Preliminary Therapy Evaluation of (225)Ac-DOTA-c(RGDyK) Demonstrates that Cerenkov Radiation Derived from (225)Ac Daughter Decay Can Be Detected by Optical Imaging for In Vivo Tumor Visualization.
Preliminary Therapy Evaluation of (225)Ac-DOTA-c(RGDyK) Demonstrates that Cerenkov Radiation Derived from (225)Ac Daughter Decay Can Be Detected by Optical Imaging for In Vivo Tumor Visualization.
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DOI：
10.7150/thno.14338
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发表时间：
2016
期刊：
影响因子：
12.4
通讯作者：
Wadas TJ
中科院分区：
文献类型：
--
作者：
Pandya DN;Hantgan R;Budzevich MM;Kock ND;Morse DL;Batista I;Mintz A;Li KC;Wadas TJ
随着研究人员寻求创新方法来利用这种放射性同位素的核衰变用于治疗和成像应用，基于225 Ac的放射性药物的治疗诊断潜力不断增加。本文描述了225 Ac-DOTA-c（RGDyK）在生物分布和Cerenkov发光成像（CLI）研究中的评价。最初，制备La-DOTA-c（RGDyK）作为非放射性替代物，以评价有助于优化放射化学合成策略的方法，并使用表面等离子体共振光谱法估计放射性缀合物对αvβ3的亲和力。表面等离子体共振光谱研究显示La-DOTA-c（RGDyK）的IC 50和Ki分别为33 ± 13 nM和26 ± 11 nM，并表明La 3+离子与缀合物的络合没有显著改变整联蛋白结合。此外，使用该替代物允许优化放射化学合成策略，以制备具有高放射化学纯度和类似于其他基于225 Ac的放射性药物的比活性的225 Ac-DOTA-c（RGDyK）。这种放射性药物在体外是高度稳定的。体内生物分布研究证实了放射性示踪剂特异性靶向αvβ3整联蛋白的能力;使用Cerenkov发光成像在荷瘤动物中检测到特异性。此外，在U87 mg荷瘤裸鼠中使用无毒剂量的放射性药物实现了肿瘤生长控制。据我们所知，这是第一份使用225 Ac原位衰变产生的子体产物描述活体动物αvβ3+肿瘤的CLI的报告。这一概念有望进一步促进靶向α粒子治疗的发展。
The theranostic potential of 225Ac-based radiopharmaceuticals continues to increase as researchers seek innovative ways to harness the nuclear decay of this radioisotope for therapeutic and imaging applications. This communication describes the evaluation of 225Ac-DOTA-c(RGDyK) in both biodistribution and Cerenkov luminescence imaging (CLI) studies. Initially, La-DOTA-c(RGDyK) was prepared as a non-radioactive surrogate to evaluate methodologies that would contribute to an optimized radiochemical synthetic strategy and estimate the radioactive conjugate's affinity for αvβ3, using surface plasmon resonance spectroscopy. Surface plasmon resonance spectroscopy studies revealed the IC50 and Ki of La-DOTA-c(RGDyK) to be 33 ± 13 nM and 26 ± 11 nM, respectively, and suggest that the complexation of the La3+ ion to the conjugate did not significantly alter integrin binding. Furthermore, use of this surrogate allowed optimization of radiochemical synthesis strategies to prepare 225Ac-DOTA-c(RGDyK) with high radiochemical purity and specific activity similar to other 225Ac-based radiopharmaceuticals. This radiopharmaceutical was highly stable in vitro. In vivo biodistribution studies confirmed the radiotracer's ability to target αvβ3 integrin with specificity; specificity was detected in tumor-bearing animals using Cerenkov luminescence imaging. Furthermore, tumor growth control was achieved using non-toxic doses of the radiopharmaceutical in U87mg tumor-bearing nude mice. To our knowledge, this is the first report to describe the CLI of αvβ3+ tumors in live animals using the daughter products derived from 225Ac decay in situ. This concept holds promise to further enhance development of targeted alpha particle therapy.