Laboratory of Physical Chemistry, Showa Pharmaceutical University, Machida 194-8543, Japan.
Central Institute of Isotope Science, Hokkaido University, Sapporo 060-0815, Japan.
J Med Chem. 2021 Nov 11;64(21):16008-16019. doi: 10.1021/acs.jmedchem.1c01396. Epub 2021 Nov 3.
Multivalent RGD peptides have been used as an excellent targeting vector to integrin αβ-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 of Tc-labeled hexavalent RGD peptides which have (CH-CH-O) ( = 4, [Tc][Tc(L1)] and = 12, [Tc][Tc(L2)]) or (Pro-Gly) ( = 1, [Tc][Tc(L3)]; = 6, [Tc][Tc(L4)]; and = 9, [Tc][Tc(L5)]) as a linker molecule. The results showed that [Tc][Tc(L4)] and [Tc][Tc(L5)] displayed slower dissociation kinetics and [Tc][Tc(L4)] showed exceptionally high cellular 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 (Pro-Gly) would maximize the binding of multivalent RGD peptides to clustered integrin αβ.
多价 RGD 肽已被用作整合素 αβ 阳性肿瘤的优异靶向载体。然而，人们对多价 RGD 肽中连接分子对其与肿瘤细胞解离动力学的影响关注甚少。在这项研究中，我们评估了 Tc 标记的六价 RGD 肽的解离动力学，这些肽具有 (CH-CH-O)（ = 4，[Tc][Tc(L1)]）或 (Pro-Gly)（ = 1，[Tc][Tc(L3)]； = 6，[Tc][Tc(L4)]；和 = 9，[Tc][Tc(L5)]) 作为连接分子。结果表明，[Tc][Tc(L4)]和 [Tc][Tc(L5)] 显示出较慢的解离动力学，而 [Tc][Tc(L4)] 表现出异常高的细胞摄取（203.1 ± 16.7% 剂量/mg 蛋白）和最高的肿瘤与血液比（4 h p.i. 时为 138.1 ± 26.3）在荷瘤裸鼠中。这些发现表明，使用适当长度的 (Pro-Gly) 将最大限度地增加多价 RGD 肽与聚集的整合素 αβ 的结合。
