{"title":"二聚体CCK2R放射治疗示踪剂与mTOR抑制协同作用增强肿瘤治疗。","authors":"Linjie Bian, Zheyi Wang, Panli Li, Simin He, Jianping Zhang, Xiaoping Xu, Xiangwei Wang, Shaoli Song","doi":"10.7150/thno.117021","DOIUrl":null,"url":null,"abstract":"<p><p><b>Purpose:</b> The cholecystokinin-2 receptor (CCK2R) is highly expressed in several neuroendocrine cancers, particularly in medullary thyroid carcinoma (MTC) and small cell lung cancer (SCLC) and represents a promising target for radiotheranostic applications. Several minigastrin-derived analogs, such as DOTA-MGS5 and DOTA-CCK-66, have demonstrated favorable tumor targeting and imaging performance. Building on these advances, we developed and evaluated a novel dimeric CCK<sub>2</sub>R-targeted radiotracer, and further investigated its radiosensitization potential in combination with mTOR inhibition. <b>Experimental Design:</b> We designed a dimeric CCK<sub>2</sub>R-targeted agent, DOTA-CCK<sub>2</sub>R-dimer, labeled with <sup>68</sup>Ga for PET imaging and <sup>177</sup>Lu for radionuclide therapy. Furthermore, we combined [<sup>177</sup>Lu]Lu-DOTA-CCK<sub>2</sub>R-dimer with the mTOR inhibitor RAD001 and used single-cell RNA sequencing (scRNA-seq) to investigate the mechanisms of radiosensitization. <b>Results:</b> Compared with its monomeric counterpart [<sup>68</sup>Ga]Ga-DOTA-CCK-66, [<sup>68</sup>Ga]Ga-DOTA-CCK<sub>2</sub>R-dimer demonstrated superior tumor targeting <i>in vivo</i>. Tumor uptake reached 26.13 ± 6.21 %ID/g at 2 h post-injection, which was significantly greater than that of the monomeric tracer (19.63 ± 3.35 %ID/g, <i>p</i> < 0.05). Additionally, [<sup>177</sup>Lu]Lu-DOTA-CCK<sub>2</sub>R-dimer selectively eliminated highly proliferative and poorly differentiated tumor cell subpopulations. Combination treatment with RAD001 improved therapeutic efficacy by suppressing glutathione-mediated detoxification and increasing oxidative stress. Furthermore, glutathione S-transferase kappa 1 (GSTK1) was identified as a key regulator that modulates radiosensitivity. Conclusions: DOTA-CCK<sub>2</sub>R-dimer exhibits favorable <i>in vivo</i> stability, notable tumor retention, and excellent imaging performance. Combining this agent with mTOR inhibition offers a synergistic strategy to sensitize tumors to radiotherapy, providing a promising approach for treating refractory CCK<sub>2</sub>R-positive malignancies.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9306-9325"},"PeriodicalIF":13.3000,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439480/pdf/","citationCount":"0","resultStr":"{\"title\":\"Dimeric CCK2R radiotheranostic tracers synergize with mTOR inhibition for enhanced tumor therapy.\",\"authors\":\"Linjie Bian, Zheyi Wang, Panli Li, Simin He, Jianping Zhang, Xiaoping Xu, Xiangwei Wang, Shaoli Song\",\"doi\":\"10.7150/thno.117021\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Purpose:</b> The cholecystokinin-2 receptor (CCK2R) is highly expressed in several neuroendocrine cancers, particularly in medullary thyroid carcinoma (MTC) and small cell lung cancer (SCLC) and represents a promising target for radiotheranostic applications. Several minigastrin-derived analogs, such as DOTA-MGS5 and DOTA-CCK-66, have demonstrated favorable tumor targeting and imaging performance. Building on these advances, we developed and evaluated a novel dimeric CCK<sub>2</sub>R-targeted radiotracer, and further investigated its radiosensitization potential in combination with mTOR inhibition. <b>Experimental Design:</b> We designed a dimeric CCK<sub>2</sub>R-targeted agent, DOTA-CCK<sub>2</sub>R-dimer, labeled with <sup>68</sup>Ga for PET imaging and <sup>177</sup>Lu for radionuclide therapy. Furthermore, we combined [<sup>177</sup>Lu]Lu-DOTA-CCK<sub>2</sub>R-dimer with the mTOR inhibitor RAD001 and used single-cell RNA sequencing (scRNA-seq) to investigate the mechanisms of radiosensitization. <b>Results:</b> Compared with its monomeric counterpart [<sup>68</sup>Ga]Ga-DOTA-CCK-66, [<sup>68</sup>Ga]Ga-DOTA-CCK<sub>2</sub>R-dimer demonstrated superior tumor targeting <i>in vivo</i>. Tumor uptake reached 26.13 ± 6.21 %ID/g at 2 h post-injection, which was significantly greater than