Autor(es): Martins, Filipa ; Arada, Renata ; Barros, Hélio ; Matos, Paulo ; Ramalho, José ; Ceña, Valentín ; Bonifácio, Vasco D.B. ; Gonçalves, Luís G. ; Serpa, Jacinta
Data: 2025
Identificador Persistente: http://hdl.handle.net/10400.18/10601
Origem: Repositório Científico do Instituto Nacional de Saúde
Assunto(s): Glioblastoma; Metabolism; Cancer; Nanoparticles; Vias de Transdução de Sinal e Patologias Associadas
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) surface functionalized with lactate (LA) (PURE-LA), 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 (PURE-LA) were efficient vehicles for cytotoxic compounds delivery, since SeChry@PURE-LA and TMZ@PURE-LA induced significant cell death in GBM cell lines, particularly in U251, which exhibits higher MCT1 expression. The anti-GLS1 siRNA-dendriplex with PURE-LA (PURE-LA-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. PURE-LA-anti-GLS1-siRNA dendriplexes cross the blood-brain barrier (BBB) and impair glioblastoma (GBM) metabolism. The BBB is formed by a thin monolayer of specialized brain microvascular endothelial cells joined together by tight junctions that selectively control the passage of substances from the blood to the brain. It is a major obstacle in the treatment of GBM, since many chemotherapeutic drugs are unable to penetrate the brain. Therefore, we developed a strategy to overcome this obstacle: a lactate-coated polyurea dendrimer generation 4 (PURE) able to cross the BBB in vitro, that act as a nanocarrier of drugs and siRNA to the GBM cells. PURE-LA are nanoparticles functionalized with lactate (LA) to target MCT1, a lactate transporter highly expressed by GBM cells. Moreover, a complex of this nanoparticle with anti-GLS1 (glutaminase) siRNA (PURE-LA-anti-GLS1-siRNA) was made, to target glutamine metabolism. It efficiently knocked down GLS1. Moreover, PURE-LA loaded with SeChry led to BBB disruption.
