目的:我们使用RGD肽([67Ga]Ga-DOTA-c[RGDf(4-I)K]([67Ga]1)和Ga-DOTA-[211At]c[RGDf(4-At)K]([211At]2))开发了用于临床应用的多放射性核素放射疗法的探针。白蛋白结合部分(ABM)的引入,如4-(4-碘苯基)-丁酸(IPBA),与血白蛋白有很高的亲和力,延长循环半衰期,可以改善药物的药代动力学。为了进行更有效的靶向α治疗(TAT),我们设计并合成了Ga-DOTA-K([211At]APBA)-c(RGDfK)([211At]5)与4-(4-苯甲酰)-丁酸(APBA),在IPBA中具有astato基团而不是碘基团。我们评估了APBA是否作为ABM和[211At]5对TAT有效。此外,我们制备了没有ABM的67Ga标记的RGD肽,[67Ga]Ga-DOTA-K-c(RGDfK)([67Ga]3),和125I标记的RGD肽与ABM,Ga-DOTA-K([125I]IPBA)-c(RGDfK)([125I]4),与[211At]5相比。
方法:没有ABM的[67Ga]3的生物分布实验,在正常小鼠和U-87MG荷瘤小鼠中使用ABM进行[125I]4和[211At]5。此外,向U-87MG荷瘤小鼠施用两个剂量的[211At]5(370或925kBq)以确认治疗效果。
结果:与[67Ga]3相比,[125I]4和[211At]5的血液保留显着增加。此外,与[67Ga]3相比,[125I]4和[211At]5显示出相似的生物分布以及明显更大的肿瘤积累和保留。此外,[211At]5以剂量依赖性方式抑制肿瘤生长。
结论:APBA作为ABM的功能与IPBA一样,并揭示了[211At]5作为TAT的放射性核素治疗剂的有用性。
OBJECTIVE: We have developed probes for multiradionuclides radiotheranostics using RGD peptide ([67Ga]Ga-DOTA-c[RGDf(4-I)K] ([67Ga]1) and Ga-DOTA-[211At]c[RGDf(4-At)K] ([211At]2)) for clinical applications. The introduction of an albumin binding moiety (ABM), such as 4-(4-iodophenyl)-butyric acid (IPBA), that has high affinity with the blood albumin and prolongs the circulation half-life can improve the pharmacokinetics of drugs. To perform more effective targeted alpha therapy (TAT), we designed and synthesized Ga-DOTA-K([211At]APBA)-c(RGDfK) ([211At]5) with 4-(4-astatophenyl)-butyric acid (APBA), which has an astato group instead of an iodo group in IPBA. We evaluated whether APBA functions as ABM and [211At]5 is effective for TAT. In addition, we prepared 67Ga-labeled RGD peptide without ABM, [67Ga]Ga-DOTA-K-c(RGDfK) ([67Ga]3), and 125I-labeled RGD peptide with ABM, Ga-DOTA-K([125I]IPBA)-c(RGDfK) ([125I]4), to compare with [211At]5.
METHODS: Biodistribution experiments of [67Ga]3 without ABM, [125I]4 and [211At]5 with ABM were conducted in normal mice and U-87 MG tumor-bearing mice. In addition, two doses of [211At]5 (370 or 925 kBq) were administered to U-87 MG tumor-bearing mice to confirm the therapeutic effects.
RESULTS: The blood retention of [125I]4 and [211At]5 was remarkably increased compared to [67Ga]3. Also, [125I]4 and [211At]5 showed similar biodistribution and significantly greater tumor accumulation and retention compared to [67Ga]3. In addition, [211At]5 inhibited tumor growth in a dose-dependent manner.
CONCLUSIONS: The functionality of APBA as ABM like IPBA, and the usefulness of [211At]5 as the radionuclide therapy agent for TAT was revealed.