Targeting efficiency of RGD-modified nanocarriers with different ligand intervals in response to integrin αvβ3 clustering
Targeting efficiency of RGD-modified nanocarriers with different ligand intervals in response to integrin αvβ3 clustering
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DOI：
10.1016/j.biomaterials.2014.04.031
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发表时间：
2014-07-01
期刊：
影响因子：
14
通讯作者：
Zhang, Qiang
中科院分区：
文献类型：
--
作者：
Guo, Zhaoming;He, Bing;Zhang, Qiang
配体结合引起的受体变化是靶向递送领域面临的新问题。受体聚集是受体变化的主要方式，由于受体位置的重新分布，降低了配体和受体之间的亲和力。为了应对这种挑战，我们设计并构建了三种具有不同配体间隔的RGD修饰的纳米载体：用单体RGD修饰的隐形脂质体（moRGD-LP），二聚体RGD（diRGD-LP）和在两个环状RGD基序之间具有接头的特殊二聚体RGD（P-diRGD-LP）。使用α v β 3阳性和α v β 3阴性肿瘤细胞（黑素瘤B16和MCF-7）作为细胞模型。结果，P-diRGD-LP在表面等离子体共振研究中表现出与B16细胞的最强相互作用，并且在实时共聚焦分析中表现出在B16细胞中的最高细胞摄取。发现P-diRGD-LP的增强的内吞作用是α v β 3介导的，并且P-diRGD-LP增加了网格蛋白依赖性途径的参与。重要的是，在体内和离体近红外荧光图像中，P-diRGD-LP在B16荷瘤小鼠中表现出最佳靶向效果，在3 h时约为moRGD-LP的2.4倍和diRGD-LP的2.8倍。此外，我们通过全内反射荧光显微镜的单分子成像验证了整合素α v β 3在B16细胞上的聚集。最后，α v β 3聚类的3D模型表明受体间隔在41.916-65.779埃内，而分子计算显示diRGD-LP、P-diRGD-LP和moRGD-LP的RGD配体间隔分别为20.944埃、42.753埃和78.196埃，证实了聚类的α v β 3和P-diRGD-LP之间的最佳匹配。综上所述，P-diRGD-LP在更好的配体-受体相容性基础上，通过增强相互作用，实现对ow 133阳性肿瘤的更高靶向性。针对受体聚集的靶向纳米载体的设计可能为基于纳米技术的抗癌治疗提供新的见解。(C)2014爱思唯尔有限公司版权所有。
Receptor change induced by ligand binding is a new issue to face in the field of targeted delivery. Receptor clustering, the main pattern of receptor changes, decreases the affinity between ligand and receptor due to the redistribution of receptor position. In an attempt to respond to such challenge, we designed and constructed three RGD-modified nanocarriers with different ligand intervals: stealth liposomes modified with the monomeric RGD (moRGD-LP), dimeric RGD (diRGD-LP) and a special dimeric RGD with a linker between two cyclic RGD motifs (P-diRGD-LP). The alpha v beta 3-positive and -negative tumor cells (Melanoma B16 and MCF-7) were used as the cell models. As a result, P-diRGD-LP demonstrated strongest interaction with B16 cells in surface plasmon resonance study and highest cellular uptake in B16 cells in real-time confocal analysis. The enhanced endocytosis of P-diRGD-LP was found to be alpha v beta 3-mediated and P-diRGD-LP increased the involvement of the clathrin-dependent pathway. Importantly, P-diRGD-LP demonstrated the best targeting effect in B16-tumor bearing mice in both in vivo and ex vivo near-infrared fluorescent images, about 2.4-fold that of moRGD-LP and 2.8-fold that of diRGD-LP at 3 h. Further, we validated integrin alpha v beta 3 clustering on B16 cells via a single-molecule imaging by a total internal reflection fluorescence microscopy. Finally, the 3D models of alpha v beta 3 clustering suggested a receptor interval within 41.916-65.779 angstrom, while the molecular computation revealed an RGD ligand interval of 20.944 angstrom, 42.753 angstrom and 78.196 angstrom for diRGD-LP, P-diRGD-LP and moRGD-LP, respectively, confirming the best matching between clustered alpha v beta 3 and P-diRGD-LP. In conclusion, P-diRGD-LP could achieve higher targeting to ow133-positive tumor via the enhanced interaction based on the better ligand-receptor compatibility. The design of targeted nanocarriers against receptor clustering might provide new insight into the nanotechnology-based anticancer therapy.(C) 2014 Elsevier Ltd. All rights reserved.