用聚乙烯甘油和Angiopep-2的Zein化学工程制造以脑靶向多西他赛纳米医学的生产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
影响因子:5.50000
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
摘要
胶质母细胞瘤（GBM）是最致命的成人脑癌。当前使用口服替莫唑胺（TMZ）的现行标准化疗表明，患者生存率的改善不佳，强调了对新疗法的迫切需求。可能的化学治疗替代方法是多西他赛（DTX），它具有较高的对GBM细胞的肿瘤效力。但是，其血脑屏障有限（BBB）的渗透性对其应用构成了限制。尽管如此，纳米医学提供了克服这一挑战的有希望的途径。 AngiOpep-2（ANG2）是一种靶向BBB过表达的低密度脂蛋白受体（LDLR）的肽。在这项工作中，我们首次管理了一种先驱方法，即在将锌蛋白与聚乙烯乙二醇（PEG）（PEG）和ANG2的配方过程中分别为纳米颗粒（ZNP）（分别具有增强的稳定性和LDLR介导的脑靶标）。优化了Carbodiimide和Click Chemistry方法，导致Zein的功能修饰，大约25％PEG，然后用近100％ANG2对PEG进行功能修饰。载有DTX的ZNP的平均大小为100 nm，表明通过受体介导的转胞细胞增多的BBB穿越高度适合。 ZNP保持了负载DTX对GBM细胞的细胞毒性作用，同时证明了针对BBB细胞的安全基质。重要的是，这些针对大脑的ZNP在BBB的体外模型中显示出多达四倍的血液渗透性增强，强调了BBB靶向这种新型方法在显着改善GBM患者治疗结果方面的潜力。该系统的多功能性以及大脑中的药物浓度显着增加的可能性打开了其未来在其他与大脑有关的疾病中的应用。
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.