Lipid-based drug delivery system---Molecular dynamics simulations and neutron scattering studies

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs used for pain, fever and inflammation. Chronic usage of NSAIDs results in gastrointestinal (GI) toxicity ranging from mild to fatal ulcers. While the mechanism by which NSAIDs cause GI toxicity is widely debated, it is well recognized that NSAIDs have strong interactions with biomembranes due to their amphiphilic nature. Using atomistic molecular dynamics (MD) simulations and neutron scattering techniques, the central hypothesis examined here is the nature of interactions between phospholipids, an important ingredient of biomembranes, and NSAIDs and their consequences on the development of adducts of phospholipids and NSAIDs.;Aspirin and Ibuprofen were predicted to mix with saturated lipid membranes, irrespective of their charge state, using free energy calculations from equilibrium MD simulations, while the location of free energy minima and the shape of the profile were found to depend on drug charge state. A systematic set of simulations over a range of drug-to-lipid ratios indicated that the NSAIDs perturb local bilayer structure. Simulations using structurally different NSAIDs indicated that the drug size is a key determinant of the NSAIDs' effect on the membrane structure.;In a neutron diffraction study, the drug distribution across the bilayer membrane was determined with sub-nm resolution and found to be in excellent agreement with the predictions from MD simulations. Further, these studies indicated that the presence of Ibuprofen lowers headgroup hydration and induces bilayer thinning. Small angle neutron scattering studies were performed on 100nm lipid vesicles loaded with Ibuprofen systematically in a physiologically relevant range of pH and over a range of drug-to-lipid ratios. These studies indicated that the Ibuprofen reduces headgroup hydration and induces bilayer thinning consistent with diffraction studies. Further, the colloidal stability of the vesicles was found to be unaffected by the presence of the drug over twenty-four hours. Finally, the bilayer membrane dynamics were probed using neutron spin echo and indicated that the bending modulus of the membrane was lowered by the presence of Ibuprofen at all pH values.