Glioblastoma (GBM) is an unmet clinical need characterized by a standard of care (SOC) 5-year survival rate of only 5%, and a treatment mostly palliative. Significant hurdles in GBM therapies include an effective penetration of therapeutics through the brain protective barrier, namely the blood–brain barrier (BBB), and a successful therapeutic delivery to brain-invading tumor cells post-BBB crossing. These hurdles, along with the poor prognosis and critical heterogeneity of the disease, have shifted attention to treatment modalities with capacity to precisely and sequentially target (i) BBB cells, inducing blood-to-brain transport, and (ii) GBM cells, leading to a higher therapeutic accumulation at the tumor site. This sequential targeting allows therapeutic molecules to reach the brain parenchyma and compromise molecular processes that support tumor cell invasion. Besides improving formulation and pharmacokinetics constraints of drugs, nanomedicines offer the possibility of being surface functionalized with multiple possibilities of targeting ligands, while delivering the desired therapeutic cargos to the biological sites of interest. Targeting ligands exploit the site-specific expression or overexpression of specific molecules on BBB and GBM cells, triggering brain plus tumor transport. Since the efficacy of single-ligand functionalized nanomedicines is limited due to the GBM anatomical site (brain) and disease complexity, this review presents an overview of multi-ligand functionalized, BBB and GBM sequentially- and dual-targeted nanomedicines reported in literature over the last 10 years. The role of the BBB in GBM progression, treatment options, and the multiple possibilities of currently available targeting ligands will be summarized.

中文翻译：

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胶质母细胞瘤纳米医学领域的多配体功能化血液至肿瘤序贯靶向策略

胶质母细胞瘤 (GBM) 是一种未满足的临床需求，其特征是标准护理 (SOC) 5 年生存率仅为 5%，且治疗大多是姑息性的。GBM 疗法的重大障碍包括治疗药物有效穿透大脑保护屏障，即血脑屏障 (BBB)，以及在 BBB 穿越后成功地将治疗传递到大脑侵袭性肿瘤细胞。这些障碍，加上疾病的不良预后和严重的异质性，已将注意力转移到能够精确、连续地靶向 (i) BBB 细胞，诱导血液到大脑转运，和 (ii) GBM 细胞，导致从而在肿瘤部位获得更高的治疗积累。这种顺序靶向允许治疗分子到达脑实质并损害支持肿瘤细胞侵袭的分子过程。除了改善药物的配方和药代动力学限制之外，纳米药物还提供了通过靶向配体的多种可能性进行表面功能化的可能性，同时将所需的治疗货物递送到感兴趣的生物位点。靶向配体利用 BBB 和 GBM 细胞上特定分子的位点特异性表达或过度表达，触发大脑和肿瘤转运。由于单配体功能化纳米药物的功效因 GBM 解剖部位（大脑）和疾病复杂性而受到限制，本综述概述了文献中报道的多配体功能化、BBB 和 GBM 顺序和双靶向纳米药物。过去10年。将总结 BBB 在 GBM 进展中的作用、治疗方案以及目前可用的靶向配体的多种可能性。