title: Venom conjugated polylactide applied as biocompatible material for passive and active immunotherapy against scorpion envenomation.
abstract: Scorpion envenoming represents a public health issue in subtropical regions of the world. Treatment and prevention need to promote antitoxin immunity. Preserving antigenic presentation while removing toxin effect remains a major challenge in toxin vaccine development. Among particulate adjuvant, particles prepared with poly (D,L-lactide) polymer are the most extensively investigated due to their excellent biocompatibility and biodegradability. The aim of this study is to develop surfactant-free PLA nanoparticles that safely deliver venom toxic fraction to enhance specific immune response. PLA nanoparticles are coated with AahG50 (AahG50/PLA) and BotG50 (BotG50/PLA): a toxic fraction purified from Androctonus australis hector and Buthus occitanus tunetanus venoms, respectively. Residual toxicities are evaluated following injections of PLA-containing high doses of AahG50 (or BotG50). Immunization trials are performed with the detoxified fraction administered alone without adjuvant. A comparative study of the effect of Freund is also included. The neutralizing capacity of sera is determined in naive mice. Six months later, immunized mice are challenged subcutaneously with increased doses of AahG50. Subcutaneous lethal dose 50 (LD50) of AahG50 and BotG50 is of 575 μg/kg and 1300 μg/kg respectively. By comparison, BotG50/PLA is totally innocuous while 50% of tested mice survive 2875 μg AahG50/kg. Alhydrogel and Freund are not able to detoxify such a high dose. Cross-antigenicity between particulate and soluble fraction is also, ensured. AahG50/PLA and BotG50/PLA induce high antibody levels in mice serum. The neutralizing capacity per mL of anti-venom was 258 μg/mL and 186 μg/mL calculated for anti-AahG50/PLA and anti-BotG50/PLA sera, respectively. Animals immunized with AahG50/PLA are protected against AahG50 injected dose of 3162 μg/kg as opposed all non-immunized mice died at this dose. We find that the detoxification approach based PLA nanoparticles, benefit the immunogenicity and protective efficacy of venom immunogen.
authors.affiliation: Laboratoire des Venins et Molécules Thérapeutiques, Institut Pasteur Tunis - University Tunis El Manar, BP 74, 13 Place Pasteur, 1002 Tunis, Tunisia; Faculté des Sciences de Bizerte, 7021 Jarzouna, Tunisia. Electronic address: sana.riabii@gmail.com.
authors.forename: Sana
authors.initials: S
authors.lastname: Ayari-Riabi
authors.affiliation: Institut de chimie radicalaire, Equipe Chimie Radicalaire, Organique et Polymères de Spécialité (CROPS), (CNRS - UMR7273), Aix-Marseille University, avenue Escadrille Normandie-Niemen, 13397 Marseille cedex 20, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Trimaille
authors.affiliation: Institut de chimie radicalaire, Equipe Chimie Radicalaire, Organique et Polymères de Spécialité (CROPS), (CNRS - UMR7273), Aix-Marseille University, avenue Escadrille Normandie-Niemen, 13397 Marseille cedex 20, France.
authors.forename: Kamel
authors.initials: K
authors.lastname: Mabrouk
authors.affiliation: Institut de chimie radicalaire, Equipe Chimie Radicalaire, Organique et Polymères de Spécialité (CROPS), (CNRS - UMR7273), Aix-Marseille University, avenue Escadrille Normandie-Niemen, 13397 Marseille cedex 20, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Bertin
authors.affiliation: Institut de chimie radicalaire, Equipe Chimie Radicalaire, Organique et Polymères de Spécialité (CROPS), (CNRS - UMR7273), Aix-Marseille University, avenue Escadrille Normandie-Niemen, 13397 Marseille cedex 20, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Gigmes
authors.affiliation: Service des Unités Animalières, Institut Pasteur Tunis - BP 74, 13 Place Pasteur, 1002 Tunis, Tunisia.
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Benlasfar
authors.affiliation: Laboratoire des Venins et Molécules Thérapeutiques, Institut Pasteur Tunis - University Tunis El Manar, BP 74, 13 Place Pasteur, 1002 Tunis, Tunisia.
authors.forename: Ahlem
authors.initials: A
authors.lastname: Zaghmi
authors.affiliation: Laboratoire des Venins et Molécules Thérapeutiques, Institut Pasteur Tunis - University Tunis El Manar, BP 74, 13 Place Pasteur, 1002 Tunis, Tunisia.
authors.forename: Balkiss
authors.initials: B
authors.lastname: Bouhaouala-Zahar
authors.affiliation: Laboratoire des Venins et Molécules Thérapeutiques, Institut Pasteur Tunis - University Tunis El Manar, BP 74, 13 Place Pasteur, 1002 Tunis, Tunisia. Electronic address: mohamed.elayeb@pasteur.rns.tn.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elayeb
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry; D000818:Animals; D000997:Antivenins / Q000737:chemistry / Q000627:therapeutic use*; D001672:Biocompatible Materials / Q000737:chemistry*; D005260:Female; D016233:Immunotherapy, Active; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D009500:Neutralization Tests; D011091:Polyesters / Q000737:chemistry*; D012604:Scorpion Venoms / Q000276:immunology*; D012605:Scorpions; D018675:Toxicity Tests
chemical_list: D000276:Adjuvants, Immunologic; D000997:Antivenins; D001672:Biocompatible Materials; D011091:Polyesters; D012604:Scorpion Venoms; C033616:poly(lactide)
keywords: Detoxification; Immunoprotection; Neutralization; PLA nanoparticles; Toxic venom fraction