{"doi":"10.3389/fonc.2024.1432286","title":"Performance of PSMA-targeted radiotheranostics in an experimental model of renal cell carcinoma","abstract":"Introduction Renal cell carcinoma (RCC) represents cancer originating from the renal epithelium and accounts for > 90% of cancers in the kidney. Prostate-specific membrane antigen (PSMA) is overexpressed in tumor-associated neovascular endothelial cells of many solid tumors, including metastatic RCC. Although studied in several small clinical studies, PSMA-based imaging and therapy have not been pursued rigorously in preclinical RCC. This study aimed to evaluate the preclinical performance of PSMA-based radiotheranostic agents in a relevant murine model. Methods A PSMA-overexpressing murine cell line, PSMA+ RENCA, was developed by lentiviral transduction. PSMA-based theranostic agents, 68 Ga-L1/ 177 Lu-L1/ 225 Ac-L1, were synthesized in high radiochemical yield and purity following our reported methods. Immunocompetent BALB/c mice were used for flank and orthotopic tumor inoculation. 68 Ga-L1 was evaluated in small animal PET/CT imaging in flank and PET/MR imaging in orthotopic models. Cell viability studies were conducted for 177 Lu-L1 and 225 Ac-L1. Proof-of-concept treatment studies were performed using 225 Ac-L1 (0, 37 kBq, 2 kBq × 37 kBq, 1 week apart) using PSMA+ RENCA in the flank model. Results Cellular uptake of 68 Ga-L1, 177 Lu-L1, and 225 Ac-L1 confirmed the specificity of the agents to PSMA+ RENCA cells rather than to RENCA (wt) cells, which are low in PSMA expression. The uptake in PSMA+ RENCA cells at 1 h for 68 Ga-L1 (49.0% incubated dose [ID] ± 3.6%ID/million cells), 177 Lu-L1 (22.1%ID ± 0.5%ID)/million cells), and 225 Ac-L1 (4.1% ± 0.2% ID)/million cells), respectively, were higher than the RENCA (wt) cells (~ 1%ID–2%ID/million cells). PET/CT images displayed > 7-fold higher accumulation of 68 Ga-L1 in PSMA+ RENCA compared to RENCA (wt) in flank implantation at 1 h. A twofold higher accumulation of 68 Ga-L1 was observed in orthotopic tumors than in normal kidneys during 1–3 h postinjection. High lung uptake was observed with 68 Ga-L1 PET/MR imaging 3 weeks after orthotopic implantation of PSMA+ RENCA due to spontaneous lung metastases. The imaging data were further confirmed by immunohistochemical characterization. 225 Ac-L1 (0-37 kBq) displayed a dose-dependent reduction of cell proliferation in the PSMA+ RENCA cells after 48 h incubation; ~ 40% reduction in the cells with treated 37 kBq compared to vehicle ( p < 0.001); however, no effect was observed with 177 Lu-L1 (0–3700 kBq) up to 144 h postinoculation, suggesting lower efficacy of β-particle-emitting radiations in cellular studies compared to α-particle-emitting 225 Ac-L1. Animals treated with 225 Ac-L1 at 1 week posttumor inoculation in flank models displayed significant tumor growth delay ( p < 0.03) and longer median survival of 21 days and 24 days for the treatment groups 37 kBq and 2 kBq × 37 kBq, respectively, compared to the vehicle group (12 days). Conclusion The results suggest that a theranostic strategy targeting PSMA, employing PET and α-emitting radiopharmaceuticals, enabled tumor growth control and enhanced survival in a relevant immunocompetent murine model of RCC. These studies provide the rationale for clinical studies of PSMA-targeted theranostic agents in patients with RCC.","journal":"Frontiers in Oncology","year":2024,"id":450622,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9683,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1271568,"name":"Anand K Thotakura","orcid":null,"position":1,"is_corresponding":false},{"id":1039601,"name":"Suresh Alati","orcid":null,"position":2,"is_corresponding":false},{"id":869180,"name":"Alla Lisok","orcid":null,"position":3,"is_corresponding":false},{"id":868473,"name":"Zirui Jiang","orcid":"0000-0003-1720-1020","position":4,"is_corresponding":false},{"id":756174,"name":"Vanessa F. Merino","orcid":"0000-0003-2251-2309","position":5,"is_corresponding":false},{"id":420232,"name":"Il Minn","orcid":"0000-0002-7822-662X","position":6,"is_corresponding":false},{"id":456544,"name":"Santosh Yadav","orcid":"0000-0003-1920-3919","position":7,"is_corresponding":false},{"id":334087,"name":"Mark C. Markowski","orcid":"0000-0003-2780-5100","position":8,"is_corresponding":false},{"id":314355,"name":"Yasser Ged","orcid":"0000-0001-6671-7002","position":9,"is_corresponding":false},{"id":313921,"name":"Christian P. Pavlovich","orcid":"0000-0002-8532-0251","position":10,"is_corresponding":false},{"id":352923,"name":"Nirmish Singla","orcid":"0000-0001-9495-6983","position":11,"is_corresponding":false},{"id":636982,"name":"Lilja B. Sólnes","orcid":"0000-0002-2192-7425","position":12,"is_corresponding":false},{"id":267828,"name":"Michael A. Gorin","orcid":"0000-0002-8315-6603","position":13,"is_corresponding":false},{"id":7932,"name":"Martin G. Pomper","orcid":"0000-0001-6753-3010","position":14,"is_corresponding":false},{"id":267038,"name":"Steven P. Rowe","orcid":"0000-0003-2897-4694","position":15,"is_corresponding":false},{"id":74819,"name":"Sangeeta Ray Banerjee","orcid":"0000-0003-3785-7385","position":16,"is_corresponding":false},{"id":1038997,"name":"Rajiv K. Singh","orcid":"0000-0002-7951-202X","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T02:02:28.969209Z","pmid":"39324008","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}