Exploiting shape, cellular-hitchhiking and antibodies to target nanoparticles to lung endothelium: Synergy between physical, chemical and biological approaches.

Delivery of nanoparticles to target specific tissues remains a challenge due to their rapid removal from circulation by the reticuloendothelial (RES) system. The majority of past research has addressed this issue via chemical modification of nanoparticles in the form of hydrophilic coatings which reduces adsorption of opsonins that trigger RES clearance. Recently, additional approaches have been developed which leverage the natural mechanisms our own circulatory cells use to avoid immune system clearance. One such method, called 'cellular-hitchhiking', accomplishes this by non-covalent attachment of nanoparticles to the surface of red blood cells. Concomitantly, approaches that make use of modified nanoparticle geometry, that is rod-shaped nanoparticles, have also been used to avoid immune system clearance and improve tissue targeting. Here, we systematically investigate three approaches and their combinations to improve lung targeting while avoiding RES clearance. Our results show that an approach that combines targeting antibodies (anti-ICAM-1), rod-shaped particles and cellular hitchhiking into one delivery system effectively lowered the accumulated concentration of nanoparticles in RES organs by over two-fold as compared to any other combination or single method, while simultaneously increasing the concentration of accumulated nanoparticles in the lungs from 1.2 to 8.9 fold. The strategy described here offers a novel means that combine chemical, physical and biological approaches to maximize tissue targeting.