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Interaction of [D-Trp6, Des-Gly10] LHRH ethylamide and hydroxy propyl beta-cyclodextrin (HPbetaCD): thermodynamics of interaction and protection from degradation by alpha-chymotrypsin.

Abstract：

PURPOSE:The purpose of this study is to investigate the mechanisms and thermodynamics of the interaction between hydroxypropyl beta-cyclodextrin (HPdetaCD) and [D-Trp6, des-Gly10] LHRH ethylamide (deslorelin), a peptide drug. METHODS:We used UV and fluorescence spectroscopy to study the interaction of HPbetaCD and deslorelin. Circular dichroism was used to study the conformational changes induced in deslorelin upon interaction with HP beta CD. The thermodynamics of the interaction of deslorelin and HPbetaCD was studied using isothermal titration calorimetry (ITC). We also determined the effect of HPbetaCD on the degradation of deslorelin by alpha-chymotrypsin. RESULTS:UV and fluorescence spectroscopy indicated that HPbetaD induced a change in polarity of the environment surrounding the chromophores of deslorelin. Wavelength selective fluorescence indicated an increase in the fluorescence polarization of deslorelin with an increase in excitation wavelength in the presence of HPbetaCD suggesting that tryptophan is present in a media of reduced mobility. Circular dichroism studies indicated that HPbetaCD stabilizes the conformation of deslorelin. In addition, ITC indicated an exothermic reaction between deslorelin and HPbetaCD with a low enthalpy of binding of approximately -600 cal/mol and a binding affinity of approximately -1.25 x 10(2) M-1. Finally, the rate of degradation of deslorelin by alpha-chymotrypsin was decreased by 33% in the presence of HPbetaCD. CONCLUSIONS:These results indicate that there is an interaction between HPbetaCD and deslorelin, which involves the inclusion of aromatic amino acids of deslorelin into the hydrophobic cavity of the cyclodextrin. This inclusion, providing steric hindrance, may be one of the mechanisms by which HPbetaCD reduces enzymatic hydrolysis of deslorelin.

journal_name

Pharm Dev Technol

journal_title

Pharmaceutical development and technology

authors

Koushik KN,Bandi N,Kompella UB

doi

10.1081/pdt-120000297

subject

Has Abstract

pub_date

2001-11-01 00:00:00

pages

595-606

issue

eissn

1083-7450

issn

1097-9867

journal_volume

pub_type

杂志文章

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Interaction of [D-Trp6, Des-Gly10] LHRH ethylamide and hydroxy propyl beta-cyclodextrin (HPbetaCD): thermodynamics of interaction and protection from degradation by alpha-chymotrypsin.