Multiscale Modeling of Transport though Blood Brain Barrier

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Transport of biologics, including antibodies, enzymes, drug molecules, etc., to the brain parenchyma is challenging due to the blood-brain barrier (BBB). A key strategy to efficiently deliver drugs across BBB is to encapsulate drugs inside a nanocarrier/nanocell (NC), then functionalize NC with bioactive peptides, proteins, or antibodies with their receptors highly expressed at targeted sites, leading to receptor-mediated active transport. The effective delivery of NCs through receptor-mediated transcytosis (RMT) is a highly complex and multiscale process, which is difficult to investigate through scale-specific techniques (both experimentally and numerically). In this project, we propose to establish an interdisciplinary research program to investigate RMT of NCs through comb"inat1on of multiscale modeling and "in vitro cell culture experiments. The proposed research aims are: (a) to develop a multiscale model for RMT through BBB, which includes a mesoscale stochastic model for NC binding, internalization and expulsion as well as an atomistic model for specific protein-protein and protein-lipid interactions at molecular level; (b) to validate our multiscale model through comparison with the in vitro cell culture experiments on the effect of ligand density; and (c) to explore the effects of particle size, particle shape/type, ligand density, ligand type, as well as the molecular interactions on the overall process of RMT through both modeling and experiments, based on which we will optimize the NC transport through BBB. The simulations and in vitro cell culture experiments will bring critical, new insight and a deeper understanding of the mechanism of RMT. The key innovation of our proposed models lay in the integration of atomistic simulations with mesoscopic model, which allows for systematic investigation of the RMT. The combination of the membrane model with the stochastic binding model is also innovative and enables a coherent exploration of RMT with extreme deformations. In addition, the coarse-grained force field in atomistic simulations is novel and crucial to capture the conformational information for protein-protein interactions. If successful, this will be the first model to study transcytosis of NCs through endothelial cells, which could be extended to study the transport mechanisms in other organs.