文章：

乳酸包覆聚脲-siRNA树状复合物：一种基于基因治疗与代谢策略靶向胶质母细胞瘤（GBM）的方法

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

原文发布日期：2025-04-27 

英文摘要：

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. PUREG4-LA12-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 (PUREG4) able to cross the BBB in vitro, that act as a nanocarrier of drugs and siRNA to the GBM cells. PUREG4-LA12 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 (PUREG4-LA12-anti-GLS1-siRNA) was made, to target glutamine metabolism. It efficiently knocked down GLS1. Moreover, PUREG4-LA24 loaded with SeChry led to BBB disruption. 

摘要翻译： 

胶质母细胞瘤（GBM）是一种高致死性疾病，由于其浸润性特性及缺乏能跨越保护性血脑屏障（BBB）的有效疗法，治疗选择十分有限。GBM的代谢特征表现为糖酵解增强和谷氨酰胺依赖性。本研究探索了一种基于代谢的新型治疗策略：使用表面经乳酸（LA）功能化的第四代聚脲树枝状聚合物（PUREG4-LA24），利用葡萄糖依赖性单羧酸转运体（MCTs）过表达的特性，负载硒-芹菜素（SeChry）和替莫唑胺（TMZ）或复合抗谷氨酰胺酶（GLS1）siRNA以消除谷氨酰胺依赖性。纳米颗粒（PUREG4-LA24）作为细胞毒性化合物的高效递送载体，SeChry@PUREG4-LA24和TMZ@PUREG4-LA24在GBM细胞系（尤其是MCT1高表达的U251细胞）中诱导了显著细胞死亡。PUREG4-LA12与抗GLS1 siRNA形成的树枝状复合物（PUREG4-LA12-anti-GLS1-siRNA）可敲低GBM细胞系中的GLS1表达。在两种体外BBB模型中，这些树枝状复合物成功跨越BBB，降低GLS1表达并改变GBM细胞系的外代谢组，同时激活自噬。我们的研究结果凸显了基于树枝状聚合物的纳米载体靶向GBM葡萄糖和谷氨酰胺代谢通路的潜力，既能克服血脑屏障障碍，又能破坏GBM细胞的关键代谢过程。

PUREG4-LA12-抗GLS1-siRNA树枝状复合物可跨越血脑屏障（BBB）并破坏胶质母细胞瘤（GBM）代谢。BBB由特化的脑微血管内皮细胞通过紧密连接形成的单薄单层结构构成，能选择性控制物质从血液到大脑的传输。由于许多化疗药物无法穿透大脑，它成为GBM治疗的主要障碍。因此我们开发了一种突破该屏障的策略：采用乳酸包被的第四代聚脲树枝状聚合物（PUREG4），该载体能在体外跨越BBB，作为向GBM细胞递送药物和siRNA的纳米载体。PUREG4-LA12是通过乳酸（LA）功能化的纳米颗粒，可靶向GBM细胞高表达的乳酸转运体MCT1。此外，该纳米颗粒与抗GLS1（谷氨酰胺酶）siRNA形成的复合物（PUREG4-LA12-抗GLS1-siRNA）可靶向谷氨酰胺代谢，有效敲低GLS1表达。同时，负载SeChry的PUREG4-LA24可导致血脑屏障通透性增加。

原文链接：

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