title: Evaluation of the cytotoxicity, genotoxicity and mucus permeation capacity of several surface modified poly(anhydride) nanoparticles designed for oral drug delivery.
abstract: The main concerns with drugs designed for oral administration are their inactivation or degradation in the harsh conditions of the gastrointestinal tract, their poor solubility through the gastrointestinal mucus gel layer, the poor intestinal epithelium permeability that limits their absorption, and their toxicity. In this context, poly(anhydride) nanoparticles are capable of protecting the drug from the harsh environment, reduce the drug's toxicity and, by virtue of surface modification, to enhance or reduce their mucus permeability and the bioadhesion to specific target cells. The copolymer between methyl vinyl ether and maleic anhydride (commercialized as Gantrez®AN 119) are part of the poly(anhydride) nanoparticles. These biocompatible and biodegradable nanoparticles (NPs) can be modified by using different ligands. Their usefulness as drug carriers and their bioadhesion with components of the intestinal mucosa have been described. However, their toxicity, genotoxicity and mucus permeation capacity has not been thoroughly studied. The aim of this work was to evaluate and compare the in vitro toxicity, cell viability and in vitro genotoxicity of the bioadhesive empty Gantrez®AN 119 NPs modified with dextran, aminodextran, 2-hydroxypropyl-β-cyclodextrin, mannosamine and poly-ethylene glycol of different molecular weights. Results showed that, in general, coated NPs exhibit better mucus permeability than the bare ones, those coated with mannosamine being the most permeable ones. The NPs studied did not affect cell metabolism, membrane integrity or viability of Caco-2 cells at the different conditions tested. Moreover, they did not induce a relevant level of DNA strand breaks and FPG-sensitive sites (as detected with the comet assay).
authors.affiliation: Department of Pharmacology and Toxicology, University of Navarra, Irunlarrea 1, 31009, Pamplona, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Iglesias
authors.affiliation: Department of Pharmacology and Toxicology, University of Navarra, Irunlarrea 1, 31009, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Spain.
authors.forename: A
authors.initials: A
authors.lastname: López de Cerain
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Navarra, Irunlarrea 1, 31009, Pamplona, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Irache
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Navarra, Irunlarrea 1, 31009, Pamplona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Martín-Arbella
authors.affiliation: Institute for Cell and Molecular Bioscience, Medical School, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK.
authors.forename: M
authors.initials: M
authors.lastname: Wilcox
authors.affiliation: Institute for Cell and Molecular Bioscience, Medical School, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK.
authors.forename: J
authors.initials: J
authors.lastname: Pearson
authors.affiliation: Department of Pharmacology and Toxicology, University of Navarra, Irunlarrea 1, 31009, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Spain. Electronic address: amazqueta@unav.es.
authors.forename: A
authors.initials: A
authors.lastname: Azqueta
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D053960:DNA Breaks / Q000187:drug effects*; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D005753:Gastric Mucosa / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008298:Maleates / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D053758:Nanoparticles / Q000737:chemistry*; D010539:Permeability; D011095:Polyethylenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D013499:Surface Properties; D013552:Swine
chemical_list: D004337:Drug Carriers; D008298:Maleates; D011095:Polyethylenes; C043105:poly(methyl vinyl ether-co-maleic anhydride)
keywords: Comet assay; Cytotoxicity; Genotoxicity; Mucus permeation; Polymeric nanoparticles; Viability