Molecular Dynamics Study of Local Anesthetics Encapsulated in Liposomes

M. PICKHOLZ; E. DE PAULA; G. GIUPPONI

Liblice

Workshop; 6th International Workshop on Drug Delivery Systems for Nanomedicine; 2008

DDS Organisation Check Republic

Molecular Dynamics Study of Local Anesthetics Encapsulated in Liposomes    Local anesthetics (LA) are pain-relief drugs. They have a big affinity for the cellular membrane because of their amphiphatic nature. It is possible to take advantage of the strong interaction between LA and lipids, using liposomes to encapsulate the drugs. In this way, became possible to control the release of the drug, in order to obtain a prolonged duration of action and reduce central nervous and/or cardiovascular system toxicity.8,9 By the other hand, Computer simulation techniques have been a powerfull tool in supplying a molecular level description of the interactions of different drugs with lipids comprising model membranes. In this work, we investigate the interaction of Prilocaine (PLC) – an aminoamide local anesthetic widely used in dentistry – with model membranes by Molecular Dynamics (MD) simulations. PLC has a pKa of 7.9, therefore both, charged and uncharged form, are relevant at physiological pH. As a first step, we carried out a series of atomistic MD simulations, where charged and uncharged PLCs were introduced into a POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine) phospholipids bilayer. Secondly, we aimed to investigate LA in small unilamellar liposome, as drug carriers. Because of the size of these systems, we use Coarse grain description of the lipids (POPC), water and PLC. We have carried out MD simulations up to the microsecond scale of such systems. Simulations for different ionization states of the PLC were able to capture important features of the PLC–phospholipid bilayer interactions: our results show that charged (protonated) PLC is predominantly found at the lipid-water interface (where it show a preferential orientation) and water phase, whereas uncharged (neutral) PLC enters more deeply into the hydrophobic tail region. This picture remains when a partition of charged/uncharged are present into the vesicle (corresponding to pH 7.4).