Metabolic implosion : engineered nanothrapeutics for glioblastoma shutdown (GBMBS)

• Autor(a) principal: Arada, Renata
• Data de Publicação: 2024
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
• Texto Completo: http://hdl.handle.net/10362/174247
• topic: Metabolic implosion; Engineered nanotherapeutics for glioblastoma shutdown; Ciências Médicas

Glioblastoma (GBM) represents one of the most aggressive and treatment-resistant forms of brain cancer, necessitating innovative therapeutic strategies. This study explores the potential of a novel dendrimer-based delivery system PUREG4-LA12 and its siRNA complex (the dendriplex PUREG4-LA12:siRNA – GBMBs), to take advantage of glucose/lactate and glutamine reliance and disrupt GBM metabolic pathways. PUREG4-LA12 is a polyurea dendrimer functionalized with lactic acid to direct GBMBs to monocarboxylate transporters (MCT1 and MCT4). We complexed this dendrimer with an anti-GLS1 siRNA to disturb specifically the glutamine dependency of GBM. The ability of GBMBs to cross the blood-brain barrier (BBB) was also addressed. Using U251 and U-87MG GBM cell lines, we conducted a comprehensive metabolomic analysis to assess the impact of these dendriplexes on cellular metabolism. We first showed that PUREG4-LA24 effectively deliver cytotoxic agents, as selenium-chrysin (SeChry) and temozolomide (TMZ), inducing significant cell death in GBM cell lines, particularly in U251, which exhibits higher MCT1 expression. After confirming that anti-GLS1 siRNAs upon transfection led to GLS1 knockdown and increased cell death, we synthesized the GBMBs (dendriplex with PUREG4-LA12:SIRNA). These GBMBs efficiently delivered the siRNA to the GBM cells, knocking down GLS1. In an in vitro BBB model, these GBMBs successfully crossed the endothelial barrier, leading to a decrease in GLS1 protein levels and alterations in the exometabolome of GBM cell lines. When we added the astrocytes to our BBB model, we also observed a decrease in the levels of GLS1 protein, validating the efficacy of GBMBs. This research highlights the promise of dendrimer-based delivery systems in targeting GBM metabolism and crossing the BBB, paving the way for tailored therapeutic strategies. Future studies should focus on optimizing dendrimer formulations, dosage schedules, and evaluating therapeutic efficacy in in vivo GBM models, as well as exploring combination treatments with a focus on the improvement of clinical outcomes.