Biodistribution and Molecular Studies on Orally Administered Nanoparticle-AON Complexes Encapsulated with Alginate Aiming at Inducing Dystrophin Rescue in<i>mdx</i>Mice

Falzarano, Maria Sofia; Passarelli, Chiara; Bassi, Elena; Fabris, M.; Perrone, Daniela; Sabatelli, Patrizia; Maraldi, Nadir M.; Donà, Silvio; Selvatici, Rita; Bonaldo, Paolo; Sparnacci, Katia; Laus, Michele; Braghetta, Paola; Rimessi, Paola; Ferlini, Alessandra

doi:10.1155/2013/527418

Cited by 22 publications

(13 citation statements)

References 50 publications

(55 reference statements)

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“…Notably, proof of concept for oral delivery of AONs has been obtained for different AON chemistries targeting other diseases, 10 , 11 , 19 while for DMD, oral delivery of 2OMePS AONs bound to nanoparticles has been previously tested in mdx mice. 20 Our study is the first to INT infuse mdx mice with naked 2OMePS AONs (with or without sodium caprate supplementation) and directly compare PK and PD profiles with IV, IP, and SC injections in detail.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy

Putten

Young

Berg

et al. 2014

Molecular Therapy - Nucleic Acids

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Antisense oligonucleotides (AONs) used to reframe dystrophin mRNA transcripts for Duchenne muscular dystrophy (DMD) patients are tested in clinical trials. Here, AONs are administered subcutaneously and intravenously, while the less invasive oral route would be preferred. Oral delivery of encapsulated AONs supplemented with a permeation enhancer, sodium caprate, has been successfully used to target tumor necrosis factor (TNF)-α expression in liver. To test the feasibility of orally delivered AONs for DMD, we applied 2′-O-methyl phosphorothioate AONs (with or without sodium caprate supplementation) directly to the intestine of mdx mice and compared pharmacokinetics and -dynamics with intravenous, intraperitoneal, and subcutaneous delivery. Intestinally infused AONs were taken up, but resulted in lower plasma levels compared to other delivery routes, although bioavailability could be largely improved by supplementation of sodium caprate. After intestinal infusion, AON levels in all tissues were lower than for other administration routes, as were the ratios of target versus nontarget organ levels, except for diaphragm and heart where comparable levels and ratios were observed. For each administration route, low levels of exon skipping in triceps was observed 3 hours post-AON administration. These data suggest that oral administration of naked 2′-O-methyl phosphorothioate AONs may be feasible, but only when high AON concentrations are used in combination with sodium caprate.

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Section: Discussionmentioning

confidence: 99%

Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy

Putten

Young

Berg

et al. 2014

Molecular Therapy - Nucleic Acids

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“…In contrast to T1 nanoparticles, ZM2 nanoparticle delivery resulted in efficient myocardial exon‐skipping. Recent studies suggest that PMMA nanoparticles can greatly improve bodywide delivery of AONs and dystrophin restoration by exon‐skipping in striated muscles . Further development of this delivery strategy is warranted.…”

Section: Nonviral‐based Nanoparticles For Dmd Therapymentioning

confidence: 99%

Nanotherapy for Duchenne muscular dystrophy

Nance

Hakim

Yang

et al. 2017

WIREs Nanomed Nanobiotechnol

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Duchenne muscular dystrophy (DMD) is a lethal X-linked childhood muscle wasting disease caused by mutations in the dystrophin gene. Nanobiotechnology-based therapies (such as synthetic nanoparticles and naturally existing viral and nonviral nanoparticles) hold great promise to replace and repair the mutated dystrophin gene and significantly change the disease course. While a majority of DMD nanotherapies are still in early preclinical development, several [such as adeno-associated virus (AAV)-mediated systemic micro-dystrophin gene therapy] are advancing for phase I clinical trials. Recent regulatory approval of Ataluren (a nonsense mutation read-through chemical) in Europe and Exondys51 (an exon-skipping antisense oligonucleotide drug) in the United States shall offer critical insight in how to move DMD nanotherapy to human patients. Progress in novel, optimized nano-delivery systems may further improve emerging molecular therapeutic modalities for DMD. Despite these progresses, DMD nanotherapy faces a number of unique challenges. Specifically, the dystrophin gene is one of the largest genes in the genome while nanoparticles have an inherent size limitation per definition. Furthermore, muscle is the largest tissue in the body and accounts for 40% of the body mass. How to achieve efficient bodywide muscle targeting in human patients with nanomedication remains a significant translational hurdle. New creative approaches in the design of the miniature micro-dystrophin gene, engineering of muscle-specific synthetic AAV capsids, and novel nanoparticle-mediated exon-skipping are likely to result in major breakthroughs in DMD therapy.

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“… 23 Sections (20 µm) were stained with hematoxylin/eosin (H&E), followed by light microscopy analysis (Zeiss, Axioskop, Germany). 24 , 25 …”

Section: Histological Analysis Of Colitismentioning

confidence: 99%

Colon-targeted delivery of budesonide using dual pH- and time-dependent polymeric nanoparticles for colitis therapy

Naeem¹,

Choi²,

Cao³

et al. 2015

DDDT

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Single pH-dependent drug delivery systems have been widely used for colon-targeted delivery, but their efficiency is often hampered by the variation in gut pH. To overcome the limitation of single pH-dependent delivery systems, in this study, we developed and evaluated the therapeutic potential of budesonide-loaded dual pH/time-dependent nanoparticles (NPs) for the treatment of colitis. Eudragit FS30D was used as a pH-dependent polymer, and Eudragit RS100 as a time-dependent controlled release polymer. Single pH-dependent NPs (pH_NPs), single time-dependent NPs (Time_NPs), and dual pH/time-dependent NPs (pH/Time_NPs) were prepared using the oil-in-water emulsion method. The physicochemical properties and drug release profiles of these NPs in gastrointestinal (GI) tract conditions were investigated. The therapeutic potential and in vivo distribution of the NPs were evaluated in a dextran sulfate sodium (DSS)-induced colitis mice model. The pH/Time_NPs prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. The in vivo distribution study in the mice GI tract demonstrated that pH/Time_NPs were more efficiently delivered to the inflamed colon than pH_NPs were. Compared to the single pH_NPs-treated group, the pH/Time_NPs-treated group showed increased body weight and colon length and markedly decreased disease activity index, colon weight/length ratios, histological damage, and inflammatory cell infiltration in colon tissue. Our results demonstrate that the dual pH/time-dependent NPs are an effective oral colon-targeted delivery system for colitis therapy.

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Biodistribution and Molecular Studies on Orally Administered Nanoparticle-AON Complexes Encapsulated with Alginate Aiming at Inducing Dystrophin Rescue inmdxMice

Cited by 22 publications

References 50 publications

Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy

Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy

Nanotherapy for Duchenne muscular dystrophy

Colon-targeted delivery of budesonide using dual pH- and time-dependent polymeric nanoparticles for colitis therapy

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