51. Dexamethasone Conjugation to Biodegradable Avidin-Nucleic-Acid-Nano-Assemblies Promotes Selective Liver Targeting and Improves Therapeutic Efficacy in an Autoimmune Hepatitis Murine Model
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Mario Salmona, Elisabetta Casarin, Laura Talamini, Simone Baldan, Renzo Bagnati, Alice Passoni, Donatella Barisani, Marie Messmer, Pietro Invernizzi, Stefano Fumagalli, Urs Christen, Paolo Bigini, Margherita Morpurgo, Luca Russo, Alessandro Rossi, Martina Bruna Violatto, Chiara Toffanin, Stefania Biffi, Camilla Tondello, Edith Hintermann, Sara Gimondi, Maria Grazia De Simoni, Violatto, M, Casarin, E, Talamini, L, Russo, L, Baldan, S, Tondello, C, Messmer, M, Hintermann, E, Rossi, A, Passoni, A, Bagnati, R, Biffi, S, Toffanin, C, Gimondi, S, Fumagalli, S, De Simoni, M, Barisani, D, Salmona, M, Christen, U, Invernizzi, P, Bigini, P, and Morpurgo, M
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Male ,Anti-Inflammatory Agents ,General Physics and Astronomy ,targeted drug release ,pH reversible linker ,02 engineering and technology ,Autoimmune hepatitis ,Pharmacology ,01 natural sciences ,Dexamethasone ,Mice ,Drug Delivery Systems ,MED/12 - GASTROENTEROLOGIA ,Nucleic Acids ,General Materials Science ,autoimmune hepatiti ,media_common ,autoimmune hepatitis ,avidin-nucleic-acid-nano-assemblies ,steroid treatment ,Drug Carriers ,biology ,Chemistry ,General Engineering ,Hydrogen-Ion Concentration ,021001 nanoscience & nanotechnology ,Hepatitis, Autoimmune ,0210 nano-technology ,medicine.drug ,Drug ,Biodistribution ,media_common.quotation_subject ,010402 general chemistry ,Pharmacokinetics ,medicine ,Animals ,Tropism ,BIO/13 - BIOLOGIA APPLICATA ,Avidin ,medicine.disease ,0104 chemical sciences ,Mice, Inbred C57BL ,Disease Models, Animal ,biology.protein ,Nucleic acid ,Nanoparticles ,avidin-nucleic-acid-nano-assemblie - 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.
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