Differential interaction behaviors of an alkaloid drug with DMPG liposome membrane as a function of the phase state of the lipid: Nonionic surfactant-induced solubilization of the lipid

Abstract

The present study demonstrates the binding interaction of a drug, berberine (BR) with DMPG liposome membrane as a function of the phase state of the lipid. Our results display an apparently contradicting interaction behavior of BR with DMPG lipid in the sense that the drug:lipid binding constant is found to be higher with the more ordered and compact solid gel (Lβ) phase at T=288K (lower permeability) of the lipid compared to the liquid crystalline (Lα) phase at T=310K (greater permeability). This result is rationalized on the basis of the probable location of the cationic drug molecules at the interfacial region of the lipid membrane having anionic headgroup. The excited-state relaxation dynamics of the lipid-bound drug coupled with rotational relaxation studies further substantiate a stronger binding of BR with the solid gel (Lβ) phase. The BR:DMPG binding interaction is meticulously quantified by calorimetric studies which reveal that the interaction phenomenon is enthalpically (ΔH<0) as well as entropically (TΔS>0) favorable, and is accompanied with marked modulation of the hydration structure surrounding the interacting species as rationalized on the basis of release of structured water molecules following the interaction. The calorimetric results also quantify the differential binding constants and binding stoichiometries of BR with DMPG; Ka=(2.32±0.09)×105M−1 and 2:1 stoichiometry in the solid gel (Lβ) phase (T=288K) versus Ka=(5.00±0.2)×104M−1 and 1:1 stoichiometry in the liquid crystalline (Lα) phase (T=310K). In addition, our results of nonionic surfactant (Triton X-100)-induced solubilization of DMPG lipid reveal differential degrees of release of lipid-bound drug depending on the phase state of the lipid. Fluorescence anisotropy and excited-state relaxation studies of the lipid-bound BR following interaction with TX100 display a greater degree of release of the drug molecules from the liquid crystalline (Lα) phase of the liposome membrane. These results are further corroborated from fluorescence correlation spectroscopic (FCS) results.