Single-Molecule Force Probing of RGD-Binding Integrins on Pancreatic Cancer Cells.
Single-Molecule Force Probing of RGD-Binding Integrins on Pancreatic Cancer Cells.
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DOI：
10.1021/acsami.1c23361
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发表时间：
2022-02-16
影响因子：
9.5
通讯作者：
Choi Y
中科院分区：
文献类型：
--
作者：
Alhalhooly L;Confeld MI;Woo SO;Mamnoon B;Jacobson R;Ghosh S;Kim J;Mallik S;Choi Y
整合素靶向的基于精氨酸-甘氨酸-天冬氨酸（RGD）的纳米载体已被广泛用于肿瘤成像、肿瘤发展的监测和抗癌药物的递送。然而，与结合动力学、亲和力和稳定性相关的RGD-整联蛋白形成和解离的热力学仍不清楚。在这里，我们使用单分子结合力光谱方法探测二元复合物与活胰腺癌细胞的结合强度，其中RGD肽通过基于PEG的双功能接头分子在力探针尖端上官能化。虽然细胞表面上整联蛋白αV受体的密度在细胞系之间变化超过两倍，但单个RGD-整联蛋白复合物显示出细胞类型无关的单价键强度。多价RGD-整合素相互作用的负荷依赖性，键强度随着键数的增加呈亚线性缩放，与非合作，平行键模型一致。此外，多价键依次断裂一个或多个，力强度与同步断裂力相当。键数的能量景观的比较显示，多价键的动力学解离速率的大幅度下降，沿着随着势阱宽度的增加和结合态和非结合态之间的势垒高度的增加，增强了它们之间的多价键的稳定性。
Integrin targeting, arginine-glycine-aspartic acid (RGD)-based nanocarriers have been widely used for tumor imaging, the monitoring of tumor development, and the delivery of anti-cancer drugs. However, the thermodynamics of an RGD-integrin formation and dissociation associated with binding dynamics, affinity, and stability remains unclear. Here, we probed the binding strength of the binary complex to live pancreatic cancer cells using single-molecule binding force spectroscopy methods, in which the RGD peptides were functionalized on a force probe tip through the PEG-based bifunctional linker molecules. While the density of integrin αV receptors on the cell surface varies more than two-fold from cell line to cell line, the individual RGD-integrin complexes exhibited a cell type-independent, monovalent bond strength. The load-dependent, bond strength of multivalent RGD-integrin interactions scaled sublinearly with increasing bond number, consistent with the noncooperative, parallel bond model. Furthermore, the multivalent bonds ruptured sequentially either by one or in multiples, and the force strength was comparable with the synchronous rupture force. Comparison of energy landscapes of the bond number revealed a substantial decrease of kinetic off rates for multivalent bonds, along with the increased width of the potential well and the increased potential barrier height between bound and unbound state, enhancing the stability of the multivalent bonds between them.
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影响因子：
4.7
作者：
Mamnoon B;Loganathan J;Confeld MI;De Fonseka N;Feng L;Froberg J;Choi Y;Tuvin DM;Sathish V;Mallik S
通讯作者：
Mallik S
影响因子：
3.4
作者：
Li, FY;Redick, SD;Moy, VT
通讯作者：
Moy, VT
影响因子：
3.4
作者：
Evans, E;Ritchie, K
通讯作者：
Ritchie, K
影响因子：
15
作者：
Gomez-Casado, Alberto;Dam, Henk H.;Huskens, Jurriaan
通讯作者：
Huskens, Jurriaan
影响因子：
17.1
作者：
Carvalho, Filomena A.;Connell, Simon;Santos, Nuno C.
通讯作者：
Santos, Nuno C.