Mixed micelles and gels of a hydrophilic poloxamine (Tetronic 1307) and miltefosine: Structural characterization by small-angle neutron scattering and in vitro evaluation for the treatment of leishmaniasis
Hypothesis/background: Tetronic is a family of four-armed amphiphilic block copolymers of polyethylene oxide (PEO) and polypropylene oxide (PPO) that self-aggregate to form micelles and hydrogels. Due to their temperature and pH-responsiveness, they are emerging as smart nanomaterials in the area...
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| Format: | info:eu-repo/semantics/article |
| Language: | eng |
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Elsevier
2023
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| Online Access: | https://hdl.handle.net/10171/67907 |
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| author | Dirany, Z. (Zeinab) El-Dirany, R. (Rima) Smith, G.N. (Gregory N.) Nguewa, P.A. (Paul Alain) González-Gaitano, G. (Gustavo) |
| author_facet | Dirany, Z. (Zeinab) El-Dirany, R. (Rima) Smith, G.N. (Gregory N.) Nguewa, P.A. (Paul Alain) González-Gaitano, G. (Gustavo) |
| author_sort | Dirany, Z. (Zeinab) |
| collection | DSpace |
| description | Hypothesis/background: Tetronic is a family of four-armed amphiphilic block copolymers of polyethylene
oxide (PEO) and polypropylene oxide (PPO) that self-aggregate to form micelles and hydrogels. Due to
their temperature and pH-responsiveness, they are emerging as smart nanomaterials in the area of drug
delivery. Here we propose the use of Tetronic 1307 (T1307) as a nanocarrier of miltefosine (MF), a zwitterionic alkylphospholipid highly active against leishmaniasis, one of the most threating neglected tropical diseases. Given the amphiphilic nature of the drug, both surfactants can combine to form mixed
micelles, reducing the cytotoxicity of MF by lowering its dose and improving its internalization, hence
its antileishmanial effect.
Experiments: The structure of the T1307 micelles, MF micelles, mixed micelles and hydrogels, formed in
buffered solution (pH = 7.4) at different concentrations has been investigated in-depth by a combination
of small-angle neutron scattering (SANS), dynamic light scattering (DLS), fluorescence spectroscopy and
nuclear magnetic resonance methods (1D, 2D NOESY, and diffusion NMR). The cytotoxicity of the aggregates in macrophages has been assessed, as well as the antileishmanial activity in both Leishmania major
promastigotes and amastigotes.
Findings: T1307 and MF combine into mixed aggregates over a wide range of temperatures and compositions, forming ellipsoidal core–shell mixed micelles. The shell is highly hydrated and comprises most
of the PEO blocks, while the hydrophobic core contains the PO blocks and the MF along with a fraction of
EO and water molecules, depending on the molar ratio in the mixture. The combination with T1307
amplified the leishmanicidal activity of the drug against both forms of the parasite and dramatically
reduced drug cytotoxicity. T1307 micelles also showed a considerable leishmanicidal activity without
exhibiting macrophage toxicity. These results support the use of T1307 as a MF carrier for the treatment
of human and animal leishmaniasis, in its different clinical forms. |
| format | info:eu-repo/semantics/article |
| id | oai:dadun.unav.edu:10171-67907 |
| institution | Universidad de Navarra |
| language | eng |
| publishDate | 2023 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oai:dadun.unav.edu:10171-679072023-11-27T06:05:59Z Mixed micelles and gels of a hydrophilic poloxamine (Tetronic 1307) and miltefosine: Structural characterization by small-angle neutron scattering and in vitro evaluation for the treatment of leishmaniasis Dirany, Z. (Zeinab) El-Dirany, R. (Rima) Smith, G.N. (Gregory N.) Nguewa, P.A. (Paul Alain) González-Gaitano, G. (Gustavo) Hydrophilic poloxamine Tetronic 1307 Leishmaniasis Hypothesis/background: Tetronic is a family of four-armed amphiphilic block copolymers of polyethylene oxide (PEO) and polypropylene oxide (PPO) that self-aggregate to form micelles and hydrogels. Due to their temperature and pH-responsiveness, they are emerging as