Synthesis and characterization of novel cyclodextrin oligomers for drug delivery

Cyclodextrins (CDs) are cyclic hollow oligosaccharide molecules that form water solublehost-guest systems, with many applications in drug formulation and delivery. CDoligomers have been previously studied due to the interest towards smart hosts withenhanced molecular recognition and binding capacity as sensors, catalysts, enzymemimics, photoreactive systems, etc. The aim of this dissertation was to prepare αCDoligomers for drug inclusion and transport with criteria: (i) ease of preparation, inaqueous media, in short steps, under mild conditions and in good yields, (ii) to obtainoligomers with satisfactory aqueous solubility and full availability of the CD cavities (iv)to achieve multiple binding with strengths better or comparable to those of parent αCD.The copper catalyzed azide-alkyne cyclization (CuAAC) reaction was utilized to preparea new water soluble cyclodextrin trimer very efficiently. The trimer engulfed threemolecules of a model guest and satisfactorily solubilized the chemotherapeutictamoxifen citrate and its active metabolite, N-desmethyltamoxifen, increasing theirsolubility by >1 order of magnitude. Moreover, for the first time the bioorthogonalStaudinger Ligation was applied to prepare αCD-dimers. For this purpose, a doublyactive linker was specifically developed that enabled dimer preparation in a single step,in aqueous/organic media, under mild conditions and with high yields. The aboveprepared products were studied in detail by NMR spectroscopy and were found toadopt, by self-inclusion, a closed conformation in aqueous solution, which completelyopened up in the presence of a suitable guest, leaving the cavities fully available to formthe corresponding inclusion complexes. Titration and DOSY NMR experimentsconfirmed the above and showed that the dimeric species form slowly diffusingaggregates in water, that in the presence of the guest partially disperse. The StaudingerLigation could thus become the method of choice for preparing CD dimers.Solubilization of practically insoluble N-desmethyl-tamoxifen was also achieved to 0.3mM. Moreover, CD dimers prepared via amide bond formation were less efficient andrequired harsh conditions. Finally, SNO-αCD derivatives were prepared andcharacterized as bimodal NO and drug carrier systems