Key Laboratory of Functional Polymer Materials of the Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.
Nanoscale. 2019 Mar 14;11(11):5005-5013. doi: 10.1039/c8nr09347d.
It is acknowledged that the targeting ability of multivalent ligand-modified nanoparticles (MLNs) strongly depends on the ligand spatial presentation determined by ligand valency. However, the receptor overexpression level varies between different types or stages of tumors. Thus, it is essential to explore the influence of ligand valency on the targeting ability of MLNs to tumors with different levels of receptor overexpression. In this study, a dual-acting agent raltitrexed was used as a ligand to target the folate receptor (FR). Different copies of the raltitrexed-modified multivalent dendritic polyethyleneimine ligand cluster PRn (n = 2, 4, and 8) were conjugated onto magnetic nanoparticles to form multivalent magnetic NPs (MMNs) with different valences. The in vitro studies demonstrated that Fe-PR4 was the most effective valency in the treatment of high FR overexpressing KB cells with a decentralized receptor distribution, owing to the fact that Fe-PR2 was negative in statistical rebinding and Fe-PR8 could induce steric hindrance in the limited binding area. Instead, in moderate FR overexpressing HeLa cells with clustered receptor display, the extra ligands on Fe-PR8 would facilitate statistical rebinding more beneficially. Furthermore, in in vivo tumor inhibition and targeted magnetic resonance imaging (MRI) of KB tumors and another moderate FR expressing H22 tumor, similar results were obtained with the cell experiments. Overall, the optimizable treatment effect of Fe-PRn by modulating the ligand valency based on the overexpressing tumor receptor distribution behavior supports the potential of Fe-PRn as a nanomedicine for personalized theranostics.
人们认识到，多价配体修饰纳米粒子（MLNs）的靶向能力强烈依赖于配体空间呈现，而配体空间呈现由配体价数决定。然而，不同类型或不同阶段的肿瘤中，受体的过表达水平存在差异。因此，探索配体价数对具有不同受体过表达水平的肿瘤中 MLNs 的靶向能力的影响至关重要。在本研究中，使用双功能药物雷替曲塞（raltitrexed）作为配体来靶向叶酸受体（FR）。将不同数量的雷替曲塞修饰的多价树枝状聚乙烯亚胺配体簇 PRn（n = 2、4 和 8）连接到磁性纳米颗粒上，形成具有不同价数的多价磁性 NPs（MMNs）。体外研究表明，对于 FR 过表达、受体分布分散的 KB 细胞，Fe-PR4 是最有效的价数，这是因为 Fe-PR2 在统计学上的再结合呈阴性，而 Fe-PR8 会在有限的结合区域中产生空间位阻。相反，在 FR 中度过表达、受体呈聚集分布的 HeLa 细胞中，Fe-PR8 上的额外配体更有利于统计学上的再结合，从而带来更好的治疗效果。此外，在 KB 肿瘤和另一个中度 FR 表达的 H22 肿瘤的体内肿瘤抑制和靶向磁共振成像（MRI）实验中，也得到了与细胞实验类似的结果。总的来说，根据过表达肿瘤受体分布行为，通过调节配体价数优化 Fe-PRn 的治疗效果，支持了 Fe-PRn 作为一种用于个体化治疗的纳米医学的潜力。
