Multi-Scale Modeling of Nanoparticle-Mediated Drug Delivery

Using multi-scale molecular dynamics (MD) simulations, we systematically study the influences of nanoparticle (NP) properties (including size, shape, elasticity and surface functionality) on the endocytosis process. Furthermore, we use MD simulations to help design new liposome-like and pH-responsive NPs. The endocytosis of elastic NPs is first investigated. With a new developed elastic NP model, we investigate NPs with different sizes, shapes, and stiffness. Our simulations provide clear evidence that the membrane wrapping efficiency of NPs is a result of competition between receptor diffusion kinetics and thermodynamic driving force. We further suggest that conflicting experimental observations on the endocytosis efficiency of elastic NPs should be caused by their different mechanical properties. We then explore the endocytosis of PEGylated liposomes and PEGylated bicelles. Comparing PEGylated rigid NPs and liposomes, we find that the mobile PEG polymers on liposome aggregate. This aggregation induces a large energy barrier and suppresses the membrane wrapping of PEGylated liposomes. Comparing PEGylated liposomes and PEGylated bicelles, we find that the aggregation of PEG polymers makes the bicelles more energetic favorable. We confirm that interplay between ligand mobility and NP geometry can significantly change the influence of NP geometry on the endocytosis. A core-polyethylene glycol-lipid shell (CPLS) NP is proposed with a lipid bilayer self-assembled at the surface of a PEGylated inorganic core. Due to the lipid surface, CPLS NPs inherit the biocompatibility of liposomes. Furthermore, they also have better properties than liposomes, including well-controlled size distribution and high mechanical stability. This self-assembly method can be generalized to fabricate liposome-like NPs incorporating different polymers. We finally study the stability of pH-responsive AuNPs and their interactions with lipid bilayers. Free energy analysis reveals that an energy barrier before the appearance of the hydrophobic driving force is critical to AuNPs’ stability. For interactions with lipid bilayers, the lipids are extracted by the AuNPs. The extracted lipids cause dehydration and disruption of the bilayers when multiple AuNPs exist. In this dissertation, our simulations provide a detailed mechanistic understanding for the endocytosis of NPs. Furthermore, we prove that MD simulations serve as a powerful tool to help design new NP platforms