title: Biodistribution and molecular studies on orally administered nanoparticle-AON complexes encapsulated with alginate aiming at inducing dystrophin rescue in mdx mice.
abstract: We have previously demonstrated that intraperitoneal injections of 2'-O-methyl-phosphorothioate (2'OMePS) antisense oligoribonucleotides adsorbed onto a cationic core-shell nanoparticles (NPs), termed ZM2, provoke dystrophin restoration in the muscles of mdx mice. The aim of the present work was to evaluate the oral route as an alternative way of administration for ZM2-antisense oligoribonucleotides complexes. The biodistribution and elimination of nanoparticles were evaluated after single and multiple oral doses of IR-dye conjugated nanoparticles. Labeled nanoparticles were tracked in vivo as well as in tissue cryosections, urines and feces by Odyssey infrared imaging system, and revealed a permanence in the intestine and abdominal lymph nodes for 72 hours to 7 days before being eliminated. We subsequently tested alginate-free and alginate-encapsulated ZM2-antisense oligoribonucleotides (AON) complexes orally administered 2 and 3 times per week, respectively, in mdx mice for a total of 12 weeks. Treatment with alginate ZM2-AON induced a slight dystrophin rescue in diaphragm and intestine smooth muscles, while no dystrophin was detected in alginate-free ZM2-AON treated mice. These data encourage further experiments on oral administration testing of NP and AON complexes, possibly translatable in oligoribonucleotides-mediated molecular therapies.
authors.affiliation: Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Maria Sofia
authors.initials: MS
authors.lastname: Falzarano
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Passarelli
authors.affiliation: Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bassi
authors.affiliation: Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Fabris
authors.affiliation: Department of Biology and Evolution, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Perrone
authors.affiliation: IGM-CNR, Unit of Bologna c/o IOR, 40136 Bologna, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sabatelli
authors.affiliation: IGM-CNR, Unit of Bologna c/o IOR, 40136 Bologna, Italy.
authors.forename: Nadir M
authors.initials: NM
authors.lastname: Maraldi
authors.affiliation: Department of Biomedical Sciences, University of Padua, 35121 Padua, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Donà
authors.affiliation: Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Selvatici
authors.affiliation: Department of Biomedical Sciences, University of Padua, 35121 Padua, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonaldo
authors.affiliation: Department of Environmental and Life Sciences INSTM, University of Eastern Piedmont, 15121 Alessandria, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Sparnacci
authors.affiliation: Department of Environmental and Life Sciences INSTM, University of Eastern Piedmont, 15121 Alessandria, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Laus
authors.affiliation: Department of Biomedical Sciences, University of Padua, 35121 Padua, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Braghetta
authors.affiliation: Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rimessi
authors.affiliation: Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy ; Department of Medical Sciences, Section of Medical Genetics, University of Ferrara, via Fossato di Mortara 74, 44121 Ferrara, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferlini
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D016189:Dystrophin / Q000378:metabolism*; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D009132:Muscles / Q000187:drug effects / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D020320:Oligoribonucleotides, Antisense / Q000008:administration & dosage* / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D016189:Dystrophin; D020320:Oligoribonucleotides, Antisense