(3) Upon exocytosis around the basolateral side of the cell, the physiological pH causes IgG Fc to dissociate from your FcRn, and NP-Fc are free to diffuse through the intestinal lamina propria to the capillaries or lacteal and enter systemic blood circulation

(3) Upon exocytosis around the basolateral side of the cell, the physiological pH causes IgG Fc to dissociate from your FcRn, and NP-Fc are free to diffuse through the intestinal lamina propria to the capillaries or lacteal and enter systemic blood circulation. Fc-fusion proteins have been used to overcome biological barriers: Fc fused with erythropoietin was measured in non-human primates (19) and humans (20) after pulmonary administration, indicating that using the FcRn is a valid transport pathway in humans; and follicle-stimulating hormone fused with Fc reached blood circulation after oral delivery in newborn rats (21). of 1 1.1 U/kg and elicited a prolonged hypoglycemic response in wild-type mice. This effect was abolished in FcRn knockout mice, indicating the enhanced nanoparticle transport was due specifically to FcRn. FcRn-targeted nanoparticles may have a major impact on the treatment of many diseases by enabling drugs currently limited by low bioavailability to be efficiently delivered though oral administration. == Introduction == Nanoparticles (NPs) have the potential to make a significant impact on the treatment of many diseases, including cancer, cardiovascular disease, and diabetes. Many NP-based therapeutics are now entering clinical trials or have been approved for use (1,2), including targeted polymeric nanoparticles ((3), clinical trialNCT01478893) based on technologies that we have previously explained (4). However, the impact of NPs in the medical center may be limited to a narrow set of indications because NP administration is currently restricted to parenteral methods. Many diseases that could benefit from NP-based therapeutics require frequent administration. Alternate routes of administration, particularly oral, are preferred because of the convenience and compliance by patients (5). Intestinal absorption of NPs is usually Rabbit polyclonal to PDE3A highly inefficient because the physicochemical parameters of NPs prevent their transport across cellular barriers such as the intestinal epithelium (6). To improve the absorption efficiency of NPs and to make the oral administration of NPs practical in the medical center, new strategies are necessary to overcome the intestinal epithelial barrier. The neonatal Fc receptor (FcRn) mediates IgG transport across polarized epithelial barriers (7,8). It was discovered as the receptor in the neonatal Galactose 1-phosphate Potassium salt intestine that transports IgG in breast milk from mother to offspring (9). However, FcRn is expressed into adulthood at levels much like fetal expression in the apical region of epithelial cells in the small intestine and diffusely throughout Galactose 1-phosphate Potassium salt the colon (10). FcRn is also expressed in the vascular endothelium, blood-brain barrier, kidneys, liver, lungs, and throughout the hematopoietic system (11,12). FcRn interacts with the Fc portion of IgG in a pH-dependent manner, binding with high affinity in acidic (pH <6.5) but not physiological environments (pH ~7.4) (13). The intracellular trafficking of the IgG:FcRn complex has been conclusively exhibited in the rat intestine using IgG Fc labeled Galactose 1-phosphate Potassium salt with 1.4-nm gold as a contrast agent for electron tomography (14). The studies revealed that Fc is usually transported through a complex pathway including a network of entangled tubular and irregular vesicles in order to reach the basolateral surface of the cell. We hypothesized that targeting NPs to FcRn using IgG Fc fragments would allow orally administered NPs to be transported across the intestinal epithelium in rodents (Fig. 1). In acidic sections of the intestine, such as the duodenum and portions of the jejunum (15), Fc fragments conjugated to NPs [Fc-targeted NPs (NP-Fc)] will bind to FcRn at the apical surface of absorptive epithelial cells, leading to receptor-mediated endocytosis (16). NP-Fc could also be taken up by fluid phase pinocytosis. During intracellular trafficking, NP-Fc and FcRn in the same acidic endosome compartments will bind with high affinity. FcRn can then guideline bound NP-Fc through a transcytosis pathway, avoiding lysosomal degradation (17). Around the basolateral side, exocytosis results in exposure to a neutral pH environment in the lamina propria, causing the release of NP-Fc (18). NP-Fc can then diffuse through the lamina propria and enter systemic blood circulation. == Fig. 1. Schematic of Fc-targeted nanoparticle transport across the intestinal epithelium by the FcRn through a transcytosis pathway. == (1) IgG Fc around the NP surface binds to the FcRn around the apical side of absorptive epithelial cells under acidic conditions in the intestine. (2) NP-Fc are then trafficked across the epithelial cell through the FcRn transcytosis pathway in acidic endosomes. (3) Upon exocytosis around the basolateral side of the cell,.