Optimizing saccharide-directed molecular delivery to biological receptors: design, synthesis, and biological evaluation of glycodendrimer-cyclodextrin conjugates.
Dendritic beta-cyclodextrin (betaCD) derivatives bearing multivalent mannosyl ligands have been prepared and assessed for their binding efficiency toward the tetrameric plant lectin concanavalin A (Con A) and a mammalian mannose/fucose specific cell surface receptor from macrophages. The synthetic strategy exploits the reactivity between isothiocyanate and amine functionalities for the high-yielding assembly via thioureido links of the various building blocks, including host, spacer, branching, and carbohydrate ligand elements. The methodology has been applied to the preparation of a series of betaCD-polymannoside scaffolds differing in the ligand valency and geometry. This series allowed us to explore: (i) The effects of the glycodendritic architecture on the binding efficiency; (ii) the mutual influence between the cyclodextrin core and the glycodendritic moieties on the molecular inclusion and lectin-binding properties; and (iii) the consequence of inclusion complex formation, using the anticancer drug docetaxel (Taxotère) as a target guest, on biological recognition. Our results confirm the high drug solubilization capability of this new type of betaCD-dendrimer construct and indicate that subtle changes in the architecture of the conjugate may have important consequences on receptor affinity. Interestingly, the host-guest interaction can be monitored to build up supramolecular dynamic glycoclusters with increased lectin affinity. Alternatively, the information obtained from the structure-lectin-binding avidity-inclusion capability studies has been put forward in the design of very efficient molecular transporters for docetaxel based on glycodendritic CD dimers.
Contribution from the Instituto de Investigaciones Químicas, CSIC, Américo Vespucio 49, Isla de la Cartuja, E-41092 Seville, Spain.
Juan M
JM
Benito
Marta
M
Gómez-García
Carmen
C
Ortiz Mellet
Isabelle
I
Baussanne
Jacques
J
Defaye
José M
JM
García Fernández
D003208:Concanavalin A / Q000737:chemistry / Q000378:metabolism; D003505:Cyclodextrins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D000077143:Docetaxel; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D037102:Lectins / Q000737:chemistry / Q000378:metabolism; D037181:Lectins, C-Type / Q000737:chemistry* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009844:Oligosaccharides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D004337:Drug Carriers; D037102:Lectins; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009844:Oligosaccharides; D011956:Receptors, Cell Surface; D043823:Taxoids; D047392:beta-Cyclodextrins; D003208:Concanavalin A; D000077143:Docetaxel; C031215:betadex; D017239:Paclitaxel