Polymeric nanoparticles conjugated with engineered albumin for enhanced FcRn-mediated delivery across mucosal barriers

To maintain patient compliance, oral administration is the preferred drug delivery route. Yet, many drugs, including biopharmaceuticals do not endure the harsh environment of the gastrointestinal tract and cross epithelial... [ view full abstract ]

To maintain patient compliance, oral administration is the preferred drug delivery route. Yet, many drugs, including biopharmaceuticals do not endure the harsh environment of the gastrointestinal tract and cross epithelial barriers inefficiently. Functionalization of nanoparticles (NPs) with ligands that can bind specifically to surface receptors may be one strategy to overcome these obstacles and to improve the delivery of pharmaceuticals through biological barriers. The neonatal Fc receptor (FcRn) is a cellular receptor that binds and rescues albumin and IgG antibodies from intracellular degradation. In addition, FcRn mediates transport of its ligands across polarized epithelial cells. We aimed to explore whether polymeric nanoparticles (NPs) conjugated with engineered human albumin for enhanced FcRn binding could be an attractive strategy for delivery of encapsulated drugs across mucosal barriers. To address this, we have designed polymeric NPs using double emulsion/evaporation technology where engineered human albumin was site-specifically conjugated to the polymers. This was done by utilizing a free cysteine residue within albumin domain I, which is located distally from the core interaction site for FcRn. By the use of maleimide chemistry, engineered albumin was conjugated to the surface of the polymer, and the designed NPs were shown to bind human FcRn with expected binding hierarchy. Next, we will explore the use of the NPs using an in vitro transcytosis assay as well as state-of-the-art human FcRn transgenic mouse model. The FcRn-targeted approach may pave the way for more efficient delivery of NP-encapsulated drugs.