Thermodynamic analysis of binding between drugs and glycosaminoglycans by isothermal titration calorimetry and fluorescence spectroscopy.
The thermodynamics of the interaction of positively charged drug molecules with negatively charged glycosaminoglycans (GAGs) is investigated by isothermal titration calorimetry (ITC) and fluorescence spectroscopy. The drugs considered are propranolol hydrochloride, tacrine, and aminacrine, and the polymers used as model GAGs are dextran sulfate, chondroitin sulfate, and hyaluronic acid. The ITC results show that the interaction between drugs and GAGs is via direct binding and that GAGs bind to drugs at one set of sites. Large negative values of heat capacity change (DeltaC(p)) are observed upon binding of GAGs to drugs. Such negative DeltaC(p) is not expected for purely electrostatic interactions and suggests that hydrophobic and other interactions may be also involved in the binding process. These results are corroborated by fluorescence spectroscopy measurements, which show that specific drug/GAG complex formation is accompanied by a clear enhancement of the fluorescence intensity. The results highlight the importance of the formation of drug/GAG complexes as a primary step for the drug delivery process into cell membranes. It is concluded that the interactions are dependent on the nature of both GAG and drug and this is a fact to be taken into account when new drugs are designed.
Santos
Hélder A
HA
Department of Chemical Technology, Laboratory of Physical Chemistry and Electrochemistry, Helsinki University of Technology, PO Box 6100, FIN-02015 HUT, Finland. helder.santos@helsinki.fi
Manzanares
José A
JA
Murtomäki
Lasse
L
Kontturi
Kyösti
K
D000585:Aminacrine / Q000737:chemistry; D002151:Calorimetry; D002241:Carbohydrates / Q000737:chemistry; D002809:Chondroitin Sulfates / Q000737:chemistry; D005456:Fluorescent Dyes; D006025:Glycosaminoglycans / Q000737:chemistry*; D006820:Hyaluronic Acid / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D008567:Membranes, Artificial; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011433:Propranolol / Q000737:chemistry; D011506:Proteins / Q000737:chemistry / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D013619:Tacrine / Q000737:chemistry; D013696:Temperature; D013816:Thermodynamics
D002241:Carbohydrates; D005456:Fluorescent Dyes; D006025:Glycosaminoglycans; D007202:Indicators and Reagents; D008567:Membranes, Artificial; D004364:Pharmaceutical Preparations; D011506:Proteins; D013619:Tacrine; D000585:Aminacrine; D006820:Hyaluronic Acid; D002809:Chondroitin Sulfates; D011433:Propranolol