- 12:30 PM

Design of Targeted Nanocarriers for Optimal Drug Delivery to Stressed Endothelium: a Multiscale Modeling Approach

Joshua Weinstein, Department of Physics, University of Pennsylvania, 120 Hayden Hall, 3320 Smithwalk, Philadelphia, PA 19104, Neeraj Agarwal, Chemical and Biomolecular Engineering, University of Pennsylvania, 120 Hayden Hall, 3320 Smithwalk, Philadelphia, PA 19104, and Ravi Radhakrishnan, Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, 240 Skirkanich Hall, Philadelphia, PA 19104.

Therapeutic effects of many drugs are accompanied by serious toxicity and severe side effects. A strategic approach in targeted drug delivery is to couple drug packaging inside sustained-release nanoreservoir (lipid or polymer vesicle or liposome) drug carriers with ligand-receptor mediated binding to vascular endothelium. Drug carrier binding can be increased selectively by incorporating adhesion molecules for receptors or ligands expressed within diseased tissue. Targeted delivery of drugs having varying potencies, drug loading, retention, release rates, and dose-related toxicity can be modulated by carefully matching carrier design to a particular drug to increase efficacy and safety. The interplay between carrier motion in blood flow, binding and transport dynamics ultimately defining drug delivery is highly complex. It is not easily discerned from experiments alone due to critical events occurring at multiple length and time scales.

We develop a multiscale hydrodynamic transport model of transvascular drug delivery from nanocarrier “encapsulated droplets” or “vesicles”. Appreciable drug loss occurs from the microcarrier from the point of injection to the point of target tissue binding. The interplay between mechanical forces due to blood flow, receptor-ligand interactions, and physicochemical processes such as membrane dynamics as well as intra-membrane (lateral) diffusion determine the timescale of nanocarrier arrest on the target cell. This is a major determinant of drug delivery efficacy into endothelial cells. Tunable properties such as nanocarrier size, receptor and ligand surface density, contact surface area between the vehicle and target cells, and drug permeability and diffusivity through the membranes influence drug transport.

We predict conditions of microcarrier arrest on target endothelial cells by modeling near wall vesicle motion and drug transport, including binding mechanics, receptor/ligand diffusion, membrane deformation, and post-attachment convection-diffusion transport interactions to evaluate drug permeation into endothelial cells. We then determine optimal parameters for the nanocarrier design to achieve/control specified drug transport into the endothelia by exploring a range of tunable properties (or parameter space) – nanocarrier size, ligand/receptor concentration, receptor-ligand interaction, drug permeability out of the nanocarrier, lateral diffusion coefficients of ligands on nanocarrier membrane, and membrane stiffness - in the simulations.

To capture the nanocarrier trajectory amidst receptor mediated adhesion to endothelial cells, a multiscale algorithm bridging a kinetic Monte Carlo approach with deterministic continuum equations was developed. Together with collaborative experiments this integrated multiscale modeling and experimental approach is employed in the optimal engineering design of drug delivery systems for targeted disease treatment.