Varying effects of cyclodextrin derivatives on aggregation and thermal behavior of insulin in aqueous solution.
Maltosyl-beta-cyclodextrin (G2-beta-CyD) suppressed the aggregation of insulin in neutral solution, while the sulfate of beta-CyD (S-beta-CyD) accelerated the aggregation. On the other hand, the sulfobutyl ether of beta-CyD (SBE-beta-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-beta-CyD and SBE-beta-CyD decreased the Tm value of insulin oligomers, while S-beta-CyD increased the Tm value. 1H-Nuclear magnetic resonance spectroscopic studies suggest that G2-beta-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 the anionic beta-CyDs seems to be more of a 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.
Tokihiro
K
K
Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Irie
T
T
Uekama
K
K
D000818:Animals; D002152:Calorimetry, Differential Scanning; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000494:pharmacology*; D007328:Insulin; D009682:Magnetic Resonance Spectroscopy; D011487:Protein Conformation / Q000187:drug effects; D012996:Solutions; D013696:Temperature
D003505:Cyclodextrins; D007328:Insulin; D012996:Solutions