that of the monomeric tracer (19.63 ± 3.35 %ID/g, <i>p</i> < 0.05). Additionally, [<sup>177</sup>Lu]Lu-DOTA-CCK<sub>2</sub>R-dimer selectively eliminated highly proliferative and poorly differentiated tumor cell subpopulations. Combination treatment with RAD001 improved therapeutic efficacy by suppressing glutathione-mediated detoxification and increasing oxidative stress. Furthermore, glutathione S-transferase kappa 1 (GSTK1) was identified as a key regulator that modulates radiosensitivity. Conclusions: DOTA-CCK<sub>2</sub>R-dimer exhibits favorable <i>in vivo</i> stability, notable tumor retention, and excellent imaging performance. Combining this agent with mTOR inhibition offers a synergistic strategy to sensitize tumors to radiotherapy, providing a promising approach for treating refractory CCK<sub>2</sub>R-positive malignancies.</p>\",\"PeriodicalId\":22932,\"journal\":{\"name\":\"Theranostics\",\"volume\":\"15 17\",\"pages\":\"9306-9325\"},\"PeriodicalIF\":13.3000,\"publicationDate\":\"2025-08-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439480/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Theranostics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/thno.117021\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.117021","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
摘要
目的:胆囊收缩素-2受体(CCK2R)在几种神经内分泌癌中高表达,特别是在甲状腺髓样癌(MTC)和小细胞肺癌(SCLC)中,是放射治疗应用的一个有希望的靶点。几种mini - migastrin衍生类似物,如DOTA-MGS5和DOTA-CCK-66,已经显示出良好的肿瘤靶向和成像性能。基于这些进展,我们开发并评估了一种新的二聚体cck2r靶向放射性示踪剂,并进一步研究了其与mTOR抑制相结合的放射增敏潜力。实验设计:我们设计了一种二聚体cck2r靶向剂,dota - cck2r -二聚体,用68Ga标记PET成像,177Lu标记放射性核素治疗。此外,我们将[177Lu] lu - dota - cck2r -二聚体与mTOR抑制剂RAD001联合使用,并使用单细胞RNA测序(scRNA-seq)研究放射增敏的机制。结果:与单体对应物[68Ga]Ga-DOTA-CCK-66相比,[68Ga] ga - dota - cck2r二聚体在体内表现出更强的肿瘤靶向性。注射后2 h肿瘤摄取率为26.13±6.21% ID/g,显著高于单体示踪剂的19.63±3.35% ID/g, p < 0.05)。此外,[177Lu] lu - dota - cck2r -二聚体选择性地消除了高增殖和低分化的肿瘤细胞亚群。RAD001联合治疗通过抑制谷胱甘肽介导的解毒和增加氧化应激提高治疗效果。此外,谷胱甘肽s -转移酶kappa 1 (GSTK1)被确定为调节辐射敏感性的关键调节因子。结论:dota - cck2r -二聚体具有良好的体内稳定性、显著的肿瘤保留性和良好的影像学表现。将该药物与mTOR抑制剂联合使用提供了一种协同策略,使肿瘤对放疗敏感,为治疗难治性cck2r阳性恶性肿瘤提供了一种有希望的方法。
Dimeric CCK2R radiotheranostic tracers synergize with mTOR inhibition for enhanced tumor therapy.
Purpose: The cholecystokinin-2 receptor (CCK2R) is highly expressed in several neuroendocrine cancers, particularly in medullary thyroid carcinoma (MTC) and small cell lung cancer (SCLC) and represents a promising target for radiotheranostic applications. Several minigastrin-derived analogs, such as DOTA-MGS5 and DOTA-CCK-66, have demonstrated favorable tumor targeting and imaging performance. Building on these advances, we developed and evaluated a novel dimeric CCK2R-targeted radiotracer, and further investigated its radiosensitization potential in combination with mTOR inhibition. Experimental Design: We designed a dimeric CCK2R-targeted agent, DOTA-CCK2R-dimer, labeled with 68Ga for PET imaging and 177Lu for radionuclide therapy. Furthermore, we combined [177Lu]Lu-DOTA-CCK2R-dimer with the mTOR inhibitor RAD001 and used single-cell RNA sequencing (scRNA-seq) to investigate the mechanisms of radiosensitization. Results: Compared with its monomeric counterpart [68Ga]Ga-DOTA-CCK-66, [68Ga]Ga-DOTA-CCK2R-dimer demonstrated superior tumor targeting in vivo. Tumor uptake reached 26.13 ± 6.21 %ID/g at 2 h post-injection, which was significantly greater than that of the monomeric tracer (19.63 ± 3.35 %ID/g, p < 0.05). Additionally, [177Lu]Lu-DOTA-CCK2R-dimer selectively eliminated highly proliferative and poorly differentiated tumor cell subpopulations. Combination treatment with RAD001 improved therapeutic efficacy by suppressing glutathione-mediated detoxification and increasing oxidative stress. Furthermore, glutathione S-transferase kappa 1 (GSTK1) was identified as a key regulator that modulates radiosensitivity. Conclusions: DOTA-CCK2R-dimer exhibits favorable in vivo stability, notable tumor retention, and excellent imaging performance. Combining this agent with mTOR inhibition offers a synergistic strategy to sensitize tumors to radiotherapy, providing a promising approach for treating refractory CCK2R-positive malignancies.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.