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Cyclodextrins: Programming Sugars at the Nanoscale for Biomolecular Recognition and Delivery
Cyclodextrins (CDs) constitute a group of cyclic oligosaccharides obtained by enzymatic conversion of starch, characterized by a macrocyclic ring composed of glucose monomers connected by α-1,4 glycosidic bonds. Typically, these rings consist of 6, 7, or 8 sugar units, and they are respectively referred to as α, β, and γCD. The widespread use of CDs in industrial applications, encompassing food, pharmaceuticals, chemical processing, agriculture, and environmental engineering, is fundamentally rooted in their unique structural and physico-chemical attributes. CDs adopt a truncated-cone shape, pictured by a toroidal structure with a larger and a smaller opening. The larger opening exposes the toroid to the surrounding solvent, and it is lined with secondary hydroxyl groups, while the smaller opening is adorned with primary hydroxyl groups. The interior of the CD cavity is notably hydrophobic, making it an ideal host for molecules of similar polarity, while the exterior exhibits significant hydrophilicity, imparting remarkable aqueous solubility. These features render CDs with a duality of hydrophobic and hydrophilic properties, making them exceptionally suitable for a wide array of requests.
CDs serve as valuable tools in pharmaceutical science, primarily aimed at enhancing drug solubility, chemical stability and bioavailability, in some cases alleviating their unwanted side-effects or facilitating precise dosage control. This is achieved through their remarkable ability to encapsulate predominantly hydrophobic small drugs or hydrophobic segments of drugs, forming host-guest complexes. Beyond their “in-out” amphiphilic nature, cyclodextrins offer distinct advantages through the differentiation of faces and varying reactivity of hydroxyl groups. These features can be harnessed to incorporate functional elements with precise orientations, enabling the deliberate programming of specific behaviors, rather than merely passively accommodating cavity-fitting motifs. Through the application of precision chemistry techniques, cyclodextrins can establish selective interactions with molecular and biomolecular partners, making them a unique platform for designing active pharmaceutical ingredients (APIs). An iconic example of this is Sugammadex (BridionTM), an antidote for the neuromuscular blocker rocuronium used in anesthesia.1
This presentation aims to provide an insightful overview of cyclodextrin chemistry and their wide-ranging applications. It places a particular focus on exploring the intricate relationships between molecular structure, supramolecular properties, self-assembly behavior, and biological activity. Furthermore, the discussion will feature examples from our laboratory, encompassing the development of targeted drug delivery,2 antitoxins,3 and nonviral molecular nanovectors for nucleic acid therapeutics.4,5