Structural characterization by scattering and spectroscopic methods and biological evaluation of polymeric micelles of poloxamines and TPGS as nanocarriers for miltefosine delivery

Abstract

Miltefosine (MF), an alkylphospholipid originally developed for breast cancer treatment, is a highly active drug for the treatment against leishmaniasis, a neglected tropical disease considered the world’s second leading cause of death by a parasitic agent after malaria. MF exhibits dose-limiting gastrointestinal side effects in patients and its penetration through lipophilic barriers is reduced. In this work we propose a reformulation of MF by incorporating the drug to poly(ethylene)oxide (PEO)-based polymeric micelles, specifically, D-α-tocopheryl polyethylene glycol succinate (TPGS) and Tetronic block copolymers (T904 and T1107). A full structural characterization of the aggregates has been carried out by SANS (small-angle neutron scattering) and dynamic light scattering (DLS), in combination with proton 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, to determine the precise location of the drug. The structure of MF micelles has been characterized as a function of the temperature and concentration. In the presence of the block-copolymers, MF forms mixed micelles in a wide range of temperatures, TPGS being the co-surfactant that incorporates more MF unimers. The hydrophobic tail of MF and those of the block copolymers are in close contact within the micelles, which present a core-shell structure with a hydrophilic corona formed by the PEG blocks of the TPGS and the zwitterion head group of the MF. In order to identify the best carrier, the antileishmanicidal activity of MF in the different formulations has been tested on macrophages, promastigotes and intracellular amastigotes. The combination of the three vehicles with MF makes the formulated drug more active than MF alone against L. major promastigotes, however, only the combination with T904 increases the MF activity against intracellular amastigotes. With the aim of exploring gel-based formulations of the drug, the combination of MF and T1107 under gelation conditions has also been investigated.