The search for new polyvalent and dendritic compounds with a well-defined chemical architecture is a hot topic in drug delivery and theranostic applications; these carriers can be employed for the delivery of multiple therapeutic agents in a single formulation, or for the combination of imaging and drug therapy to monitor effects in real time. Cyclodextrins (CDs) constitute ideal scaffolds for this task, as they are essentially non-immunogenic and non-toxic, and they can accept various organic molecules into their truncated cone-shaped hydrophobic cavity generating host-guest supramolecular species in aqueous solution. While the preparation of CD trimers and tetramers has already been described, there are very few examples of larger constructs. We have recently introduced a new efficient synthetic protocol based on the MW-promoted Cu-catalyzed 1,3-dipolar cycloaddition (CuAAC) of CD monoazides to CD monoacetylenes, which results in the formation of a triazole bridge. Using the aforementioned procedure as the key step, a star-shaped, highly water soluble dendrimeric multicarrierhas been designed, which consists of eight beta-CD units anchored to a gamma-CD core via bis(triazolyl)alkyl spacers. The behaviour of the gamma1-beta8-nonamer in water solution was simulated in silico by molecular dynamics. The solvent accessible surface of the CDs in the oligomer relative to their monomeric counterparts was computed with OpenCDSurf, an open-source software that we developed for this purpose. On average, about 60% of the monomeric beta-CD accessibility is retained, while the average accessibility of the gamma-CD in the nonamer is more than 1.5-fold greater than in the monomer, since the eight substituents contribute to keeping open the entrance to the cavity. An assessment of the platform's potential application as a carrier of contrast agents for MRI was carried out by relaxometric titrations, NMRD profiling and cytotoxicity tests. Overall, the poly-CD dendrimer fulfils the main requirements for such a carrier, namely water solubility, surface accessibility and hosting capability. These claims may open the road to a wide range of potential pharmaceutical, diagnostic and theranostic applications.
Design, synthesis and computational study of a γ1β8-cyclodextrin oligomer. International Conference on Chemistry for Health
TOSCO, Paolo
2012-01-01
Abstract
The search for new polyvalent and dendritic compounds with a well-defined chemical architecture is a hot topic in drug delivery and theranostic applications; these carriers can be employed for the delivery of multiple therapeutic agents in a single formulation, or for the combination of imaging and drug therapy to monitor effects in real time. Cyclodextrins (CDs) constitute ideal scaffolds for this task, as they are essentially non-immunogenic and non-toxic, and they can accept various organic molecules into their truncated cone-shaped hydrophobic cavity generating host-guest supramolecular species in aqueous solution. While the preparation of CD trimers and tetramers has already been described, there are very few examples of larger constructs. We have recently introduced a new efficient synthetic protocol based on the MW-promoted Cu-catalyzed 1,3-dipolar cycloaddition (CuAAC) of CD monoazides to CD monoacetylenes, which results in the formation of a triazole bridge. Using the aforementioned procedure as the key step, a star-shaped, highly water soluble dendrimeric multicarrierhas been designed, which consists of eight beta-CD units anchored to a gamma-CD core via bis(triazolyl)alkyl spacers. The behaviour of the gamma1-beta8-nonamer in water solution was simulated in silico by molecular dynamics. The solvent accessible surface of the CDs in the oligomer relative to their monomeric counterparts was computed with OpenCDSurf, an open-source software that we developed for this purpose. On average, about 60% of the monomeric beta-CD accessibility is retained, while the average accessibility of the gamma-CD in the nonamer is more than 1.5-fold greater than in the monomer, since the eight substituents contribute to keeping open the entrance to the cavity. An assessment of the platform's potential application as a carrier of contrast agents for MRI was carried out by relaxometric titrations, NMRD profiling and cytotoxicity tests. Overall, the poly-CD dendrimer fulfils the main requirements for such a carrier, namely water solubility, surface accessibility and hosting capability. These claims may open the road to a wide range of potential pharmaceutical, diagnostic and theranostic applications.
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