Supramolecular assemblies from antimony(V) complexes for the treatment of leishmaniasis

Abstract

The pentavalent meglumine antimoniate (MA) is still a first-line drug in the treatment of leishmaniasis in several countries. As an attempt to elucidate its mechanism of action and develop new antimonial drugs with improved therapeutic profile, Sb(V) complexes with different ligands, including β-cyclodextrin (β-CD), nucleosides and non-ionic surfactants, have been studied. Interestingly, Sb(V) oxide, MA, its complex with β-CD, Sb(V)-guanosine complex and amphiphilic Sb(V) complexes with N-alkyl-N-methylglucamide, have shown marked tendency to self-assemble in aqueous solutions, forming nanoaggregates, hydrogel or micelle-like nanoparticles. Surprisingly, the resulting assemblies presented in most cases slow dissociation kinetics upon dilution and a strong influence of pH, which impacted on their pharmacokinetic and therapeutic properties against leishmaniasis. To explain this unique property, we raised the hypothesis that multiple pnictogen bonds could contribute to the formation of these assemblies and their kinetic of dissociation. The present article reviews our current knowledge on the structural organization and physicochemical characteristics of Sb-based supramolecular assemblies, as well as their pharmacological properties and potential for treatment of leishmaniasis. This review supports the feasibility of the rational design of new Sb(V) complexes with supramolecular assemblies for the safe and effective treatment of leishmaniasis.

Keywords: Antimony; Drug delivery; Leishmaniasis; Nanoassemblies; Pnictogen bonding; Supramolecular.

Fig. 1

Sb(V) species identified by ESI–MS in the positive and the negative modes in diluted aqueous solution of MA (Frézard et al. 2008a) (a) and evidence by DLS for existence of supramolecular assemblies in Glucantime® (b)

Fig. 2

Proposed mode of action of MA-β-CD ternary complex to increase the serum level of Sb after oral administration. The MA/β-CD composition consists in high molecular-weight ternary complexes, such as NMG-Sb-β-CD-Sb-NMG species, which migrate along the gastrointestinal tract and slowly release MA in the form of 1:1 Sb-NMG complex that permeates by simple diffusion across the intestinal epithelium. Figure 2b is reprinted from Frézard et al. (2008b) and minimally adapted, with permission from Elsevier

Fig. 3

1:1 and 1:2 Sb(V)-G complexes identified by ESI–MS (a) and characterization of the supramolecular assemblies by circular dichroism (b). (a) ESI–MS(-) spectrum of the Sb(V)–G hydrogel, registered after dilution in water/methanol. (b) Circular dichroism spectra obtained for G and Sb(V)-G mixture at 1:2 molar ratio, just after heating for 90 min at 60 °C and after cooling at room temperature and for Sb(V)-GMP mixture (1:2 molar ratio) after heating and cooling. Samples were diluted in water at 1 mM of G for measurement. Figures 3a and 3b reprinted from Demicheli et al. (2006) with permission from Elsevier

Fig. 4

Structure of the main species identified in SbL8 by ESI–MS. Figure reprinted from Lanza et al. (2022), in accordance with Creative Commons Attribution 4.0 International

Fig. 5

Characterization of the supramolecular assemblies in SbL8, using atomic force microscopy (AFM) (a, b) and diphenyhexatriene (DPH) fluorescence at equilibrium (c) and after dilution (d). Amplitude AFM images (2 µm) of SbL8 in (a) propylene glycol and (b) PBS 7.2, registered just after deposition and partial drying onto hydrophobic parafilm and cleaved mica, respectively. DPH fluorescence as a function of L8 concentration in SbL8 suspensions in PBS either at pH 5.8 or 7.2, water (pH 5.5), and HCl 0.05 M after incubation for 24 h at 25 °C (c) or after dilution of DPH-loaded SbL8 suspensions at 37 °C in PBS at pH 7.2, 5.8 or 4.5 or HCl 0.05 M, and final L8 concentration of 1 mM (d). In (d), data were fitted according to mono-exponential decay (half-times of DPH release at different pHs are shown in brackets). Figures 5c and 5d were reprinted and minimally adapted from Lanza et al. (2022), in accordance with Creative Commons Attribution 4.0 International

Fig. 6

Accumulation of Sb in the liver of mice 24 h after administration of SbL8 or SbL10 by oral (200 mg Sb/kg) or i.p. (20 mg Sb/kg) route or after Glucantime® i.p. (20 mg Sb/kg). The liver was collected after 24 h, homogenized and digested with nitric acid for subsequent determination of Sb by graphite furnace atomic absorption spectroscopy. Data are shown as medians ± 95% confidence intervals (n = 5). *p < 0.05, **p < 0.01; ***p < 0.001, Kruskal–Wallis followed by Dunn’s multiple comparison test. Figure reprinted and minimally adapted from Lanza et al. (2022) in accordance with Creative Commons Attribution 4.0 International

Fig. 7

Illustration of Sb…O pnictogen bonds (dashed line) in a simple alkoxide complex. Reprinted with permission from Moaven et al. (2017), Copyright 2017 American Chemical Society