In-vitro and in-vivo antileishmanial activity of inexpensive Amphotericin B formulations: Heated Amphotericin B and Amphotericin B-loaded microemulsion

  • Exp Parasitol. 2018 Sep;192:85-92. doi: 10.1016/j.exppara.2018.07.017.
Andreza Rochelle do Vale Morais  1 ,  André Leandro Silva  2 ,  Sandrine Cojean  3 ,  Kaluvu Balaraman  4 ,  Christian Bories  3 ,  Sébastien Pomel  3 ,  Gillian Barratt  5 ,  Eryvaldo Sócrates Tabosa do Egito  6 ,  Philippe M Loiseau  7
Affiliations
  • 1. Universidade Federal do Rio Grande do Norte (UFRN), Programa de Pós-graduação em Nanotecnologia Farmacêutica, Rua Gustavo Cordeiro de Farias, SN. Petrópolis, CEP: 59012-570 Natal, RN, Brazil; Université Paris-Sud, Institut Galien Paris-Sud, UMR-CNRS 8612, 5, Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry cedex, France.
  • 2. UFRN, Programa de Pós-graduação em Biotecnologia (RENORBIO), Av. Senador Salgado Filho, 3000. Campus Universitário, CEP: 59078-970 Natal, RN, Brazil; Université Paris-Sud, Institut Galien Paris-Sud, UMR-CNRS 8612, 5, Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry cedex, France; Centro das Ciências Biológicas e da Saúde, Universidade Federal do Oeste da Bahia (UFOB), R. Prof. José Seabra de Lemos, 316, CEP: 47.808-021 Barreiras, BA, Brazil.
  • 3. Université Paris-Sud, Faculté de Pharmacie, UMR 8076 CNRS BioCIS, Châtenay-Malabry, France.
  • 4. Université Paris-Sud, Faculté de Pharmacie, UMR 8076 CNRS BioCIS, Châtenay-Malabry, France; Chemical Biology Lab, Department of Biotechnology, IITM, Technology Madras, Chennai, India.
  • 5. Université Paris-Sud, Institut Galien Paris-Sud, UMR-CNRS 8612, 5, Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry cedex, France.
  • 6. Universidade Federal do Rio Grande do Norte (UFRN), Programa de Pós-graduação em Nanotecnologia Farmacêutica, Rua Gustavo Cordeiro de Farias, SN. Petrópolis, CEP: 59012-570 Natal, RN, Brazil; UFRN, Programa de Pós-graduação em Biotecnologia (RENORBIO), Av. Senador Salgado Filho, 3000. Campus Universitário, CEP: 59078-970 Natal, RN, Brazil.
  • 7. Université Paris-Sud, Faculté de Pharmacie, UMR 8076 CNRS BioCIS, Châtenay-Malabry, France. Electronic address: [email protected].
PMID: 30075233 DOI: 10.1016/j.exppara.2018.07.017
Abstract

Amphotericin B (AmB) is effective against visceral leishmaniasis (VL), but the renal toxicity of the conventional form, mixed micelles with deoxycholate (M-AmB), is often dose-limiting, while the less toxic lipid-based formulations such as AmBisome® are very expensive. Two different strategies to improve the therapeutic index of AmB with inexpensive ingredients were evaluated on this work: (i) the heat treatment of the commercial formulation (H-AmB) and (ii) the preparation of an AmB-loaded microemulsion (ME-AmB). M-AmB was heated to 70 °C for 20 min. The resulting product was characterized by UV spectrophotometry and circular dichroism, showing super-aggregates formation. ME-AmB was prepared from phosphate buffer pH 7.4, Tween 80®, Lipoid S100® and Mygliol 812® with AmB at 5 mg/mL. The droplet size, measured by dynamic light scattering, was about 40 nm and transmission electron microscopy confirmed a spherical shape. Rheological analysis showed low viscosity and Newtonian behavior. All the formulations were active in vitro and in vivo against Leishmania donovani (LV9). A selectivity index (CC50 on RAW/IC50 on LV9) higher than 10 was observed for ME-AmB, H-AmB and AmBisome®. Furthermore, no important in vivo toxicity was observed for all the samples. The in-vivo efficacy of the formulations after IV administration was evaluated in Balb/C mice infected with LV9 (three doses of 1 mg/kg AmB) and no significant difference was observed between H-AmB, M-AmB, ME-AmB and AmBisome®. In conclusion, these two inexpensive alternative formulations for AmB showing good efficacy and selectivity for Leishmania donovani merit further investigation.

Keywords
Amphotericin B; Microemulsion; Superaggregates; Visceral leishmaniasis.
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