Polarity-sensitive nanocarrier for oral delivery of Sb(V) and treatment of cutaneous leishmaniasis.
There is a great need for orally active drugs for the treatment of the neglected tropical disease leishmaniasis. Amphiphilic Sb(V) complexes, such as 1:3 Sb-N-octanoyl-N-methylglucamide complex (SbL8), are promising drug candidates. It has been previously reported that SbL8 forms kinetically stabilized nanoassemblies in water and that this simple dispersion exhibits antileishmanial activity when given by oral route to a murine model of visceral leishmaniasis. The main objective of the present work was to interfere in the structural organization of these nanoassemblies so as to investigate their influence on the oral bioavailability of Sb, and ultimately, optimize an oral formulation of SbL8 for the treatment of cutaneous leishmaniasis. The structural organization of SbL8 nanoassemblies was manipulated through addition of propylene glycol (PG) to the aqueous dispersion of SbL8. The presence of 50% (v/v) PG resulted in the loss of hydrophobic microenvironment, as evidenced by fluorescence probing. However, nanostructures were still present, as demonstrated by dynamic light scattering, small-angle X-ray scattering, and atomic force microscopy (AFM). A remarkable property of these nanoassemblies, as revealed by AFM analysis, is the flexibility of their supramolecular organization, which showed changes as a function of the solvent and substrate polarities. The formulation of SbL8 in 1:1 water:PG given orally to mice promoted significantly higher and more sustained serum levels of Sb, when compared to SbL8 in water. The new formulation, when given as repeated doses (200 mg Sb/kg/day) to BALB/c mice infected with Leishmania amazonensis, was significantly more effective in reducing the lesion parasite burden, compared to SbL8 in water, and even, the conventional drug Glucantime(®) given intraperitoneally at the same dose. In conclusion, this work introduces a new concept of polarity-sensitive nanocarrier that was successfully applied to optimize an oral formulation of Sb(V) for treating cutaneous leishmaniasis.
Department of Physiology and Biophysics, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Juliane S
JS
Lanza
Department of Physiology and Biophysics, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Flaviana R
FR
Fernandes
Department of Morphology, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
José D
JD
Corrêa-Júnior
Innovation and Technology Center SENAI FIEMG - Campus CETEC, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
José Mc
JM
Vilela
Department of Physics, Instituto de Ciências Exatas (ICEX), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Rogério
R
Magalhães-Paniago
Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Lucas Am
LA
Ferreira
Innovation and Technology Center SENAI FIEMG - Campus CETEC, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Margareth S
MS
Andrade
Department of Chemistry, Instituto de Ciências Exatas (ICEX), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Cynthia
C
Demicheli
Department of Parasitology, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Maria N
MN
Melo
Department of Physiology and Biophysics, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Frédéric
F
Frézard
D000284:Administration, Oral; D000818:Animals; D000965:Antimony / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D057927:Hydrophobic and Hydrophilic Interactions; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy*; D008536:Meglumine / Q000627:therapeutic use; D000077485:Meglumine Antimoniate; D008807:Mice, Inbred BALB C; D018625:Microscopy, Atomic Force; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009942:Organometallic Compounds / Q000627:therapeutic use; D053838:Scattering, Small Angle; D012997:Solvents; D016896:Treatment Outcome; D014961:X-Ray Diffraction
D000981:Antiprotozoal Agents; D004337:Drug Carriers; D009942:Organometallic Compounds; D012997:Solvents; D008536:Meglumine; D000077485:Meglumine Antimoniate; D000965:Antimony
AFM; Leishmania amazonensis; SAXS; amphiphilic complex; antimony; propylene glycol