Engineering Therapeutic Nanocarriers with Optimal Adhesion for Targeting

Abstract

There is considerable interest in developing therapeutic delivery carriers that can be targeted via receptor-ligand interactions to sites within the blood stream. The adhesion of carriers is determined by the combined effects of transport phenomena, hydrodynamic force, and the dynamics of multivalent receptor/ligand bonding. Optimizing the adhesion of carriers requires developing relationships between these factors and carrier properties such as size and receptor coating density. Recently, we developed canonical relationships for the binding of antibody-conjugated 200 nm particles to surfaces coated with a vascular adhesion molecule, intercellular adhesion molecule-1. Here we extend our previous studies of adhesion to particles of different size, including 40 nm and 1 μm particles. Particle binding is assessed under fluid flow in a parallel plate flow chamber while varying particle receptor density, substrate ligand density, and flow rate. Using a stochastic simulation and transport-reaction model we then extract multivalent kinetic rate constants for particle attachment and detachment from the binding data. We demonstrate that particles go though a maximum in binding with particle size. For small particles, increasing size increases receptor-ligand encounter rates; for larger particles, fluid shear force begins to dominate, leading to higher forces and decreased adhesion. Our methods provide a means for optimizing particle size and receptor density for the selective binding of particles to vascular endothelium under flow.