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.
Benito
Juan M
JM
Contribution from the Instituto de Investigaciones Químicas, CSIC, Américo Vespucio 49, Isla de la Cartuja, E-41092 Seville, Spain.
Gómez-García
Marta
M
Ortiz Mellet
Carmen
C
Baussanne
Isabelle
I
Defaye
Jacques
J
García Fernández
José M
JM
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