title: Biophysically inspired model for functionalized nanocarrier adhesion to cell surface: roles of protein expression and mechanical factors.
abstract: In order to achieve selective targeting of affinity-ligand coated nanoparticles to the target tissue, it is essential to understand the key mechanisms that govern their capture by the target cell. Next-generation pharmacokinetic (PK) models that systematically account for proteomic and mechanical factors can accelerate the design, validation and translation of targeted nanocarriers (NCs) in the clinic. Towards this objective, we have developed a computational model to delineate the roles played by target protein expression and mechanical factors of the target cell membrane in determining the avidity of functionalized NCs to live cells. Model results show quantitative agreement with in vivo experiments when specific and non-specific contributions to NC binding are taken into account. The specific contributions are accounted for through extensive simulations of multivalent receptor-ligand interactions, membrane mechanics and entropic factors such as membrane undulations and receptor translation. The computed NC avidity is strongly dependent on ligand density, receptor expression, bending mechanics of the target cell membrane, as well as entropic factors associated with the membrane and the receptor motion. Our computational model can predict the in vivo targeting levels of the intracellular adhesion molecule-1 (ICAM1)-coated NCs targeted to the lung, heart, kidney, liver and spleen of mouse, when the contributions due to endothelial capture are accounted for. The effect of other cells (such as monocytes, etc.) do not improve the model predictions at steady state. We demonstrate the predictive utility of our model by predicting partitioning coefficients of functionalized NCs in mice and human tissues and report the statistical accuracy of our model predictions under different scenarios.
authors.affiliation: Department of Bioengineering , University of Pennsylvania , Philadelphia, PA 19104, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ramakrishnan
authors.affiliation: Department of Chemical and Biomolecular Engineering , University of Pennsylvania , Philadelphia, PA 19104, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tourdot
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Eckmann
authors.affiliation: Department of Mechanical Engineering and Applied Mechanics , University of Pennsylvania , Philadelphia, PA 19104, USA.
authors.forename: Portonovo S
authors.initials: PS
authors.lastname: Ayyaswamy
authors.affiliation: Center for Targeted Therapeutics and Translational Nanomedicine, Institute for Translational Medicine and Therapeutics and Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Translational Research Center, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Radhakrishnan
keywords: excess area; functionalized nanocarrier; membrane biophysics