Cyclodextrins are utilized in many diverse fields of analytical chemistry, due to their propensity to form reversible inclusion complexes and recognize analytes selectively. This Feature shows how these nanocavities can serve analysts in sample preparation, sensitivity and selectivity improvement, enantio-separation, creating single-molecule sensors, and automatizing DNA sequencing.

ObjectiveNiemann–Pick type C (NPC) disease is a fatal, neurodegenerative, lysosomal storage disorder characterized by intracellular accumulation of unesterified cholesterol (UC) and other lipids. While its mechanism of action remains unresolved, administration of 2‐hydroxypropyl‐β‐cyclodextrin (HPβCD) has provided the greatest disease amelioration in animal models but is ototoxic. We evaluated other cyclodextrins (CDs) for treatment outcome and chemical interaction with disease‐relevant substrates that could pertain to mechanism.MethodsNPC disease mice treated for 2 weeks with nine different CDs were evaluated for UC, and GM2 and GM3 ganglioside accumulation using immunohisto/cytochemical and biochemical assays. Auditory brainstem responses were determined in wild‐type mice administered CDs. CD complexation with UC, gangliosides, and other lipids was quantified.ResultsFour HPβCDs varying in degrees of substitution, including one currently in clinical trial, showed equivalent storage reduction, while other CDs showed significant differences in relative ototoxicity and efficacy, with reductions similar for the brain and liver. Importantly, HPγCD and two sulfobutylether‐CDs showed efficacy with reduced ototoxicity. Complexation studies showed: incomplete correlation between CD efficacy and UC solubilization; an inverse correlation for ganglioside complexation; substantial interaction with several relevant lipids; and association between undesirable increases of UC storage in Kupffer cells and UC solubilization.InterpretationCDs other than HPβCD identified here may provide disease amelioration without ototoxicity and merit long‐term treatment studies. While direct interactions of CD‐UC are thought central to the mechanism of correction, the data show that this does not strictly correlate with complexation ability and suggest interactions with other NPC disease‐relevant substrates should be considered.

Since the discovery about 30 years ago (2-hydroxypropyl) beta-cyclodextrin, a highly soluble derivative of beta-cyclodextrin, has become an approved excipient of drug formulations included both in the United States and European Pharmacopoeias. It is recommended to use as solubilizer and stabilizer for oral and parenteral formulations. Recently, its pharmacological activity has been recognized in various diseases. The increasing applications require a closer look to the structure-activity relationship. As (2-hydroxypropyl) beta-cyclodextrin (HPBCD) is always a mixture of isomers with various degrees and pattern of hydroxypropylation, no wonder that the products of different manufacturers are often different. Several HPBCDs were compared applying a battery of analytical tools including thin layer chromatography, high performance liquid chromatography (HPLC), HPLC-mass spectrometry (MS), and matrix-assisted laser desorption MS. We studied how the average degree of substitution affects the aggregation behavior, the toxicity, and the solubilizing effect on poorly soluble drugs. We found that the products with low average degree of substitution are more prone to aggregation. The samples studied are nontoxic to Caco-2 cells and have low hemolytic activity. The solubility enhancement of poorly soluble drugs decreases or increases with increasing degree of substitution or shows a maximum curve depending on the properties of the guest.

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