Yang Guangjie, Gao Hannan, Luo Chuangwei, Zhao Xiaoyu, Luo Qi, Shi Jiyun, Wang Fan
Medical Isotopes Research Center and Department of Radiation Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Pharmaceutics. 2022 Jun 23;14(7):1327. doi: 10.3390/pharmaceutics14071327.
Peptide receptor radionuclide therapy (PRRT) is an emerging approach for patients with unresectable or metastatic tumors. Our previously optimized RGD peptide (3PRGD) has excellent targeting specificity for a variety of integrin αβ/αβ-positive tumors and has been labeled with the therapeutic radionuclide [Lu]LuCl for targeted radiotherapy of tumors. However, the rapid clearance of [Lu]Lu-DOTA-3PRGD (Lu-3PRGD) in vivo requires two doses of 111 MBq/3 mCi to achieve effective tumor suppression, limiting its further clinical application. Albumin binders have been attached to drugs to facilitate binding to albumin in vivo to prolong the drug half-life in plasma and obtain long-term effects. In this study, we modified 3PRGD with albumin-binding palmitic acid (Palm-3PRGD) and then radiolabeled Palm-3PRGD with Lu. [Lu]Lu-DOTA-Palm-3PRGD (Lu-Palm-3PRGD) retained a specific binding affinity for integrin αβ/αβ, with an IC value of 5.13 ± 1.16 nM. Compared with Lu-3PRGD, the Lu-Palm-3PRGD circulation time in blood was more than 6 times longer (slow half-life: 73.42 min versus 11.81 min), and the tumor uptake increased more than fivefold (21.34 ± 4.65 %IA/g and 4.11 ± 0.70 %IA/g at 12 h post-injection). Thus, the significant increase in tumor uptake and tumor retention resulted in enhanced efficacy of targeted radiotherapy, and tumor growth was completely inhibited by a single and relatively lowdose of 18.5 MBq/0.5 mCi. Thus, Lu-Palm-3PRGD shows great potential for clinical application.
肽受体放射性核素治疗（PRRT）是一种针对不可切除或转移性肿瘤患者的新兴治疗方法。我们之前优化的RGD肽（3PRGD）对多种整合素αβ/αβ阳性肿瘤具有优异的靶向特异性，并已用治疗性放射性核素[镥]LuCl进行标记，用于肿瘤的靶向放疗。然而，[镥]Lu-DOTA-3PRGD（Lu-3PRGD）在体内的快速清除需要两剂111 MBq/3 mCi才能实现有效的肿瘤抑制，这限制了其进一步的临床应用。白蛋白结合剂已被连接到药物上，以促进其在体内与白蛋白结合，从而延长药物在血浆中的半衰期并获得长期疗效。在本研究中，我们用结合白蛋白的棕榈酸修饰3PRGD（Palm-3PRGD），然后用镥对Palm-3PRGD进行放射性标记。[镥]Lu-DOTA-Palm-3PRGD（Lu-Palm-3PRGD）对整合素αβ/αβ保留了特异性结合亲和力，IC值为5.13±1.16 nM。与Lu-3PRGD相比，Lu-Palm-3PRGD在血液中的循环时间延长了6倍多（半衰期：73.42分钟对11.81分钟），肿瘤摄取增加了五倍多（注射后12小时时分别为21.34±4.65 %IA/g和4.11±0.70 %IA/g）。因此，肿瘤摄取和肿瘤滞留的显著增加导致靶向放疗疗效增强，单次相对低剂量的18.5 MBq/0.5 mCi即可完全抑制肿瘤生长。因此，Lu-Palm-3PRGD显示出巨大的临床应用潜力。
