetylmuramyldipeptide is strictly inactive. Similarly, N-acetylmuramyldipeptide bound to the same glycoconjugates induces an active antiviral effect. Glycoconjugates are also suitable for carrying antisense oligonucleotides specific for viral sequences. Antisense oligonucleotides protected at both ends and linked through a disulfide bridge to the glycoconjugates are 10 times more efficient than the corresponding free oligonucleotides. Poly-l-lysine containing about 190 lysine residues has been substituted by three components: sugars as recognition signal, antiviral (or antiparasite) agents as therapeutic elements and gluconoic acid as neutralizing and solubilizing agent. This type of neutral, highly water-soluble glycosylated polymer is a very efficient carrier to deliver drugs in infected cells according to the nature of the sugar borne on the polymer and to the specificity of the lectin present at the surface of the infected cells. Finally, poly-l-lysine (190 residues) partially substituted with sugars (60 units) is a polycationic glycosylated polymer which easily makes complexes with plasmids. These complexes are very efficient in transfecting cells in a sugar-dependent manner. The expression of reporter gene is greatly enhanced when cells are incubated with the plasmid-glycosylated poly-l-lysine complex in the presence of either 100 μM chloroquine or 10 μM fusogenic docosapeptide. Furthermore, this transfection method leads to a much larger number of stable transfectants than the classical method using calcium phosphate precipitate. The general properties of glycosylated proteins and of glycosylated polymers are presented and their efficiency in targeting genes in comparison with that of other available targeted transfection methods is discussed.

Dates et versions

hal-02163748 , version 1 (24-06-2019)

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Michel Monsigny, Annie-Claude Roche, Patrick Midoux, Roger Mayer. Glycoconjugates as carriers for specific delivery of therapeutic drugs and genes. Advanced Drug Delivery Reviews, 1994, 14 (1), pp.1-24. ⟨10.1016/0169-409X(94)90003-5⟩. ⟨hal-02163748⟩
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