Detection of Drug−Membrane Interactions in Individual Phospholipid Vesicles by Confocal Raman Microscopy

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Abstract
Optical-trapping confocal Raman microscopy is developed as a method to study the interactions of drugs or other compounds with the membranes of individual phospholipid vesicles. This technique allows membrane disorder, permeability, and drug localization to be assessed without the need for labeling of the membrane or the compounds of interest. We have applied this technique to study the interactions of two nonsteroidal antiinflammatory drugs, salicylate and ibuprofen, with vesicles prepared from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). The results show that both salicylate and ibuprofen increase membrane disorder, as determined from increases in the Raman scattering from gauche conformers in the phospholipid acyl chains. By monitoring the Raman scattering of the drug molecules in optically trapped DMPC vesicles, the membrane permeability and partitioning of the drugs could be determined; the spatial distributions of the drugs were also measured by scanning the laser focus through surface-adhered 1,2-dipalmitoyl-sn-glycero-3-phosphocholine vesicles, producing a profile of the vesicle and its contents. Though the membrane is permeable to both drugs, ibuprofen preferentially accumulates in the membrane, whereas salicylate does not. The measured ibuprofen accumulation agrees quantitatively with the water/octanol partition coefficient of the drug and the estimated volume of the lipid membrane. The results suggest that ibuprofen localizes in the hydrophobic acyl chain region of the membrane, whereas salicylate weakly associates with the phospholipid headgroups.