Dataset Information

Transepithelial transport of Fc-targeted nanoparticles by the neonatal fc receptor for oral delivery.

ABSTRACT: Nanoparticles are poised to have a tremendous impact on the treatment of many diseases, but their broad application is limited because currently they can only be administered by parenteral methods. Oral administration of nanoparticles is preferred but remains a challenge because transport across the intestinal epithelium is limited. We show that nanoparticles targeted to the neonatal Fc receptor (FcRn), which mediates the transport of immunoglobulin G antibodies across epithelial barriers, are efficiently transported across the intestinal epithelium using both in vitro and in vivo models. In mice, orally administered FcRn-targeted nanoparticles crossed the intestinal epithelium and reached systemic circulation with a mean absorption efficiency of 13.7%*hour compared with only 1.2%*hour for nontargeted nanoparticles. In addition, targeted nanoparticles containing insulin as a model nanoparticle-based therapy for diabetes were orally administered at a clinically relevant insulin dose of 1.1 U/kg and elicited a prolonged hypoglycemic response in wild-type mice. This effect was abolished in FcRn knockout mice, indicating that the enhanced nanoparticle transport was specifically due 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.

SUBMITTER: Pridgen EM

PROVIDER: S-EPMC4023672 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Transepithelial transport of Fc-targeted nanoparticles by the neonatal fc receptor for oral delivery.

Pridgen Eric M EM Alexis Frank F Kuo Timothy T TT Levy-Nissenbaum Etgar E Karnik Rohit R Blumberg Richard S RS Langer Robert R Farokhzad Omid C OC

Science translational medicine 20131101 213

Nanoparticles are poised to have a tremendous impact on the treatment of many diseases, but their broad application is limited because currently they can only be administered by parenteral methods. Oral administration of nanoparticles is preferred but remains a challenge because transport across the intestinal epithelium is limited. We show that nanoparticles targeted to the neonatal Fc receptor (FcRn), which mediates the transport of immunoglobulin G antibodies across epithelial barriers, are e ...[more]

PMID: 24285486

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Project description:Oral insulin delivery could change the life of millions of diabetic patients as an effective, safe, easy-to-use, and affordable alternative to insulin injections, known by an inherently thwarted patient compliance. Here, we designed a multistage nanoparticle (NP) system capable of circumventing the biological barriers that lead to poor drug absorption and bioavailability after oral administration. The nanosystem consists of an insulin-loaded porous silicon NP encapsulated into a pH-responsive lignin matrix, and surface-functionalized with the Fc fragment of immunoglobulin G, which acts as a targeting ligand for the neonatal Fc receptor (FcRn). The developed NPs presented small size (211 ± 1 nm) and narrow size distribution. The NPs remained intact in stomach and intestinal pH conditions, releasing the drug exclusively at pH 7.4, which mimics blood circulation. This formulation showed to be highly cytocompatible, and surface plasmon resonance studies demonstrated that FcRn-targeted NPs present higher capacity to interact and being internalized by the Caco-2 cells, which express FcRn, as demonstrated by Western blot. Ultimately, in vitro permeability studies showed that Fc-functionalized NPs induced an increase in the amount of insulin that permeated across a Caco-2/HT29-MTX co-culture model, showing apparent permeability coefficients (Papp) of 2.37 × 10−6 cm/s, over the 1.66 × 10−6 cm/s observed for their non-functionalized counterparts. Overall, these results demonstrate the potential of these NPs for oral delivery of anti-diabetic drugs. Graphical abstract Image 1 Highlights • Multistage nanoparticle (NP) system targeted for the neonatal Fc receptor (FcRn) aimed at oral insulin delivery.• NPs released insulin under precisely controlled pH conditions.• FcRn expression in the cell culture model used was demonstrated by Western blot.• FcRn-targeted NPs presented higher capacity to interact with the intestinal cells.• Increased insulin permeation was obtained when using Fc-functionalized NPs.

Dataset Information

Transepithelial transport of Fc-targeted nanoparticles by the neonatal fc receptor for oral delivery.

Publications

Transepithelial transport of Fc-targeted nanoparticles by the neonatal fc receptor for oral delivery.

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