title: Nanocomplexes for gene therapy of respiratory diseases: Targeting and overcoming the mucus barrier.
abstract: Gene therapy, i.e. the delivery and expression of therapeutic genes, holds great promise for congenital and acquired respiratory diseases. Non-viral vectors are less toxic and immunogenic than viral vectors, although they are characterized by lower efficiency. However, they have to overcome many barriers, including inflammatory and immune mediators and cells. The respiratory and airway epithelial cells, the main target of these vectors, are coated with a layer of mucus, which hampers the effective reaching of gene therapy vectors carrying either plasmid DNA or small interfering RNA. This barrier is thicker in many lung diseases, such as cystic fibrosis. This review summarizes the most important advancements in the field of non-viral vectors that have been achieved with the use of nanoparticulate (NP) systems, composed either of polymers or lipids, in the lung gene delivery. In particular, different strategies of targeting of respiratory and airway lung cells will be described. Then, we will focus on the two approaches that attempt to overcome the mucus barrier: coating of the nanoparticulate system with poly(ethylene glycol) and treatment with mucolytics. Our conclusions are: 1) Ligand and physical targeting can direct therapeutic gene expression in specific cell types in the respiratory tract; 2) Mucopenetrating NPs are endowed with promising features to be useful in treating respiratory diseases and should be now advanced in pre-clinical trials. Finally, we discuss the development of such polymer- and lipid-based NPs in the context of in vitro and in vivo disease models, such as lung cancer, as well as in clinical trials.
authors.affiliation: Department of Medical and Surgical Sciences, University of Foggia, Viale L. Pinto 1, 71122 Foggia, Italy.
authors.forename: Sante
authors.initials: S
authors.lastname: Di Gioia
authors.affiliation: Department of Pharmacy-Drug Sciences, University of Bari "Aldo Moro", Via Orabona, 4, 70125 Bari, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Trapani
authors.affiliation: Department of Medical and Surgical Sciences, University of Foggia, Viale L. Pinto 1, 71122 Foggia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Castellani
authors.affiliation: Department of Medical and Surgical Sciences, University of Foggia, Viale L. Pinto 1, 71122 Foggia, Italy; Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Commenda 12, 20122 Milan, Italy.
authors.forename: Annalucia
authors.initials: A
authors.lastname: Carbone
authors.affiliation: Department of Medical and Surgical Sciences, University of Foggia, Viale L. Pinto 1, 71122 Foggia, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Belgiovine
authors.affiliation: Biological Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Laboratory of Biocompatible Polymers, University of Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Emanuela Fabiola
authors.initials: EF
authors.lastname: Craparo
authors.affiliation: Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale A. Doria, 6, 95125 Catania, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Puglisi
authors.affiliation: Biological Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Laboratory of Biocompatible Polymers, University of Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Gennara
authors.initials: G
authors.lastname: Cavallaro
authors.affiliation: Department of Pharmacy-Drug Sciences, University of Bari "Aldo Moro", Via Orabona, 4, 70125 Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Trapani
authors.affiliation: Department of Medical and Surgical Sciences, University of Foggia, Viale L. Pinto 1, 71122 Foggia, Italy. Electronic address: massimo.conese@unifg.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Conese
mesh_terms: D003550:Cystic Fibrosis / Q000378:metabolism / Q000628:therapy*; D005100:Expectorants / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D009093:Mucus / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry*; D010957:Plasmids / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage; D013678:Technology, Pharmaceutical
chemical_list: D005100:Expectorants; D018836:Inflammation Mediators; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols
keywords: 1,2-Dioctadecanoyl-sn-glycero-3-phosphoethanolamine (PubMed CID: 102547); 1,2-Dioleoylphosphatidylethanolamine (PubMed CID: 6437083); Asthma; Chitosan (PubMed CID: 71853); Cystic fibrosis; Ethylene glycol (PubMed CID: 174); Lung cancer; Mucolytics; N-(1-(2,3-Dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (PubMed CID: 6438350); N-acetylcystein (PubMed CID: 12035); PAMAM G0 dendrimer (PubMed CID: 4140276); Poly(ethylene glycol); Poly-l-lysine (PubMed CID: 53628747); Polyethyleinimine (PubMed CID: 9033); Sputum