(749e) Molecular Simulations of Liposomal Anti-Cancer Drug Carriers

Liposomes mediate the intracellular delivery of both hydrophilic and hydrophobic cancer therapies by protecting healthy cells from the cargo they encapsulate while accumulating specifically in target cells. An implicit solvent intermediate-resolution model of lipid geometry and energetics, inspired in part by the ?Martini? model, was developed to facilitate the design and optimization of liposomes proposed by the Sofou lab. All inter- and intra- molecular interactions are modeled by a combination of hard-sphere, square well and square shoulder potentials, as opposed to the Lennard Jones, Coulombic and harmonic potentials in the ?Martini? model. This allows use of the discontinuous molecular dynamics (DMD) technique., a very fast alternative to traditional molecular dynamics simulation that is applicable to systems of molecules interacting via discontinuous potentials. DMD allows sampling of much wider regions of conformational space, longer time scales, and larger systems than traditional molecular dynamics simulations. The model is applied to aqueous bilayers composed of a range of phospholipids including 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphate (DPPA) and mixtures thereof. Simulations are performed to determine how phospholipid compositions, mole ratios, and tail lengths affect: (1) the formation of heterogeneous domains and membrane permeability, (2) the release of model drug molecules through the leaky liposome surface, and (3) fusion of the liposomal membrane to the endosomal membrane. The model is also used to predict the optimal distribution of PEG, targeting functionalities and fusion peptides on the liposome surface.