Structure and activity of amphiphilic PEO-PPO-based polymeric micelles and gels incorporating host–guest complexes of miltefosine as novel formulations for the treatment of leishmaniasis

Hypothesis: Poloxamines are amphiphilic block copolymers that self-assemble forming polymeric micelles (PMs) and hydrogels. They have emerged as promising colloidal carriers for their potential in improving drug delivery and controlled release through their multi-responsive properties. Tetronic® 1307 (T1307) PMs and gels have been used herein to incorporate host–guest complexes of cyclodextrins (CDs) and miltefosine (MF), an amphiphilic, anti-parasitic drug effective against leishmaniasis. Experiments: The association of MF to αCD, βCD, and HPβCD and the topology of the complexes have been fully characterized by NMR spectroscopy. Then, the structure of the complex-loaded PMs and hydrogels investigated using diffusion nuclear magnetic resonance (DOSY), small angle neutron scattering (SANS), and dynamic light scattering (DLS). The antileishmanial activity of the constructs was evaluated against Leishmania major promastigotes and amastigotes, as well as their cytotoxicity in macrophages. Findings: All the CDs form highly stable inclusion complexes with MF in a 2CD:1MF stoichiometry that allow the existence of considerable proportions of complexed drug at high dilution, the HPβCD providing the highest stability and compatibility with the poloxamine. The complex incorporates preferentially into the hydrophilic shell of the PMs, inducing the elongation of the aggregates and the dehydration of the micellar core, formed mainly by the PPO blocks. At high concentrations and physiological temperature, the complex-loaded PMs pack in a BCC-type paracrystal network. The micellar formulations of the CD-complexed MF reduced the cytotoxicity of the drug, while improving its antileishmanial activity. This approach would improve the treatment, facilitating the administration of MF at lower concentrations and achieving relevant therapeutic effects, not only through the intravenous route, but also by topical formulations as injectable thermogels for the cure of cutaneous and mucocutaneous forms of the disease.