Author(s): Martins, Filipa ; Arada, Renata ; Barros, Hélio ; Matos, Paulo ; JS, Ramalho ; Ceña, Valentin ; D. B. Bonifácio, Vasco ; G Goncalves, Luis ; Serpa, Jacinta
Date: 2025
Persistent ID: http://hdl.handle.net/10362/188802
Origin: Repositório Institucional da UNL
Subject(s): Molecular Medicine; Molecular Biology; Cancer Research; SDG 3 - Good Health and Well-being
Funding Information: This work benefited from access to CERMAX, ITQB-NOVA, Oeiras, Portugal with equipment funded by FCT, project AAC 01/SAICT/2016. Funding Information: The institutions are funded by Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia/Minist\u00E9rio da Ci\u00EAncia, Tecnologia e Ensino Superior (FCT/MCTES, Portugal) through national funds to iNOVA4Health (UIDB/04462/2020 and UIDP/04462/2020), to MOSTMICRO-ITQB (UIDB/04612/2020 and UIDP/04612/2020), to BioISI (Center Grant doi 10.54499/UIDB/04046/2020), and the Associated Laboratory LS4FUTURE (LA/P/0087/2020). Filipa Martins was funded by a FCT individual Ph.D. fellowship (2020.04780.BD). Luis G. Gon\u00E7alves was financed by a FCT contract according to DL57/2016, [SFRH/BPD/111100/2015]. Data availability in a public repository is supported by NIH U2C-DK119886 and OT2-OD030544 grants. Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
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. (Figure presented.)
