Model-Based Design and Optimization of Functionalized Nanocarriers for Vascular Targeted Drug Delivery

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 (100-200 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 (ss) of NC on binding simulations reveals a threshold ss 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 ss around the threshold is through a change in multivalent interactions; however, the loss in translational and rotational entropies is also important. We also discuss the roles of hydrodynamic flow, membrane deformation in mediating the NC adhesion. We validate the simulations against four distinct classes of experiments: in vivo targeting in mice, cellular targeting in cultured cells under flow, targeting in a tissue, and binding assays using AFM.

References:
1A Computational Model for Nanocarrier Binding to Endothelium Validated Using In vivo, In vitro, and Atomic Force Microscopy Experiments, J. Liu, G. E. R. Weller, B. Zern, P. S. Ayyaswamy, D. M. Eckmann, V. Muzykantov, R. Radhakrishnan, Proceedings of the National Academy of Sciences, 107(38), 16530-16535, 2010. Pubmed ID: 20823256.
2Dynamic factors controlling carrier anchoring on vascular cells, T. N. Swaminathan, J. Liu, B. Uma, P. S. Ayyaswamy, R. Radhakrishnan, D. M.Eckmann, IUBMB Life, 2011, 63(8):640-647. Pubmed ID: 21721099
3Dynamic factors controlling targeting nanocarriers to vascular endothelium, D. M. Eckmann, R. Radhakrishnan, V. Muzykantov, R. Radhakrishnan, D. M. Eckmann, Current Drug Metabolism, 2012, 113, 70. Pubmed ID: 22292809.
4Multiscale Modeling of Functionalized Nanocarriers in Targeted Drug Delivery, J. Liu, R. P. Bradley, D. M. Eckmann, P. S. Ayyaswamy, R. Radhakrishnan, Current Nanoscience, 2011, 7(5): 727-735. Pubmed ID: 22116782.
5Multivalent binding of nanocarrier to endothelial cells under shear flow, J. Liu, N. J. Agrawal, A. Calderon, P. S. Ayyaswamy, D. M. Eckmann, R. Radhakrishnan, Biophysical J., 2011, 101(2):319-326. Pubmed ID: 21767483