(613c) Molecular Simulations of Nanoparticles Permeating Lipid Membranes for Drug Delivery Applications

The study of effectiveness of surface-decorated nanoparticles is important for developing targeted drug delivery systems where functionalized nanoparticles act as carriers for therapeutic agents delivered to specific sites in the body. Computational modeling of the transport of functionalized nanoparticles across membranes and nanoparticle-membrane interactions is valuable to experimentalists exploring a variety of nanoparticles as practical candidates for biological applications such as cancer therapeutics or imaging. In this study, we use molecular dynamics simulations to investigate permeation of lipid bilayer membranes by surface-functionalized nanoparticles and to provide molecular-level detailed mechanisms that are otherwise not readily available via most experimental means. Permeation of small molecules through lipid bilayer membranes is a fundamental biological process that is important to understand in developing therapeutic applications. Nanoparticles have recently become important carriers for drug delivery in such therapeutic applications. We describe coarse-grained simulation methods applicable to such large systems and use examples where the permeants are bare gold nanocrystals, gold-core nanoparticles with hydrophobic ligands (alkanethiol ligands of various lengths), and gold-core nanoparticles with hydrophilic ligands (methyl-terminated polyethylene glycol ligands of various lengths). In addition to spherical gold nanoparticles, we also examine the characteristic permeation mechanisms of the differently shaped gold nanorods with polyethylene glycol ligands, where the aspect ratio different from 1 makes the permeation event dependent on the angle of the nanorod axis relative to the membrane surface. We have examined the phenomena associated with the interaction of these various permeants with the phospholipid bilayer that serves as our model membrane. We consider adsorption at the interface, the permeant within the top lipid leaflet, in the middle of the membrane within the lipid tail region, and finally exiting the membrane on the way to recovery, for the various permeants. As a consequence of nanocarrier permeation, we observe the formation of a water pore, occasional transport of ions across the lipid bilayer, lipid translocation, and lipid displacement from the membrane. We investigate the rotational behavior of PEGylated nanorods during the permeation process and the available pathways for these nanorods in completing the permeation. These events differ depending on the chemical nature (hydrophobic or hydrophilic) of the ligands, their length, the surface coverage density on the gold surface, and the aspect ratio of the gold nanocarrier core. Our work, which highlights comparisons of permeation of nanoparticles with size, shape, and functional diversity, should aid experimentalists who are designing desirable candidates for drug delivery applications.