390787 Biodetoxification By Lipid Emulsion Droplets: Coarse Grained Molecular Dynamics at the Oil/Water Interface

Monday, November 17, 2014
Galleria Exhibit Hall (Hilton Atlanta)
Belinda S. Akpa and Manuela A. A. Ayee, Chemical Engineering, University of Illinois at Chicago, Chicago, IL

Drug intoxications cause 2 million emergency room visits each year and now lead to more accidental deaths than motor vehicle accidents. As specific antidotes do not always exist and often the particular intoxicant may not be readily identified, there has been increasing interest in broad-spectrum detoxification agents.  Lipid droplets have exhibited considerable promise as resuscitation agents, and it is becoming increasingly clear that their multifunctionality imbues them with advantages beyond simply corporeal scavenging, or entrapment, of toxins. Their action is both direct stimulation of toxin-impaired function in critical organs such as the heart and indirect organ protection via local toxin sequestration and subsequent redistribution to ‘storage’ organs (e.g. adipose tissue). This indirect mechanism depends on the reversible uptake of drug molecules by lipid droplets.  The requisite scavenging action, known as the ‘lipid sink’, is thought to be limited to acting on highly lipophilic toxins, with hydrophobic partitioning as the primary driving force. However, many of the compounds in question contain regions of considerable polarity or exist in a predominantly charged state at physiological pH. Hence, polar and electrostatic interactions are likely to play an important role in driving the sequestration of toxins.  Furthermore, one-off clinical reports exist that credit lipid droplets with reversing toxicities due to drugs of low lipophilicity.  Rational application of lipid biodetoxification and optimization of therapeutic formulations requires identification of  the key physicochemical characteristics that govern association of toxin molecules with lipid droplets.

We have employed coarse-grained molecular dynamics simulations utilizing the MARTINI force field to develop molecular topologies for the multiphase system of interest (aqueous/oil system with phospholipid monolayer interface). The MARTINI scheme has also been used to represent the drug molecules of interest, ranging from local anesthetics to antidepressants and anticoagulants.  In the case of the cardiotoxic and lipophilic local anesthetic bupivacaine, both enantiomers are sequestered within the phospholipid monolayer, where they are preferentially located near the phospholipid backbone. The presence of the anesthetic alters the monolayer structure and dynamics in a manner that depends on both the isomer and its charge. The highly lipophilic molecule brodifacoum causes considerable disruption of the monolayer, with the initial approach driven by hydrophobic partitioning and subsequent entrapment promoted by polar interactions between the toxin’s hydroxycoumarin region and the phospholipid head group. The less lipophilic molecule acetaminophen also readily embeds within the lipid monolayer – even in its protonated form. If penetration into the oil core occurs, it does so over timescales greater than 200 ns and, in some cases, re-entry into the monolayer has been observed. In our initial studies, it appears that lipophilicity alone is not a good predictor of droplet association. A similar observation was made through an experimental study of drug uptake by commercial lipid emulsions.

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