Increased Body Exposure to New Anti-Trypanosomal Through Nanoencapsulation

Renata Tupinambá Branquinho,Margareth Spangler Andrade,José Mário Carneiro Vilela,Matheus Marques Milagre,Gwenaelle Pound-Lana,Dênia Antunes Saúde-Guimarães,Vanessa Carla Furtado Mosqueira,Marta de Lana

doi:10.1038/s41598-017-08469-x

Renata Tupinambá Branquinho, Margareth Spangler Andrade + Show 6 more

Open Access

https://doi.org/10.1038/s41598-017-08469-x

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Abstract

Lychnopholide, a lipophilic sesquiterpene lactone, is efficacious in mice at the acute and chronic phases of Chagas disease. Conventional poly-ε-caprolactone (PCL) and long-circulating poly(D,L-lactide)-block-polyethylene glycol (PLA-PEG) nanocapsules containing lychnopholide were developed and characterized. Lychnopholide presented high association efficiency (>90%) with the nanocapsules. A new, fast and simple HPLC-UV-based bioanalytical method was developed, validated in mouse plasma and applied to lychnopholide quantification in in vitro release kinetics and pharmacokinetics. The nanocapsules had mean hydrodynamic diameters in the range of 100–250 nm, negative zeta potentials (−30 mV to −57 mV), with good physical stability under storage. Atomic force microscopy morphological analysis revealed spherical monodispersed particles and the absence of lychnopholide crystallization or aggregation. Association of lychnopholide to PLA-PEG nanocapsules resulted in a 16-fold increase in body exposure, a 26-fold increase in plasma half-life and a dramatic reduction of the lychnopholide plasma clearance (17-fold) in comparison with free lychnopholide. The improved pharmacokinetic profile of lychnopholide in long-circulating nanocapsules is in agreement with the previously reported improved efficacy observed in Trypanosoma cruzi-infected mice. The present lychnopholide intravenous dosage form showed great potential for further pre-clinical and clinical studies in Chagas disease and cancer therapies.

Highlights

Lychnopholide (LYC) is a lipophilic sesquiterpene lactone isolated from Lychnophora trichocarpha Spreng
Such an accumulation of NC at the site of the parasite infection, which is characterized by leaky endothelium induced by inflammation, may be expected due to the enhanced permeation and retention (EPR) effect[16], whereby PEGylated NC may selectively extravasate from the blood into surrounding inflamed tissues[17]
We developed and validated a simple bioanalytical method based on high performance liquid chromatography with ultraviolet detection (HPLC-UV) for the quantification of LYC in plasma samples, applicable to perform in vitro release kinetic studies and to compare the pharmacokinetics of LYC in mice after intravenous administration of the formulations

Summary

Introduction

Lychnopholide (LYC) is a lipophilic sesquiterpene lactone isolated from Lychnophora trichocarpha Spreng. In its free form and in NC formulation described LYC was able to cure mice experimentally infected with T. cruzi strains sensitive, partially resistant and resistant to benznidazole at the acute[6] and the chronic phases of the disease[6, 7] Such efficacy had never been achieved by any other drug/formulation to date. Long-circulating NC, which are surface-modified with covalently linked hydrophilic chains of polyethylene glycol (PEG) show slower recognition and uptake by phagocytic cells[13] and exhibit longer plasma half-lives after intravenous administration[14] The latter type of NC have higher chances of delivering lipophilic substances such as lychnopholide to the blood trypomastigote parasites that prevail in the acute phase of infection[15]. Such an accumulation of NC at the site of the parasite infection, which is characterized by leaky endothelium induced by inflammation, may be expected due to the enhanced permeation and retention (EPR) effect[16], whereby PEGylated NC may selectively extravasate from the blood into surrounding inflamed tissues[17]

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