Bioorganic chemistry · 2026
Development and preclinical evaluation of NYM074 as a novel Theranostic ligand targeting carbonic anhydrase IX in renal cell carcinoma.
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Li Shun, Chen Yinian, Li Jie, Zhou Xuan, Miao Wei, Shu Hongrui, Zhao Weijia, Wang Yujie, Wu Tao, Luo Jialun, Xue Yangyang, Dai Peng-Fei, Yin Shuiping, Si Hongwei
Аннотация
PURPOSE: Carbonic anhydrase IX (CAIX) is specifically overexpressed in clear cell renal cell carcinoma (ccRCC) and represents an ideal target for molecular imaging and radionuclide therapy. This study aimed to develop and systemically evaluate NYM074, a novel small-molecule CAIX-targeting ligand compatible with dual radiolabeling (68Ga for imaging, 177Lu for therapy), as a potential theranostic agent for ccRCC.
METHODS: NYM074 was radiolabeled with 68Ga and 177Lu, with the yield, radiochemical purity and serum stability verified via radio-HPLC. Human CAIX binding affinity of NYM074 was determined by surface plasmon resonance. Radiolabeled products were validated for cell uptake, and target expression in tumor cell lines was confirmed by Western blotting. MicroPET/SPECT imaging, target specificity, biodistribution, pharmacokinetic analysis, safety and therapeutic efficacy evaluations were performed in OS-RC-2 xenograft model or ICR mice.
RESULTS: Radiolabeled products [68Ga]Ga-NYM074 and [177Lu]Lu-NYM074 were successfully synthesized with high yields, radiochemical purity (>95%) and excellent serum stability ([68Ga]Ga-NYM074, 94.75% at 2 h). SPR assays demonstrated NYM074 had a high affinity to human CAIX (Kd = 0.65 nM). [68Ga]Ga-NYM074 PET exhibited time-dependent tumor uptake in OS-RC-2 xenografts, peaking at 9.57%ID/g at 60 min, and renal uptake gradually decreased; competitive binding experiments achieved 78.69% tumor uptake inhibition, verifying specific CAIX targeting. Biodistribution showed [177Lu]Lu-NYM074 had tumor uptake of 29.15%ID/g in OS-RC-2 model, with liver and kidney radioactivity declining significantly over time. [68Ga]Ga-NYM074 had consistent metabolic patterns in ICR mice, whose pharmacokinetic parameters included a half-life of 3.3 h and moderate clearance rate, with both radioligands having safe absorbed doses. [177Lu]Lu-NYM074 achieved a high tumor growth inhibition of 73.90% (T/C = 25.33%) in OS-RC-2 tumor-bearing mice, with no significant body weight loss observed, indicating favorable anti-tumor efficacy and safety.
CONCLUSION: NYM074-based radiopharmaceuticals enable rapid, high-contrast CAIX-targeted PET imaging and potent radionuclide therapy, with excellent tolerability in OS-RC-2 model mice. These findings support NYM074 as a promising CAIX-directed theranostic agent for clinical translation in ccRCC.
METHODS: NYM074 was radiolabeled with 68Ga and 177Lu, with the yield, radiochemical purity and serum stability verified via radio-HPLC. Human CAIX binding affinity of NYM074 was determined by surface plasmon resonance. Radiolabeled products were validated for cell uptake, and target expression in tumor cell lines was confirmed by Western blotting. MicroPET/SPECT imaging, target specificity, biodistribution, pharmacokinetic analysis, safety and therapeutic efficacy evaluations were performed in OS-RC-2 xenograft model or ICR mice.
RESULTS: Radiolabeled products [68Ga]Ga-NYM074 and [177Lu]Lu-NYM074 were successfully synthesized with high yields, radiochemical purity (>95%) and excellent serum stability ([68Ga]Ga-NYM074, 94.75% at 2 h). SPR assays demonstrated NYM074 had a high affinity to human CAIX (Kd = 0.65 nM). [68Ga]Ga-NYM074 PET exhibited time-dependent tumor uptake in OS-RC-2 xenografts, peaking at 9.57%ID/g at 60 min, and renal uptake gradually decreased; competitive binding experiments achieved 78.69% tumor uptake inhibition, verifying specific CAIX targeting. Biodistribution showed [177Lu]Lu-NYM074 had tumor uptake of 29.15%ID/g in OS-RC-2 model, with liver and kidney radioactivity declining significantly over time. [68Ga]Ga-NYM074 had consistent metabolic patterns in ICR mice, whose pharmacokinetic parameters included a half-life of 3.3 h and moderate clearance rate, with both radioligands having safe absorbed doses. [177Lu]Lu-NYM074 achieved a high tumor growth inhibition of 73.90% (T/C = 25.33%) in OS-RC-2 tumor-bearing mice, with no significant body weight loss observed, indicating favorable anti-tumor efficacy and safety.
CONCLUSION: NYM074-based radiopharmaceuticals enable rapid, high-contrast CAIX-targeted PET imaging and potent radionuclide therapy, with excellent tolerability in OS-RC-2 model mice. These findings support NYM074 as a promising CAIX-directed theranostic agent for clinical translation in ccRCC.
Предметные рубрики MeSH
Carbonic Anhydrase IXHumansAnimalsMiceCarcinoma, Renal CellLigandsKidney NeoplasmsAntigens, NeoplasmTissue DistributionAntineoplastic AgentsMice, Inbred ICRRadiopharmaceuticalsDrug DevelopmentMolecular StructureCell Line, TumorStructure-Activity RelationshipDrug Screening Assays, AntitumorDose-Response Relationship, DrugCarbonic Anhydrase InhibitorsGallium RadioisotopesDrug Evaluation, PreclinicalNeoplasms, ExperimentalLutetiumCell ProliferationTheranostic Nanomedicine