The effects of ligand valency and density on the targeting ability of multivalent nanoparticles based on negatively charged chitosan nanoparticles
The effects of ligand valency and density on the targeting ability of multivalent nanoparticles based on negatively charged chitosan nanoparticles
复制标题
配体价态和密度对基于带负电壳聚糖纳米颗粒的多价纳米颗粒靶向能力的影响
DOI：
10.1016/j.colsurfb.2017.11.015
复制
发表时间：
2018-01-01
影响因子：
5.8
通讯作者：
Yuan, Zhi
中科院分区：
文献类型：
--
作者：
Cao, Jing;Zhang, Yahui;Yuan, Zhi
已经表明，与单价配体相比，多价配体可以显著增强结合亲合力;因此，一旦掺入纳米颗粒中，它们促进上级靶向能力而不增加配体密度。虽然配体的价态和密度对相应纳米颗粒的靶向能力起着关键作用，但这些因素在很大程度上尚未探索，缺乏详细的研究。本文中，通过将不同拷贝的叶酸配体与聚（丙烯酸）（PAA）缀合，已经方便地合成了一系列具有一定化合价（FA，n表示配体的化合价：n =3，5，7）的多价配体。带负电荷的壳聚糖纳米颗粒（CTS-SA NPs）由于能够在不干扰多价配体靶向能力的情况下强烈抑制非特异性蛋白质吸附和细胞摄取而被用作合适的多价平台。随后，使用不同量的FA（n）修饰CTS-SA NP的结构以形成具有各种化合价和密度的多价纳米颗粒（FA（n）-CTS-SA NP）。对它们的一系列具体研究表明，即使在相似的配体密度下，多价纳米颗粒的细胞摄取也随着配体价态的变化而变化;即使在相同的配体价态下，也随着配体密度的变化而变化。本研究中确定的中间价和密度值（即，5和2.4重量%）提供了最好的细胞摄取，在相对低的配体化合价和密度下促进了上级靶向能力。出乎意料的是，在使用单一抑制剂的内吞抑制测定期间没有观察到明显差异，这可能归因于多价纳米颗粒的多个途径的协同内吞机制。最佳的多价纳米颗粒也表现出优异的生物相容性，体外长期稳定性和体内循环时间延长，从而证明了它们在靶向药物递送方面的潜力。(C)2017 Elsevier B. V.版权所有。
It has been shown that multivalent ligands could significantly enhance the binding avidity compared with the monovalent ones; therefore, once incorporated into nanoparticles, they promote superior targeting ability without increasing the ligand density. Although ligand valency and density play a key role on the targeting ability of corresponding nanoparticles, these facotrs remain largely unexplored and detailed studies are lacking. Herein, a series of multivalent ligands with certain valencies (FA,,, n indicates the valency of ligand: n =3, 5, 7) has been conveniently synthesized by conjugating different copies of folate ligands with poly(acrylic acid) (PAA). Negatively charged chitosan nanoparticles (CTS-SA NPs) have been utilized as proper multivalent platforms because they can strongly suppress non-specific protein adsorption and cellular uptake without interfering with the targeting ability of multivalent ligands. Subsequently, the structure of CTS-SA NPs has been modified using different amounts of FA(n) to form multivalent nanoparticles (FA(n)-CTS-SA NPs) with various valencies and densities. A series of specific investigations of them suggested that the cellular uptake of multivalent nanoparticles has largely varied with the ligand valency variation even at similar ligand densities; and also largely varied with ligand density variation even at the same ligand valencies. The intermediate valency and density values determined in the current study (ie., 5 and 2.4 wt%, respectively) have provided the best cellular uptake, facilitating superior targeting ability at relatively low ligand valency and density. Unexpectedly, no conspicuous difference has been observed during endocytotic inhibition assays with single inhibitors, which may be attributed to the synergetic endocytotic mechanism with multiple pathways of multivalent nanoparticles. The optimal multivalent nanoparticles have also exhibited excellent biocompatibility, long-term stability in vitro and enhanced circulation time in vivo, thus demonstrating their potential for targeted drug delivery. (C) 2017 Elsevier B.V. All rights reserved.