利用聚乙二醇和Angiopep-2对玉米蛋白（zein）进行化学工程，制造靶向脑部的多西他赛纳米药物用于胶质母细胞瘤治疗
Chemical engineering of zein with polyethylene glycol and Angiopep-2 to manufacture a brain-targeted docetaxel nanomedicine for glioblastoma treatment
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影响因子:5.5
分区:医学3区 / 医学：研究与实验3区 药学3区
发表日期:2024 Dec
作者:
Seem Awad, Marco Araújo, Paulo Faria, Bruno Sarmento, Cláudia Martins
DOI:
10.1007/s13346-024-01659-x
摘要
胶质母细胞瘤（GBM）是成人中最致命的脑肿瘤。目前标准化的口服化疗药物替莫唑胺（TMZ）对患者存活率的改善有限，强调迫切需要新型疗法。另一种潜在的化疗替代药物是多西他赛（DTX），其对GBM细胞具有更强的细胞毒性。然而，其血脑屏障（BBB）穿透能力有限，限制了其应用。纳米药物提供了克服这一挑战的有希望途径。Angiopep-2（ANG2）是一种靶向BBB上过表达的低密度脂蛋白受体（LDLR）的肽。本研究首次采用创新方法，将玉米蛋白（zein）与聚乙二醇（PEG）和ANG2共价连接，然后制备成具有增强稳定性和LDLR介导的脑靶向性的纳米粒（ZNPs）。优化了羧基偶联和点击化学方法，实现了约25%的PEG修饰的玉米蛋白，随后几乎100%的ANG2修饰了PEG。载有DTX的ZNPs平均粒径为100 nm，表明其高度适合通过受体介导的转胞作用穿越BBB。ZNPs保持了载药DTX对GBM细胞的细胞毒性，同时对BBB细胞表现出安全性。重要的是，这些靶向脑的ZNPs在BBB体外模型中血-脑渗透率提高了四倍，显示出这种新型BBB靶向策略在显著改善GBM患者治疗效果方面的潜力。系统的多功能性和显著增加药物在脑中的浓度，为其在其他脑部疾病中的未来应用打开了大门。
Abstract
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.