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A two-pronged approach against glioblastoma: drug repurposing and nanoformulation design for in situ-controlled release
Glioblastoma (GB) is one of the most lethal types of neoplasms. Its biologically aggressive nature and the presence of the blood–brain barrier (BBB) limit the efficacy of standard therapies. Several strategies are currently being developed to both overcome the BBB and deliver drugs site specifically...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10624718/ https://www.ncbi.nlm.nih.gov/pubmed/37574500 http://dx.doi.org/10.1007/s13346-023-01379-8 |
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author | Mendes, Maria Branco, Francisco Vitorino, Rui Sousa, João Pais, Alberto Vitorino, Carla |
author_facet | Mendes, Maria Branco, Francisco Vitorino, Rui Sousa, João Pais, Alberto Vitorino, Carla |
author_sort | Mendes, Maria |
collection | PubMed |
description | Glioblastoma (GB) is one of the most lethal types of neoplasms. Its biologically aggressive nature and the presence of the blood–brain barrier (BBB) limit the efficacy of standard therapies. Several strategies are currently being developed to both overcome the BBB and deliver drugs site specifically to tumor cells. This work hypothesizes a two-pronged approach to tackle GB: drug repurposing with celecoxib (CXB) and a nanoformulation using ultra-small nanostructured lipid carriers (usNLCs). CXB antitumor druggable activity was inspected bioinformatically and screened in four glioma cell lines aiming at the comparison with temozolomide (TMZ), as standard of care. Delving into formulation design, it was tailored aiming at (i) improving the drug solubility/loading properties, (ii) assigning a thermal-triggerable drug release based on a lipid matrix with a low melting point, and (iii) enhancing the cytotoxic effect by selecting a template targetable to tumor cells. For this purpose, an integrated analysis of the critical material attributes (CMAs), critical process parameters (CPPs), and critical quality attributes (CQAs) was conducted under the umbrella of a quality by design approach. CMAs that demonstrate a high-risk level for the final quality and performance of the usNLCs include the drug solubility in lipids (solid and liquid), the lipid composition (envisioning a thermoresponsive approach), the ratio between lipids (solid vs. liquid), and the surfactant type and concentration. Particle size was shown to be governed by the interaction lipid-surfactant followed by surfactant type. The drug encapsulation did not influence colloidal characteristics, making it a promising carrier for lipophilic drugs. In general, usNLCs exhibited a controlled drug release during the 72 h at 37 °C with a final release of ca. 25%, while at 45 °C this was doubled. The in vitro cellular performance depended on the surfactant type and lipid composition, with the formulations containing a sole solid lipid (Suppocire(®) NB) and Kolliphor(®) RH40 as surfactant being the most cytotoxic. usNLCs with an average diameter of ca. 70 nm and a narrow size distribution (PdI lower than 0.2) were yielded, exhibiting high stability, drug protection, sustained and thermo-sensitive release properties, and high cytotoxicity to glioma cells, meeting the suitable CQAs for parenteral administration. This formulation may pave the way to a multi-addressable purpose to improve GB treatment. GRAPHICAL ABSTRACT: [Image: see text] |
format | Online Article Text |
id | pubmed-10624718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-106247182023-11-05 A two-pronged approach against glioblastoma: drug repurposing and nanoformulation design for in situ-controlled release Mendes, Maria Branco, Francisco Vitorino, Rui Sousa, João Pais, Alberto Vitorino, Carla Drug Deliv Transl Res Original Article Glioblastoma (GB) is one of the most lethal types of neoplasms. Its biologically aggressive nature and the presence of the blood–brain barrier (BBB) limit the efficacy of standard therapies. Several strategies are currently being developed to both overcome the BBB and deliver drugs site specifically to tumor cells. This work hypothesizes a two-pronged approach to tackle GB: drug repurposing with celecoxib (CXB) and a nanoformulation using ultra-small nanostructured lipid carriers (usNLCs). CXB antitumor druggable activity was inspected bioinformatically and screened in four glioma cell lines aiming at the comparison with temozolomide (TMZ), as standard of care. Delving into formulation design, it was tailored aiming at (i) improving the drug solubility/loading properties, (ii) assigning a thermal-triggerable drug release based on a lipid matrix with a low melting point, and (iii) enhancing the cytotoxic effect by selecting a template targetable to tumor cells. For this purpose, an integrated analysis of the critical material attributes (CMAs), critical process parameters (CPPs), and critical quality attributes (CQAs) was conducted under the umbrella of a quality by design approach. CMAs that demonstrate a high-risk level for the final quality and performance of the usNLCs include the drug solubility in lipids (solid and liquid), the lipid composition (envisioning a thermoresponsive approach), the ratio between lipids (solid vs. liquid), and the surfactant type and concentration. Particle size was shown to be governed by the interaction lipid-surfactant followed by surfactant type. The drug encapsulation did not influence colloidal characteristics, making it a promising carrier for lipophilic drugs. In general, usNLCs exhibited a controlled drug release during the 72 h at 37 °C with a final release of ca. 25%, while at 45 °C this was doubled. The in vitro cellular performance depended on the surfactant type and lipid composition, with the formulations containing a sole solid lipid (Suppocire(®) NB) and Kolliphor(®) RH40 as surfactant being the most cytotoxic. usNLCs with an average diameter of ca. 70 nm and a narrow size distribution (PdI lower than 0.2) were yielded, exhibiting high stability, drug protection, sustained and thermo-sensitive release properties, and high cytotoxicity to glioma cells, meeting the suitable CQAs for parenteral administration. This formulation may pave the way to a multi-addressable purpose to improve GB treatment. GRAPHICAL ABSTRACT: [Image: see text] Springer US 2023-08-13 2023 /pmc/articles/PMC10624718/ /pubmed/37574500 http://dx.doi.org/10.1007/s13346-023-01379-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Mendes, Maria Branco, Francisco Vitorino, Rui Sousa, João Pais, Alberto Vitorino, Carla A two-pronged approach against glioblastoma: drug repurposing and nanoformulation design for in situ-controlled release |
title | A two-pronged approach against glioblastoma: drug repurposing and nanoformulation design for in situ-controlled release |
title_full | A two-pronged approach against glioblastoma: drug repurposing and nanoformulation design for in situ-controlled release |
title_fullStr | A two-pronged approach against glioblastoma: drug repurposing and nanoformulation design for in situ-controlled release |
title_full_unstemmed | A two-pronged approach against glioblastoma: drug repurposing and nanoformulation design for in situ-controlled release |
title_short | A two-pronged approach against glioblastoma: drug repurposing and nanoformulation design for in situ-controlled release |
title_sort | two-pronged approach against glioblastoma: drug repurposing and nanoformulation design for in situ-controlled release |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10624718/ https://www.ncbi.nlm.nih.gov/pubmed/37574500 http://dx.doi.org/10.1007/s13346-023-01379-8 |
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