胶质母细胞瘤（GBM）是最致命的成人脑癌。目前使用口服替莫唑胺 (TMZ) 的标准护理化疗对患者生存率的改善很差，这强调了对新疗法的迫切需求。一种可能的化疗替代方案是多西他赛 (DTX)，它对 GBM 细胞具有更高的杀肿瘤效力。然而，其有限的血脑屏障（BBB）渗透性限制了其应用。尽管如此，纳米医学为克服这一挑战提供了有希望的途径。 Angiopep-2 (ANG2) 是一种针对 BBB 过度表达的低密度脂蛋白受体 (LDLR) 的肽。在这项工作中，我们首次采用了一种开创性的方法，将玉米醇溶蛋白与聚乙二醇 (PEG) 和 ANG2 共价连接，然后将其配制成纳米颗粒 (ZNP)，分别具有增强的稳定性和 LDLR 介导的脑靶向性。对碳二亚胺和点击化学方法进行了优化，对玉米醇溶蛋白进行了约 25% PEG 的功能修饰，随后对 PEG 进行了近 100% ANG2 的功能修饰。负载 DTX 的 ZNP 平均尺寸为 100 nm，表明非常适合通过受体介导的转胞吞作用进行 BBB 穿越。 ZNP 保持了负载的 DTX 对 GBM 细胞的细胞毒性作用，同时证明了对 BBB 细胞的安全基质。重要的是，这些脑靶向 ZNP 在 BBB 体外模型中表现出高达四倍的血脑通透性增强，凸显了这种 BBB 靶向新方法在显着改善 GBM 患者治疗结果方面的潜力。该系统的多功能性以及显着增加大脑中药物浓度的可能性为其未来在广泛的其他大脑相关疾病中的应用打开了大门。© 2024。作者。

Glioblastoma (GBM) is the deadliest adult brain cancer. The current standard-of-care chemotherapy using orally administered temozolomide (TMZ) presents poor improvement in patient survival, emphasizing the compelling need for new therapies. A possible chemotherapeutic alternative is docetaxel (DTX), which possesses higher tumoricidal potency against GBM cells. However, its limited blood-brain barrier (BBB) permeability poses a constraint on its application. Nonetheless, nanomedicine offers promising avenues for overcoming this challenge. Angiopep-2 (ANG2) is a peptide that targets the BBB-overexpressed low-density lipoprotein receptor (LDLR). In this work, we managed, for the first time, to employ a pioneering approach of covalently linking zein protein with polyethylene glycol (PEG) and ANG2 prior to its formulation into nanoparticles (ZNPs) with enhanced stability and LDLR-mediated brain targetability, respectively. Carbodiimide and click chemistry approaches were optimized, resulting in functional modification of zein with around 25% PEG, followed by functional modification of PEG with nearly 100% ANG2. DTX-loaded ZNPs presented 100 nm average size, indicating high suitability for BBB crossing through receptor-mediated transcytosis. ZNPs maintained the cytotoxic effect of the loaded DTX against GBM cells, while demonstrating a safe matrix against BBB cells. Importantly, these brain-targeted ZNPs showcased up to fourfold enhancement in blood-to-brain permeability in a BBB in vitro model, highlighting the potential of this novel approach of BBB targeting in significantly improving therapeutic outcomes for GBM patients. The versatility of the system and the possibility of significantly increasing drug concentration in the brain open the door to its future application in a wide range of other brain-related diseases.© 2024. The Author(s).