Santos Hélder A, Manzanares José A, Murtomäki Lasse, Kontturi Kyösti
Department of Chemical Technology, Laboratory of Physical Chemistry and Electrochemistry, Helsinki University of Technology, PO Box 6100, FIN-02015 HUT, Finland.
Eur J Pharm Sci. 2007 Oct;32(2):105-14. doi: 10.1016/j.ejps.2007.06.003. Epub 2007 Jun 19.
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.
通过等温滴定量热法（ITC）和荧光光谱法研究了带正电荷的药物分子与带负电荷的糖胺聚糖（GAGs）之间相互作用的热力学。所研究的药物为盐酸普萘洛尔、他克林和氨基吖啶，用作模型GAGs的聚合物为硫酸葡聚糖、硫酸软骨素和透明质酸。ITC结果表明，药物与GAGs之间的相互作用是通过直接结合，且GAGs在一组位点上与药物结合。在GAGs与药物结合时观察到热容变化（ΔC(p)）的大的负值。对于纯粹的静电相互作用，这种负的ΔC(p)是预期不到的，这表明疏水相互作用和其他相互作用也可能参与了结合过程。荧光光谱测量结果证实了这些结果，其表明特定的药物/GAG复合物形成伴随着荧光强度的明显增强。这些结果突出了药物/GAG复合物形成作为药物递送至细胞膜过程的第一步的重要性。得出的结论是，相互作用取决于GAG和药物两者的性质，这是设计新药时需要考虑的一个事实。
