Quantitative basis for design and vascular targeting of flexible polymeric nanoparticles*

Targeted nanometer-sized particles filled with therapeutics or imaging agents that are directed to precise locations in the body promise to improve the treatment and detection of many diseases. Targeting of nanoparticles (NPs) functionalized with antibodies to endothelial surface molecules depends on physiological factors such as cellular mechanical factors and hydrodynamic conditions and design factors such as size, shape and flexibility of NP. Using a theoretical model and coarse-grained Brownian dynamics simulations to compute the structural and dynamic properties of a deformable polymer-based NP, we explore the effects of wall-confinement,the glycocalyx layer and margination due to RBCs and NP synthesis factors such as the degree of cross-linking on the NP microstructure. Through quantitative modelling and experimentation, we uncover rational design principles for engineering polymeric NPs through mechanistic studies of hydrodynamic interactions and multivalent binding for achieving efficient margination and enhanced binding to the endothelium. The reported computational and experimental approach and results are expected to enable fine-tuning of design and optimization of flexible NP which are quite distinct from rigid and regular-shaped NP.