錸188(I)三羰基標誌His3-octreotide胜肽作為胰臟癌造影及治療劑之研究

鄭宇恩

doi:10.6843/NTHU.2009.00357

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铼188(I)三羰基标志His3-octreotide胜肽作为胰脏癌造影及治疗剂之研究

Study on 188Re(I)-Tricarbonyl Labeled His3-Octreotide as an Imaging and Therapeutic Agent for Pancreas Tumor

郑宇恩 , 硕士　　导师：罗建苗;张志贤　　

英文 DOI： 10.6843/NTHU.2009.00357

组胺酸；体抑素第二型；铼188(I)三羰基離子；体抑素； octreotide ； 188Re(I)-his3-octreotide ；生物分布；活体动物造影； histidine ； somatostatin receptor 2 ； [188Re(OH2)3(CO)3]+ ； somatostatin ； octreotide ； 188Re(I)-his3-octreotide ； biodistribution ； microSPECT/CT

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摘要 │ 国际计量

摘要〈TOP〉

由8个胺基酸组成的环型胜肽，octreotide，是一种体抑素类似物，对体抑素受体具有高度亲和力。近年，利用系统性的受器标靶或代谢性引导的放射核种治疗术用於治疗神经内分泌肿瘤在核子医学界引起广泛的兴趣。[90Y-DOTA0-Tyr3]octreotide和[177Lu-DOTA0,Tyr3]octreotate为目前临床上用以治疗此类肿瘤的药物。然而，它们会造成在肾脏或骨髓的高辐射剂量，对人体产生一定的副作用。
    本研究欲尝试以铼188(I)三羰基离子[188Re(OH2)3(CO)3]+为前驱物直接标志耦合有3个组胺酸（histidine）之octreotide，简称为188Re(I)-his3-octreotide，作为治疗表现体抑素受器之胰脏肿瘤治疗剂。
　　实验方法：本研究以固相胜肽合成法制备his3-octreotide。以市售的sst2 receptor进行his3-octreotide受器竞争试验。以铼188(I)三羰基离子为前驱物直接标志his3-octreotide，得188Re(I)-his3-octreotide，经高效能液相层析(HPLC)进行放射化学纯度分析，并以C18 Sep-Pak管柱进行纯化，去除未反应的[188Re(OH2)3(CO)3]+或188ReO4-。测试188Re(I)-his3-octreotide在生理食盐水及血清中之稳定度。以植有AR42J肿瘤的小鼠，进行生物分布及造影等试验。
    结果：由体抑素受器竞争实验，证实his3-octreotide对体抑素受器保持有高度亲和力，其IC50接近octreotide之值。[188Re(OH2)3(CO)3]+合成产率可达85 %左右。经纯化的188Re(I)-his3-octreotide的放化纯度可达95 %以上。在稳定度试验中，188Re(I)-his3-octreotide在生理食盐水中的稳定度在48小时後降至60 %，可能受水中氧氧化的缘故，造成不稳定。在人类血清中之稳定度在48小时降至50 %，而在大鼠血清中则降至10 %。在生物分布试验中，发现在肝脏、肾脏及脾脏有大量放射活度累积。肝脏累积可能是由於188Re(I)-his3-octreotide 在血清中稳定度不佳，分解出之[188Re(OH2)3(CO)3]+与血清蛋白结合之产物大量累积於肝脏。而在肾脏累积则符合文献报导胜肽生物分布的结果。在肿瘤之累积在1小时及4小时分别为1.17 ± 0.41 %ID/g及2.83 ± 0.74 %ID/g，在8小时仍维持在2.41 ± 0.45 %ID/g，但在24小时则降至1.19 ± 0.3 %ID/g，在48小时降至0.88 ± 0.2 %ID/g。在活体动物造影与生物分布趋势相似，大量放射活度累积在肝脏、肾脏及脾脏，肿瘤位置在注射後1小时及4小时可见放射活度累积的影像，显示188Re(I)-his3-octreotide对具体抑素受体之肿瘤的专一性，但可能因此188Re(I)标志octreotide试剂稳定度不佳，经长时间（24小时後）不见有肿瘤累积。在另注入过量未标志的his3-octreotide发现AR42J肿瘤从一开始即不见有放射活度累积的影像，印证188Re(I)-his3-octreotide对体抑素受器确实具有专一性。
    结论：由实验结果显示，在体抑素受器竞争实验，his3-octreotide与体抑素受器有很高的亲和力。但在活体内试验，可能因188Re(I)-his3-octreotide在血液中稳定度不佳，仅在4小时内有较些微的肿瘤累积。由本研究所得结论，若将his3-octreotide进一步改为his6-octreotide，再以[188Re(OH2)3(CO)3]+标志，制备为188Re(I)-his6-octreotide，预期若此188Re标志胜肽耦合物有良好稳定度，值得发展为新的神经内分泌肿瘤的造影及治疗试剂。

并列摘要〈TOP〉

Octreotide, a somatostatin analogue, is consisted of eight amino acids as a cyclic octapeptide and has a high binding affinity to somatostatin receptor 2 (sst2). Recently, systematic receptor-targeted or metabolically directed radiotherapy using various radioisotopes for therapy of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has aroused extensive interest in nuclear medicine. [90Y-DOTA0-Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate are currently clinically used for GEP-NETs therapy. However, they may cause high radiation dose in kidney or bone marrow. The aim of this study was to develop a novel radiolabeled octreotide analogue, 188Re(I)-his3-octreotide, as an imaging and therapeutic agent for neuroendocrine tumors.
  Methods：First, octreotide was conjugated with three histidines, referred to his3-octreotide, by a solid phase peptide synthesizer. Binding affinity of his3-octreotide for sst2 was measured by competitive binding assay. Then, [188Re(OH2)3(CO)3]+ was prepared as a precursor and labeled directly to his3-octreotide. The resultant solution containing 188Re(I)-his3-octreotide was measured for its radiochemical purity by high performance liquid chromatography (HPLC) and purified by C18 Sep-Pak cartridge. In vitro stability and in vivo targeting in AR42J-bearing mice were assessed.
  Results：In competitive binding assay, his3-octreotide showed high affinity for sst2 and IC50 value was similar to the value of octreotide. The radiochemical purity of [188Re(OH2)3(CO)3]+ reached about 85 %. The radiochemical purity of purified 188Re(I)-his3-octreotide achieved greater than 95 %. In stability test, the stability of 188Re(I)-his3-octreotide decreased to 60 % in saline at 48 h post-injection. However, in human serum and rat serum, the stability of 188Re(I)-his3-octreotide decreased to 50 % and 10 %, respectively at 48 h post-injection. In biodistribution study, it was indicated that 188Re(I)-his3-octreotide had high accumulations in liver, kidneys, and spleen. In microSPECT/CT imaging, the AR42J tumor in the SCID mouse could be slightly visualized at 1 and 4 h postinjection. The AR42J tumor uptake of 188Re(I)-his3-octreotide was blocked completely in the case of additional administration of a large excess amount (100 μg) of unlabeled his3-octreotide.
  Conclusion：From the work, it is evident from the in vivo study that his3-octreotide exhibits a high affinity for sst2. However, the accumulation of the 188Re(I) labeled peptide in AR42J tumor in the animal was slightly displayed within 4 h post-injection but become dim later. The poor uptake in the tumor might be due to the unstability of the agent in blood. If 188Re(I)-his3-octreotide could be modified further to be 188Re(I)-his6-octreotide, the new designed 188Re(I) labeled octreotide would become stable and worthy to be developed as an imaging and therapeutic agent for GEP-NETs.

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