{"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}
引用次数: 0
Abstract
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.