Abstract
Maltosyl-β-cyclodextrin (G2-β-CyD) suppressed the aggregation of insulin in neutral solution, while the sulfate of β-CyD (S-β-CyD) accelerated the aggregation. On the other hand, the sulfobutyl ether of β-CyD (SBE-β-CyD) showed varying effects on insulin aggregation, depending on the degree of substitution of the sulfobutyl group : i.e., the inhibition at relatively low substitution and acceleration at higher substitution. Differential scanning calorimetric studies indicate that the self-association of insulin stabilized the native conformation of the peptide, as indicated by an increase in the mean unfolding temperature (Tm). G2-β-CyD and SBE-β-CyD decreased the Tm value of insulin oligomers, while S-β-CyD increased the Tm value. 1H-Nuclear magnetic resonance spectroscopic studies suggest that G2-β-CyD includes accessible hydrophobic side chains of insulin within the CyD cavity, and hence perturbs the intermolecular hydrophobic contacts between aromatic side chains across the monomer-monomer interfaces. By contrast, the electrostatic interaction between the positive charges of insulin and the concentrated negative charges of the sulfate and sulfonate groups of a the anionic β-CyDs seems to be more of factor than the inclusion effects. These results suggest proper use of the CyD derivatives could be effective in designing rapid or long-acting insulin preparations.
