Combating Glioblastoma by Codelivering the Small-Molecule Inhibitor of STAT3 and STAT3siRNA with α5ß1 Integrin Receptor-Selective Liposomes.
Mol Pharm
; 17(6): 1859-1874, 2020 06 01.
Article
em En
| MEDLINE
| ID: mdl-32343904
ABSTRACT
Glioblastoma multiforme (GBM) is one of the most aggressive tumors with a median survival of only 15 months. Effective therapeutics need to overcome the formidable challenge of crossing the blood-brain barrier (BBB). Receptors and transporters overexpressed on BCECs are being used for designing liposomes, polymers, polymeric micelles, peptides, and dendrimer-based drug carriers for combating brain tumors. Herein, using the orthotopic mouse glioblastoma model, we show that codelivering a small-molecule inhibitor of the JAK/STAT pathway (WP1066) and STAT3siRNA with nanometric (100-150 nm) α5ß1 integrin receptor-selective liposomes of RGDK-lipopeptide holds therapeutic promise in combating glioblastoma. Rh-PE (red)-labeled liposomes of RGDK-lipopeptide were found to be internalized in GL261 cells via integrin α5ß1 receptors. Intravenously administered near-infrared (NIR)-dye-labeled α5ß1 integrin receptor-selective liposomes of RGDK-lipopeptide were found to be accumulated preferentially in the mouse brain tumor tissue. Importantly, we show that iv injection of WP1066 (a commercially sold small-molecule inhibitor of the JAK/STAT pathway) and STAT3siRNA cosolubilized within the liposomes of RGDK-lipopeptide leads to significant inhibition (>350% compared to the untreated mice group) of orthotopically growing mouse glioblastoma. The present strategy may find future use in combating GBM.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Glioblastoma
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RNA Interferente Pequeno
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Fator de Transcrição STAT3
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article