TY - JOUR
T1 - Dexamethasone Conjugation to Biodegradable Avidin-Nucleic-Acid-Nano-Assemblies Promotes Selective Liver Targeting and Improves Therapeutic Efficacy in an Autoimmune Hepatitis Murine Model
AU - Violatto, Martina Bruna
AU - Casarin, Elisabetta
AU - Talamini, Laura
AU - Russo, Luca
AU - Baldan, Simone
AU - Tondello, Camilla
AU - Messmer, Marie
AU - Hintermann, Edith
AU - Rossi, Alessandro
AU - Passoni, Alice
AU - Bagnati, Renzo
AU - Biffi, Stefania
AU - Toffanin, Chiara
AU - Gimondi, Sara
AU - Fumagalli, Stefano
AU - De Simoni, Maria Grazia
AU - Barisani, Donatella
AU - Salmona, Mario
AU - Christen, Urs
AU - Invernizzi, Pietro
AU - Bigini, Paolo
AU - Morpurgo, Margherita
PY - 2019/4/23
Y1 - 2019/4/23
N2 - 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.
AB - 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.
KW - autoimmune hepatitis
KW - avidin-nucleic-acid-nano-assemblies
KW - pH reversible linker
KW - steroid treatment
KW - targeted drug release
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U2 - 10.1021/acsnano.8b09655
DO - 10.1021/acsnano.8b09655
M3 - Article
C2 - 30883091
AN - SCOPUS:85063406047
VL - 13
SP - 4410
EP - 4423
JO - ACS Nano
JF - ACS Nano
SN - 1936-0851
IS - 4
ER -