Mingqiu Wang, Shreyas R. Ravindranath, Maha K Rahim, Elliot Botvinick, and Jered Brackston Haun
The targeted delivery of nanoparticle carriers holds tremendous potential to transform the detection and treatment of diseases. A major attribute of nanoparticles is the ability to form multiple bonds with target cells, which greatly improves adhesion strength. However, multivalent binding of nanoparticles is still poorly understood, particularly from a dynamic perspective. In previous experimental work, we studied the kinetics of nanoparticle adhesion and found that the rate of detachment decreased over time. Here, we have applied the Adhesive Dynamics simulation framework to investigate binding dynamics between an antibody-conjugated, 200 nm diameter sphere and ICAM-1 on a surface at the scale of individual bonds. We found that Nano Adhesive Dynamics (NAD) simulations could replicate the time-varying nanoparticle detachment behavior that we observed in experiments. As expected, this was correlated with a steady increase in mean bond number with time, but this was only attributed to bond accumulation during the first second that nanoparticles were bound. Longer-term increases in bond number instead manifested from nanoparticle detachment serving as a selection mechanism to eliminate nanoparticles that had randomly been confined to lower bond valencies. Thus, time-dependent nanoparticle detachment reflects an evolution of the remaining nanoparticle population towards higher overall bond valency. We also found that NAD simulations precisely matched experiments whenever mechanical force loads on bonds was high enough to directly induce rupture. These mechanical forces were in excess of 300 pN and primarily arose from the Brownian motion of the nanoparticle, but we also identified a valency-dependent contribution from bonds pulling on each other. In summary, we have achieved excellent kinetic consistency between NAD simulations and experiments, which has revealed new insights into the dynamics and biophysics of multivalent nanoparticle adhesion. In future work we will seek to leverage the simulation as a design tool for optimizing targeted nanoparticle agents.