Two 90Y-Labeled Multimeric RGD Peptides RGD4 and 3PRGD2 for Integrin Targeted Radionuclide Therapy
Two 90Y-Labeled Multimeric RGD Peptides RGD4 and 3PRGD2 for Integrin Targeted Radionuclide Therapy
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用于整合素靶向放射性核素治疗的两种 90Y 标记的多聚体 RGD 肽 RGD4 和 3PRGD2
DOI：
10.1021/mp100403y
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发表时间：
2011-03-01
影响因子：
4.9
通讯作者：
Wang, Fan
中科院分区：
文献类型：
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作者：
Liu, Zhaofei;Shi, Jiyun;Wang, Fan
我们最近开发了一系列新的Arg-Gly-Asp（RGD）二聚体肽，用于特异性靶向整合素α（v）β（3），具有增强的肿瘤摄取和改善的药代动力学。在这项研究中，我们研究了Y-90标记的RGD四聚体（RGD 4）和新型RGD二聚体（3 PRGD 2），用于整合素α（v）β（3）阳性肿瘤的放射性核素治疗。对In-111标记的RGD 4和3 PRGD 2进行了生物分布和γ显像研究。使用裸鼠组来确定Y-90-D 0 TA-RGD 4和Y-90-D 0 TA-3 PRGD 2的最大耐受剂量（MTD）。在荷U87 MG瘤裸鼠中评价了Y-90-DOTA-RGD 4和90 Y-DOTA-3 PRGD 2的放射性核素治疗效果。In-111-DOTA-3 PRGD 2的U87 MG肿瘤摄取略低于In-111-DOTA-RGD 4的摄取（例如，6.13+/- 0.82%ID/g对比注射后4小时的6.43 +/- 1.6%ID/g），但In-111-DOTA-3 PRGD 2在正常器官（如肝脏和肾脏）中的摄取远低于In-111-DOTA-RGD 4，这导致高得多的肿瘤与非肿瘤比率和低得多的毒性。Y-90-DOTA-RGD 4在裸鼠中的MTD小于44.4MBq，而Y-90-DOTA-3 PRGD 2在小鼠中的MTD大于55.5MBq。Y-90-DOTA-3 PRGD 2给药与相同剂量的Y-90-DOTA-RGD 4相比显示出相似的肿瘤抑制效果。Y-90-D 0 TA-3 PRGD 2治疗组中的肿瘤脉管系统比对照组少得多。放射性核素治疗研究表明，Y-90-DOTA-RGD 4和Y-90-DOTA-3 PRGD 2在U87 MG肿瘤模型中均引起显著的肿瘤生长延迟。与Y-90-DOTA-RGD 4相比，Y-90-DOTA-3 PRGD 2在正常器官中的低蓄积导致在裸鼠中的较低毒性和较高MTD，这将使其更适合于高剂量或多次给药方案，以达到最大治疗功效。
We have recently developed a series of new Arg-Gly-Asp (RGD) dimeric peptides for specific targeting of integrin alpha(v)beta(3) with enhanced tumor uptake and improved pharmacokinetics. In this study, we investigated Y-90-labeled RGD tetramer (RGD4) and the new type of RGD dimer (3PRGD2), for the radionuclide therapy of integrin alpha(v)beta(3)-positive tumors. Biodistribution and gamma imaging studies of In-111 labeled RGD4 and 3PRGD2 were performed. Groups of nude mice were used to determine maximum tolerated dose (MTD) of Y-90-DOTA-RGD4 and Y-90-DOTA-3PRGD2. The radionuclide therapeutic efficacy of Y-90-DOTA-RGD4 and 90Y-DOTA-3PRGD2 was evaluated in U87MG tumor-bearing nude mice. The U87MG tumor uptake of In-111-DOTA-3PRGD2 was slightly lower than that of the In-111-DOTA-RGD4 (e.g., 6.13 +/- 0.82%ID/g vs 6.43 +/- 1.6%ID/g at 4 h post-injection), but the uptake of In-111-DOTA-3PRGD2 in normal organs, such as liver and kidneys, was much lower than that of In-111-DOTA-RGD4, which resulted in much higher tumor-to-nontumor ratios and lower toxicity. The MTD of Y-90-DOTA-RGD4 in nude mice is less than 44.4 MBq, while the MTD of Y-90-DOTA-3PRGD2 in mice is more than 55.5 MBq. Y-90-DOTA-3PRGD2 administration exhibited a similar tumor inhibition effect as compared with Y-90-DOTA-RGD4 at the same dose. The tumor vasculature in the Y-90-DOTA-3PRGD2 treatment group was much less than the control groups. Radionuclide therapy studies exhibited that both Y-90-DOTA-RGD4 and Y-90-DOTA-3PRGD2 caused significant tumor growth delay in the U87MG tumor model. Compared to Y-90-DOTA-RGD4, the low accumulation of Y-90-DOTA-3PRGD2 in normal organs led to lower toxicity and higher MTD in nude mice, which would make it more suitable for high dose or multiple-dose regimens, in order to achieve maximum therapeutic efficacy.