{"doi":"10.1089/cbr.2024.0066","title":"Searching for Protein Off-Targets of Prostate-Specific Membrane Antigen-Targeting Radioligands in the Salivary Glands","abstract":"Background: Prostate specific membrane antigen (PSMA)-targeted radioligand therapies represent a highly effective treatment for metastatic prostate cancer. However, high and sustain uptake of PSMA-ligands in the salivary glands led to dose limiting dry mouth (xerostomia), especially with α-emitters. The expression of PSMA and histologic analysis couldn’t directly explain the toxicity, suggesting a potential off-target mediator for uptake. In this study, we searched for possible off-target non-PSMA protein(s) in the salivary glands. Methods: A machine-learning based quantitative structure activity relationship (QSAR) model was built for seeking the possible off-target(s). The resulting target candidates from the model prediction were subjected to further analysis for salivary protein expression and structural homology at key regions required for PSMA-ligand binding. Furthermore, cellular binding assays were performed utilizing multiple cell lines with high expression of the candidate proteins and low expression of PSMA. Finally, PSMA knockout (PSMA−/−) mice were scanned by small animal PET/MR using [ 68 Ga]Ga-PSMA-11 for in-vivo validation. Results: The screening of the trained QSAR model did not yield a solid off-target protein, which was corroborated in part by cellular binding assays. Imaging using PSMA−/− mice further demonstrated markedly reduced PSMA-radioligand uptake in the salivary glands. Conclusion: Uptake of the PSMA-targeted radioligands in the salivary glands remains primarily PSMA-mediated. Further investigations are needed to illustrate a seemingly different process of uptake and retention in the salivary glands than that in prostate cancer.","journal":"Cancer Biotherapy and Radiopharmaceuticals","year":2024,"id":450638,"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":0.962,"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":1271123,"name":"Olga Sergeeva","orcid":"0000-0003-0819-1967","position":1,"is_corresponding":false},{"id":1271124,"name":"Wei Cao","orcid":"0000-0001-8461-4138","position":2,"is_corresponding":false},{"id":852920,"name":"Chunying Wu","orcid":"0000-0001-9657-6634","position":3,"is_corresponding":false},{"id":446182,"name":"Bernadette O. Erokwu","orcid":null,"position":4,"is_corresponding":false},{"id":326253,"name":"Chris A. Flask","orcid":"0000-0002-1066-333X","position":5,"is_corresponding":false},{"id":1095865,"name":"Lifang Zhang","orcid":"0000-0001-8950-2936","position":6,"is_corresponding":false},{"id":296387,"name":"Xinning Wang","orcid":"0000-0001-7729-0534","position":7,"is_corresponding":false},{"id":297134,"name":"James P. Basilion","orcid":null,"position":8,"is_corresponding":false},{"id":355236,"name":"Sichun Yang","orcid":"0000-0002-1726-0576","position":9,"is_corresponding":false},{"id":975585,"name":"Zhenghong Lee","orcid":"0000-0002-2429-9911","position":10,"is_corresponding":false},{"id":1271598,"name":"William Julian","orcid":null,"position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:02:28.969209Z","pmid":"39268679","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":[]}