Encapsulation of Local anesthetics in liposomes

M PICKHOLZ

Los Cocos (Cordoba)

Encuentro; XXXVIII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE BIOFÍSICA; 2009

Sociedad Argentina de Biofísica

Encapsulation of Neutral and Protonated  Local anesthetics  in liposomesMónica Pickholz and Giovanni GiupponiFacultad de Farmacia y Bioquímica, Universidad de Buenos Aires,  Buenos Aires,Argentina.Departament de Fisica Fonamental, Universitat de Barcelona, Barcelona (Spain)}keywords{local anesthetics, vesicle, drug delivery, MARTINI force field, coarse graining} Relief of localized pain is a challenging problem in medical and odontological research. Local anesthetic agents used to relieve pain symptoms are characterized by limited duration of analgesia and may result in both systemic and local toxicity. However, many of the pharmacologicalproperties of conventional drugs can be improved through the use of drug delivery systems, which include particulate carriers, composed primarily of lipids and/or polymers, and their associated therapeutics.  For instance,  local anesthetics encapsulated in liposomes haveshown to gradual release the drug, obtaining a prolonged duration of the anesthetic action and reducing the central nervous and/or cardiovascular system toxicity [1].  In this work, we investigate the encapsulation of prilocaine, an aminoamide local anesthetic widely used in dentistry, in a small unilamellar liposome. We carried out a series of molecular dynamics simulations  using a coarse grain model. We extended the recently developed MARTINI [2] coarse grain model to access relevant time and length scales.  Our simulations for different protonation states of the PLC captured important features of the PLC-vesicle interactions. We found that all neutral prilocaine molecules rapidly diffuse into the hydrophobic region of the vesicle adopting an asymmetric bimodal distribution, with the neutral prilocaine molecules jumping between the internal and external vesicle monolayers. Protonated prilocaine molecules initially placed in water were instead only found on the external monolayer, with an high rate of exchange with the water phase and no access to the inner part of the liposome.  Besides we found that some protonated prilocaines remains trapped within the interior water phase of liposome when starting from a configuration with drugs distributed within the lipisome.