Computational Model for Nanocarrier Adhesion to Cell Surfaces Validated Using in Vivo, in Vitro, and Atomic Force Microscopy Experiments

Our objective is to develop a computational platform for targeting of functionalized nanocarriers to optimize experimental design protocols for drug delivery. A computational methodology based on Monte Carlo and the weighted histogram analysis method has been developed to calculate the absolute binding free energy between functionalized nanocarriers (NC) and endothelial cell (EC) surfaces. The calculated NC binding free energy landscapes yield binding affinities that agree quantitatively when directly compared against analogous measurements of specific antibody-coated NCs (100 nm in diameter) to intracellular adhesion molecule-1 (ICAM-1) expressing EC surface in in vitro cell-culture experiments. The effect of antibody surface coverage (σs) of NC on binding simulations reveals a threshold σs value below which the NC binding affinities reduce drastically and drop lower than that of single anti-ICAM-1 molecule to ICAM-1. The model suggests that the dominant effect of changing σs around the threshold is through a change in multivalent interactions; however, the loss in translational and rotational entropies are also important. We also discuss the role of membrane deformation in mediating the NC adhesion. We validate the simulations against three distinct classes of experiments: invivo targeting in mice, cellular targeting in cultured cells under flow, and binding assays using AFM.

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