Dexamethasone Conjugation to Biodegradable Avidin-Nucleic-Acid-Nano-Assemblies Promotes Selective Liver Targeting and Improves Therapeutic Efficacy in an Autoimmune Hepatitis Murine Model.

Abstract

Steroids are the standard therapy for autoimmune hepatitis (AIH) but the long-lasting administration is hampered by severe side effects. Methods to improve the tropism of the drug toward the liver are therefore required. Among them, conjugation to nanoparticles represents one possible strategy. In this study, we exploited the natural liver tropism of Avidin-Nucleic-Acid-Nano-Assemblies (ANANAS) to carry dexamethasone selectively to the liver in an AIH animal model. An acid-labile biotin-hydrazone linker was developed for reversible dexamethasone loading onto ANANAS. The biodistribution, pharmacokinetics and efficacy of free and ANANAS-linked dexamethasone (ANANAS-Hz-Dex) in healthy and AIH mice were investigated upon intraperitoneal administration. In ANANAS-treated animals, the free drug was detected only in the liver. Super-resolution microscopy showed that nanoparticles segregate inside lysosomes of liver immunocompetent cells, mainly involved in AIH progression. In agreement with these observational results, chronic low-dose treatment with ANANAS-Hz-Dex reduced the expression of liver inflammation markers and, in contrast to the free drug, also the levels of circulating AIH-specific autoantibodies. These data suggest that the ANANAS carrier attenuates AIH-related liver damage without drug accumulation in off-site tissues. The safety and biodegradability of the ANANAS carrier make this formulation a promising tool for the treatment of autoimmune liver disorders.

• Authors: Martina Bruna Violatto, Elisabetta Casarin, Laura Talamini, Luca Russo, Simone Baldan, Camilla Tondello, Marie Messmer, Edith Hintermann, Alessandro Rossi, Alice Passoni, Renzo Bagnati, Stefania Biffi, Chiara Toffanin, Sara Gimondi, Stefano Fumagalli, Maria-Grazia De Simoni, Donatella Barisani, Mario Salmona, Urs Christen, Pietro Invernizzi, Paolo Bigini, Margherita Morpurgo
• Journal: ACS nano (ACS Nano) Vol. 13 Issue 4 Pg. 4410-4423 (04 23 2019) ISSN: 1936-086X [Electronic] United States
• PMID: 30883091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Drug Carriers
• Nucleic Acids
• Avidin
• Dexamethasone

Topics

• Animals
• Anti-Inflammatory Agents (administration & dosage, therapeutic use)
• Avidin (chemistry)
• Dexamethasone (administration & dosage, therapeutic use)
• Disease Models, Animal
• Drug Carriers (chemistry)
• Drug Delivery Systems
• Hepatitis, Autoimmune (drug therapy)
• Hydrogen-Ion Concentration
• Male
• Mice
• Mice, Inbred C57BL
• Nanoparticles (chemistry)
• Nucleic Acids (chemistry)