(557d) A Receptor-Based Strategy to Increase the Circulation Time of Delivery Vehicles

Rapid clearance of drug delivery systems from systemic circulation typically occurs by mononuclear phagocytes residing in the liver and spleen. Cellular recognition is facilitated through absorption of blood components onto the surfaces of delivery vehicles, in turn engaging specific surface receptors and triggering phagocytosis. In the past, surface modifications using hydrophilic polymers have aimed to thwart phagocytic clearance. These inert materials rely on the general strategy of increasing circulation times through steric stabilization, which impedes both specific and nonspecific interactions. Poly (ethylene glycol) (PEG) is the most widely studied surface-modifying polymer and has been shown to improve the half-life of delivery vehicles. However, repeated administrations drastically diminish this effect, suggesting complement activation and possible sensitivity to the surface heterogeneity of the delivery vehicle. Therefore, the inherently passive approach of using hydrophilic coatings is insufficient by itself to impede the dynamic recognition process of the immune system.

Specific receptor-ligand interactions govern the functionality of macrophages both in homeostasis and host defense. This specificity is evident in clearance protection of native cells (i.e., red blood cells) through the use of inhibitory receptor-ligand pairings. We intend to mimic this biological process using short peptide sequences that suppress phagocytosis through similarly specific receptor-ligand interactions. Using phage display technology, we have developed a screening technique that allows for the selection and isolation of peptides that can to bind to phagocytic cell surfaces (THP-1, RAW264.7) under normal physiological conditons without triggering internalization. Preliminary results have already identified one group of peptides that bind with high affinity. It is our objective to produce phagocytic-resistant delivery vehicles by conjugating such synthetic immuno-modulating peptides onto the surfaces of carrier particles. The resulting strategy will have broad potential applications in drug delivery, immunotherapy, and bioimaging.