(64a) A Physical, Chemical and Biological Approach to Targeting Nanoparticles to Lung Endothelium: Leveraging Shape Effects, Cellular Hitchhiking and Antibody Targeting

Targeted delivery of nanoparticles to specific tissues remains a challenge due to the rapid removal of nanoparticles from circulation by the reticuloendothelial (RES) system. The liver and spleen, the primary RES organs which are home to phagocytotic macrophages, efficiently remove foreign entities from circulation, including nanoparticles. The majority of past research has addressed this issue via chemical modification of nanoparticles in the form of hydrophilic coatings which shields nanoparticles from these organs by reducing nanoparticle adsorption of opsonins. Recently, numerous other approaches have been developed which exploit the natural stealth abilities of our own circulatory cells use to avoid immune system clearance. One such method, called ‘cellular-hitchhiking’, facilitates this by non-covalent adsorption of nanoparticles to the surface of red blood cells, the longest circulating cell in the body. Alongside this, approaches using rod-shaped nanoparticles, which avoid RES clearance to a higher extent as compared to their spherical counterparts, have also been developed. In addition to enhanced circulation, both these methods have also been shown to confer enhanced targeting of nanoparticles, specifically to the lungs. Here, we systematically investigate three approaches and establish their roles, both independently and in combination, to improve lung targeting while avoiding RES clearance. Our results show that an approach combining targeting antibodies, rod-shaped particles and cellular hitchhiking offer the best targeting to lungs and RES avoidance as compared to any individual or dual-combination approach studied here.  The strategy described here offers a novel means that combine chemical, physical and biological approaches to maximize tissue targeting.