Design of a Tetravalent RGD Peptide Capable of Simultaneous Binding with Multiple Integrin αvβ3 for Targeted Radionuclide Therapy

For targeted radionuclide therapy, radioligands that exhibit high and persistent tumor uptake are indispensable. We previously synthesized a 99mTc-labeled hexavalent RGD peptide (99mTc-(RGD)6) as a tumor imaging agent targeting integrin αvβ3. 99mTc-(RGD)6 showed high in vivo tumor uptake with long retention due to simultaneous binding to multiple integrin αvβ3 receptors. The purpose of this study was to apply this finding to the design of a multivalent RGD peptide labeled with 211At, a promising α-emitting radionuclide for radionuclide therapy. As a candidate compound, a tetravalent RGD peptide (H2N-(RGD)4) was synthesized and radiolabeled with 125I, a homologous element of At, for basic studies. As expected, 125I-(RGD)4 retained the capability of simultaneous binding and showed comparable in vivo tumor uptake to 99mTc-(RGD)6. Finally, 211At-(RGD)4 was synthesized with >95% radiochemical purity and exhibited an almost identical biodistribution pattern to 125I-(RGD)4. These results indicate that 211At-(RGD)4 might be a potential radioligand for integrin αvβ3-targeted radionuclide therapy.针对靶向放射性核素治疗（targeted radionuclide therapy）而言，具备高肿瘤摄取能力且持续滞留的放射性配体（radioligand）是不可或缺的。本课题组此前已合成一种经99mTc标记的六价RGD肽（99mTc-(RGD)6），作为靶向整合素αvβ3（integrin αvβ3）的肿瘤显像剂。99mTc-(RGD)6可通过同时结合多个整合素αvβ3受体，实现体内高肿瘤摄取与长时滞留效果。本研究旨在将上述发现应用于经211At标记的多价RGD肽的设计中：211At是一种极具应用前景的发射α粒子的放射性核素（α-emitting radionuclide），适用于放射性核素治疗。作为候选化合物，我们合成了四价RGD肽（H2N-(RGD)4），并以砹的同系元素125I对其进行放射性标记，以开展基础研究。如预期一致，125I-(RGD)4保留了同时结合受体的能力，其体内肿瘤摄取效果与99mTc-(RGD)6相当。最终，我们合成了放射化学纯度（radiochemical purity）>95%的211At-(RGD)4，其生物分布（biodistribution）特征与125I-(RGD)4几乎完全一致。上述结果表明，211At-(RGD)4有望成为靶向整合素αvβ3的放射性核素治疗用放射性配体。