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Combination oral therapy against Leishmania amazonensis infection in BALB/c mice using nanoassemblies made from amphiphilic antimony(V) complex incorporating miltefosine

  • Virgínia M. Carregal
  • Juliane S. Lanza
  • Daniel M. Souza
  • Arshad Islam
  • Cynthia Demicheli
  • Ricardo T. Fujiwara
  • Luis Rivas
  • Frédéric FrézardEmail author
Treatment and Prophylaxis - Original Paper

Abstract

Clinically available drugs for mucocutaneous and cutaneous leishmaniases (CL) include mainly pentavalent antimony (Sb(V)) complexes, liposomal amphotericin B, and miltefosine (HePC). However, they present at least one of the following limitations: long-term parenteral administration through repeated doses, severe side effects, drug resistance, and high cost. HePC is the only oral drug available, but the appearance of resistance has resulted in changes of its use from monotherapy to combination therapy. Amphiphilic Sb(V) complexes, such as SbL8 obtained from reaction of Sb(V) with N-octanoyl-N-methylglucamide, were recently found to be orally active against experimental CL. The property of SbL8 to self-assemble in aqueous solution, forming nanostructures, led us to investigate the incorporation of HePC into SbL8 nanoassemblies and the therapeutic efficacy of SbL8/HePC nanoformulation by oral route in a murine model of CL. HePC incorporation into the SbL8 nanosystem was evidenced by using a fluorescent analog of HePC. The antileishmanial activity of SbL8/HePC nanoassemblies was evaluated after daily oral administration for 30 days in Leishmania amazonensis-infected BALB/c mice, in comparison with monotherapies (SbL8 or HePC) and saline control. All the treatments resulted in significant reduction in the lesion size growth, when compared with control. Strikingly, only SbL8/HePC nanoassemblies promoted a significant decrease of the parasite burden in the lesion. This work establishes the therapeutic benefit of SbL8/HePC association by oral route in a CL model and constitutes an important step towards the development of new orally active drug combination.

Keywords

Miltefosine Antimony Nanoparticles Leishmaniasis Oral route Drug combination 

Notes

Acknowledgements

The authors specially thank Nayara K. L. M. Moura, Larissa P. Carvalho, Flaviana R. Fernandes, and Pablo H. P. Matias for technical support.

Funding information

This work was supported by the Brazilian agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grant number: 425332/2018–7), Coordenação de Aperfeicoamento de Pessoal de Nível Superior (CAPES, grant number: PNPD20131163), and Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG, grant number: APQ-03129-16) for financial support. F.F. was recipient of fellowship from CNPq (grant number: 305659/2017-0) and Chaire Jean d’Alembert, Université Paris-Saclay, France (ANR-11-IDEX-0003-02). L.R was supported by Program of Redes Temáticas de Investigación Cooperativa RETICS-FEDER (grant number: RD16/0027/0010).

Compliance with ethical standards

The study involving animals was approved by the Ethical Committee for Animal Experimentation of the UFMG with protocol number 318/2013.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

436_2019_6419_MOESM1_ESM.pdf (545 kb)
ESM 1 (PDF 545 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Departamento de Fisiologia e Biofísica, Instituto de Ciências BiológicasUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  2. 2.Colégio Técnico da UFMGUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  3. 3.Departamento de Química, Instituto de Ciências ExatasUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  4. 4.Departamento de Parasitologia, Instituto de Ciências BiológicasUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  5. 5.Centro de Investigaciones Biologicas-CSICMadridSpain

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