smart nanomaterials in the area of drug delivery. Here we propose the use of Tetronic 1307 (T1307) as a nanocarrier of miltefosine (MF), a zwitterionic alkylphospholipid highly active against leishmaniasis, one of the most threating neglected tropical diseases. Given the amphiphilic nature of the drug, both surfactants can combine to form mixed micelles, reducing the cytotoxicity of MF by lowering its dose and improving its internalization, hence its antileishmanial effect. Experiments: The structure of the T1307 micelles, MF micelles, mixed micelles and hydrogels, formed in buffered solution (pH = 7.4) at different concentrations has been investigated in-depth by a combination of small-angle neutron scattering (SANS), dynamic light scattering (DLS), fluorescence spectroscopy and nuclear magnetic resonance methods (1D, 2D NOESY, and diffusion NMR). The cytotoxicity of the aggregates in macrophages has been assessed, as well as the antileishmanial activity in both Leishmania major promastigotes and amastigotes. Findings: T1307 and MF combine into mixed aggregates over a wide range of temperatures and compositions, forming ellipsoidal core–shell mixed micelles. The shell is highly hydrated and comprises most of the PEO blocks, while the hydrophobic core contains the PO blocks and the MF along with a fraction of EO and water molecules, depending on the molar ratio in the mixture. The combination with T1307 amplified the leishmanicidal activity of the drug against both forms of the parasite and dramatically reduced drug cytotoxicity. T1307 micelles also showed a considerable leishmanicidal activity without exhibiting macrophage toxicity. These results support the use of T1307 as a MF carrier for the treatment of human and animal leishmaniasis, in its different clinical forms. 2023-11-21T10:04:04Z 2023-11-21T10:04:04Z 2023 info:eu-repo/semantics/article https://hdl.handle.net/10171/67907 eng info:eu-repo/grantAgreement/AEI/Programa Estatal de I+D+i Orientada a los Retos de la Sociedad/PID2020-112713RB-C21/[ES]/EMBEDDING OF DRUGS IN POLYMERIC FIBERS FOR DERMAL RELEASE: APPLICATION TO THE TREATMENT OF CUTANEOUS LEISHMANIASIS AND SKIN INFECTIONS info:eu-repo/grantAgreement/EC/H2020/654000/EU info:eu-repo/semantics/openAccess application/pdf Elsevier |
| spellingShingle | Hydrophilic poloxamine Tetronic 1307 Leishmaniasis Dirany, Z. (Zeinab) El-Dirany, R. (Rima) Smith, G.N. (Gregory N.) Nguewa, P.A. (Paul Alain) González-Gaitano, G. (Gustavo) Mixed micelles and gels of a hydrophilic poloxamine (Tetronic 1307) and miltefosine: Structural characterization by small-angle neutron scattering and in vitro evaluation for the treatment of leishmaniasis |
| title | Mixed micelles and gels of a hydrophilic poloxamine (Tetronic 1307) and miltefosine: Structural characterization by small-angle neutron scattering and in vitro evaluation for the treatment of leishmaniasis |
| title_full | Mixed micelles and gels of a hydrophilic poloxamine (Tetronic 1307) and miltefosine: Structural characterization by small-angle neutron scattering and in vitro evaluation for the treatment of leishmaniasis |
| title_fullStr | Mixed micelles and gels of a hydrophilic poloxamine (Tetronic 1307) and miltefosine: Structural characterization by small-angle neutron scattering and in vitro evaluation for the treatment of leishmaniasis |
| title_full_unstemmed | Mixed micelles and gels of a hydrophilic poloxamine (Tetronic 1307) and miltefosine: Structural characterization by small-angle neutron scattering and in vitro evaluation for the treatment of leishmaniasis |
| title_short | Mixed micelles and gels of a hydrophilic poloxamine (Tetronic 1307) and miltefosine: Structural characterization by small-angle neutron scattering and in vitro evaluation for the treatment of leishmaniasis |
| title_sort | mixed micelles and gels of a hydrophilic poloxamine (tetronic 1307) and miltefosine: structural characterization by small-angle neutron scattering and in vitro evaluation for the treatment of leishmaniasis |
| topic | Hydrophilic poloxamine Tetronic 1307 Leishmaniasis |
| url | https://hdl.handle.net/10171/67907 |
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