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<p>Glioblastoma (GBM) is a highly lethal disease with limited treatment options due to its infiltrative nature and the lack of efficient therapy able to cross the protective blood-brain barrier (BBB). GBMs are metabolically characterized by increased glycolysis and glutamine dependence. This study explores a novel metabolism-based therapeutic approach using a polyurea generation 4 dendrimer (PURE<sub>G4</sub>) surface functionalized with lactate (LA) (PURE<sub>G4</sub>-LA<sub>24</sub>), to take advantage of glucose-dependent monocarboxylate transporters (MCTs) overexpression, loaded with selenium-chrysin (SeChry) and temozolomide (TMZ) or complexed with anti-glutaminase (<i>GLS1</i>) siRNAs to abrogate glutamine dependence. The nanoparticles (PURE<sub>G4</sub>-LA<sub>24</sub>) were efficient vehicles for cytotoxic compounds delivery, since SeChry@PURE<sub>G4</sub>-LA<sub>24</sub> and TMZ@PURE<sub>G4</sub>-LA<sub>24</sub> induced significant cell death in GBM cell lines, particularly in U251, which exhibits higher MCT1 expression. The anti-<i>GLS1</i> siRNA-dendriplex with PURE<sub>G4</sub>-LA<sub>12</sub> (PURE<sub>G4</sub>-LA<sub>12</sub>-anti-<i>GLS1</i>-siRNA) knocked down <i>GLS1</i> in the GBM cell lines. In two in vitro BBB models, these dendriplexes successfully crossed the BBB, decreased GLS1 expression and altered the exometabolome of GBM cell lines, concomitantly with autophagy activation. Our findings highlight the potential of targeting glucose and glutamine pathways in GBM using dendrimer-based nanocarriers, overcoming the BBB and disrupting key metabolic processes in GBM cells.</p><p></p>

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Lactate-coated polyurea-siRNA dendriplex: a gene therapy-directed and metabolism-based strategy to impair glioblastoma (GBM)

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月27日

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  • Filipa Martins,
  • Renata Arada,
  • Hélio Barros,
  • Paulo Matos,
  • José Ramalho,
  • Valentín Ceña,
  • Vasco D. B. Bonifácio,
  • Luís G. Gonçalves,
  • Jacinta Serpa

摘要

Glioblastoma (GBM) is a highly lethal disease with limited treatment options due to its infiltrative nature and the lack of efficient therapy able to cross the protective blood-brain barrier (BBB). GBMs are metabolically characterized by increased glycolysis and glutamine dependence. This study explores a novel metabolism-based therapeutic approach using a polyurea generation 4 dendrimer (PUREG4) surface functionalized with lactate (LA) (PUREG4-LA24), to take advantage of glucose-dependent monocarboxylate transporters (MCTs) overexpression, loaded with selenium-chrysin (SeChry) and temozolomide (TMZ) or complexed with anti-glutaminase (GLS1) siRNAs to abrogate glutamine dependence. The nanoparticles (PUREG4-LA24) were efficient vehicles for cytotoxic compounds delivery, since SeChry@PUREG4-LA24 and TMZ@PUREG4-LA24 induced significant cell death in GBM cell lines, particularly in U251, which exhibits higher MCT1 expression. The anti-GLS1 siRNA-dendriplex with PUREG4-LA12 (PUREG4-LA12-anti-GLS1-siRNA) knocked down GLS1 in the GBM cell lines. In two in vitro BBB models, these dendriplexes successfully crossed the BBB, decreased GLS1 expression and altered the exometabolome of GBM cell lines, concomitantly with autophagy activation. Our findings highlight the potential of targeting glucose and glutamine pathways in GBM using dendrimer-based nanocarriers, overcoming the BBB and disrupting key metabolic processes in GBM cells.