Concentration Effects on the Encapsulation of Prilocaine in Liposomes by Computer Simulations

M PICKHOLZ; G. GIUPPONI

Budapest

Congreso; 8th European Biophysical Congress; 2011

EBSA

Local anesthetics (LA) are pain-relief drugs, widely used in medicine and dentistry. The relatively short duration of analgesia - due to their transfer and redistribution from the site of injection - still restricts their clinical use for the treatment of chronic pain. Nowadays, intensive research is focused on anesthetics entrapped into liposomes to enhance their activity and pharmacokinetic properties. Thus , LA are slowly released from these drug delivery systems preventing peak plasma levels, prolonging the duration of nerve block and therefore reducing the risk of systemic toxicity [1]. In this work, we investigated the encapsulation of prilocaine (PLC), an aminoamide local anesthetic, into a small unilamellar liposome. On the line of our previous work [2], we have carried out Molecular Dynamics (MD) simulations using a Coarse Grain model up the microsecond time scale. In this way, we compare the effects of the concentration of LA at fisiological pH. We were able to capture important features of the PLC-vesicle interactions. The behavior of PLCs at fisiological pH is essentially a combination of high and low pH: we found that all neutral PLC molecules rapidly diffuse into the hydrophobic region of the vesicle adopting an asymmetric bimodal density distribution. Protonated PLC molecules (pPLC) initially placed in water were instead only found on the external monolayer, with a high rate of exchange with the water phase and no access to the inner part of the liposome in a concentration dependent way. Besides, the encapsulation of protonated PLCs could be improved by the addition of anionic lipids into the outer liposome monolayer.