Influence of Linker Molecules in Hexavalent RGD Peptides on Their Multivalent Interactions with Integrin αvβ3
Influence of Linker Molecules in Hexavalent RGD Peptides on Their Multivalent Interactions with Integrin αvβ3
复制标题
六价 RGD 肽中连接分子对其与整合素 αvβ3 多价相互作用的影响
DOI：
10.1021/acs.jmedchem.1c01396
复制
发表时间：
2021
影响因子：
7.3
通讯作者：
Akizawa Hiromichi
中科院分区：
文献类型：
--
作者：
Mizuno Yuki;Kimura Kohta;Onoe Satoru;Shukuri Miho;Kuge Yuji;Akizawa Hiromichi
多价 RGD 肽已被用作整合素 αvβ3 阳性肿瘤的优异靶向载体。然而，很少有人关注多价 RGD 肽中的连接分子对其从肿瘤细胞解离动力学的影响。在这项研究中，我们评估了 99mTc 标记的六价 RGD 肽的解离动力学，这些肽具有 (CH2-CH2-O)n(n= 4、[99mTc][Tc(L1)6]+andn= 12、[99mTc][Tc(L2)6]+) 或 (DPro-Gly)n(n= 1， [99mTc][Tc(L3)6]+;n= 6, [99mTc][Tc(L4)6]+; andn= 9, [99mTc][Tc(L5)6]+) 作为连接分子。结果显示，[99mTc][Tc(L4)6]+ 和 [99mTc][Tc(L5)6]+ 显示出较慢的解离动力学，而 [99mTc][Tc(L4)6]+ 显示出异常高的体外细胞摄取（203.1 ± 16.7% 剂量/mg 蛋白质）和最高的肿瘤与血液比率（4 时为 138.1 ± 26.3）。 h p.i.）在荷瘤裸鼠中。这些发现表明，使用适当长度的 (DPro-Gly)n 可以最大限度地提高多价 RGD 肽与聚集的整联蛋白 αvβ3 的结合。
Multivalent RGD peptides have been used as an excellent targeting vector to integrin αvβ3-positive tumors. However, little attention has been paid to the influence of linker molecules in multivalent RGD peptides on their dissociation kinetics from tumor cells. In this study, we evaluated the dissociation kinetics of99mTc-labeled hexavalent RGD peptides which have (CH2-CH2-O)n(n= 4, [99mTc][Tc(L1)6]+andn= 12, [99mTc][Tc(L2)6]+) or (DPro-Gly)n(n= 1, [99mTc][Tc(L3)6]+;n= 6, [99mTc][Tc(L4)6]+; andn= 9, [99mTc][Tc(L5)6]+) as a linker molecule. The results showed that [99mTc][Tc(L4)6]+and [99mTc][Tc(L5)6]+displayed slower dissociation kinetics and [99mTc][Tc(L4)6]+showed exceptionally highin vitrocellular uptake (203.1 ± 16.7% dose/mg protein) and the highest tumor to blood ratio (138.1 ± 26.3 at 4 h p.i.) in tumor bearing nude mice. These findings indicate that the use of appropriate length of (DPro-Gly)nwould maximize the binding of multivalent RGD peptides to clustered integrin αvβ3.