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内容記述 |
Targeting metabotropic glutamate receptor 1 (mGluR1), a key regulator of glutamine metabolism frequently overexpressed in cancers, is a promising strategy for cancer treatment and management (Xie L, et al. Cell Rep Med. 2023). Here, we engineered a mGluR1-targeted radiotheranostic strategy integrating positron emission tomography (PET) with targeted α-particle therapy (TAT) using a novel small-molecule pair, β⁺-emitting 11C-IMTM and α-emitting 211At-AMTM, to identify and eradicate refractory cancers, including melanoma and pancreatic cancer. The radioligand pair, 11C-IMTM and 211At-AMTM, was designed and synthesized based on the mGluR1 structure (Wu H, et al. Science. 2014), both sharing the same small-molecule backbone (Xie L, et al. J Nucl Med. 2020). The diagnostic and therapeutic efficacy, as well as safety, were evaluated in xenograft mouse models of localized and metastatic melanoma and pancreatic cancer. Mechanistic studies were performed to elucidate the antitumor effects of the mGluR1-targeted TAT. 11C-IMTM PET clearly visualized primary and metastatic melanoma lesions, while α-particles from 211At-AMTM anchored to mGluR1 to downregulate this oncoprotein, which is subsequently internalized to trigger cancer cell senescence via the p21–caveolin-1 pathway. In mice with localized and metastatic melanoma, a single dose of 211At-AMTM induced a >86% reduction in tumor volume and a twofold increase in survival. Moreover, complete eradication of pancreatic cancer was observed in 46.67% (7/15) of treated mice, without significant toxicity. This mGluR1-targeted radiotheranostic strategy, 11C-IMTM PET-guided 211At-AMTM TAT, represents a novel and effective approach for the diagnosis and treatment of melanoma and pancreatic cancer, and provides new insights into clinical development and application of approaches targeting cancer-specific metabolic vulnerabilities. |
