{"doi":"10.1007/s00280-019-03903-5","title":"Species-specific optimization of PEG~SN-38 prodrug pharmacokinetics and antitumor effects in a triple-negative BRCA1-deficient xenograft","abstract":null,"journal":"Cancer Chemotherapy and Pharmacology","year":2019,"id":625053,"datarank":0.515098080672772,"base_score":3.4339872044851463,"endowment":3.4339872044851463,"self_citation_contribution":0.515098080672772,"citation_network_contribution":0.0,"self_endowment_contribution":0.515098080672772,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":30,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":323013,"name":"Byron Hann","orcid":"0000-0002-0715-5166","position":1,"is_corresponding":false},{"id":1616067,"name":"Ralph Reid","orcid":null,"position":2,"is_corresponding":false},{"id":894779,"name":"Gary W. Ashley","orcid":"0000-0002-5366-9109","position":3,"is_corresponding":false},{"id":894783,"name":"Daniel V. Santi","orcid":"0000-0002-3790-0673","position":4,"is_corresponding":false},{"id":894782,"name":"Shaun D. Fontaine","orcid":"0000-0002-5800-0391","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Species-specific optimization of PEG~SN-38 prodrug pharmacokinetics and antitumor effects in a triple-negative BRCA1-deficient xenograft","abstract":"<h4>Purpose</h4>Optimal efficacy of a macromolecular prodrug requires balancing the rate of drug release with the rate of prodrug elimination. Since circulating macromolecules have different elimination rates in different species, a prodrug optimal for one species will likely not be for another. The objectives of this work were (a) to develop an approach to optimize pharmacokinetics of a PEG~SN-38 prodrug in a particular species, (b) to use the approach to predict the pharmacokinetics of various prodrugs of SN-38 in the mouse and human, and (c) to develop a PEG~SN-38 conjugate that is optimized for mouse tumor models.<h4>Methods</h4>We developed models that describe the pharmacokinetics of a drug released from a prodrug by the relationship between the rates of drug release and elimination of the prodrug. We tested the model by varying the release rate of SN-38 from PEG~SN-38 conjugates in the setting of a constant prodrug elimination rate in the mouse. Finally, we tested the antitumor efficacy of a PEG~SN-38 optimized for the mouse.<h4>Results</h4>Optimization of a PEG~SN-38 prodrug was achieved by adjusting the rate of SN-38 release such that the ratio of t<sub>1/2,β</sub> of released SN-38 to the t<sub>1/2</sub> of prodrug elimination was 0.2-0.8. Using this approach, we could rationalize the efficacy of previous PEGylated SN-38 prodrugs in the mouse and human. Finally, a mouse-optimized PEG~SN-38 showed remarkable antitumor activity in BRCA1-deficient MX-1 xenografts; a single dose gave tumor regression, suppression, and shrinkage of massive tumors.<h4>Conclusions</h4>The efficacy of a macromolecular prodrug can be optimized for a given species by balancing the rate of drug release from the carrier with the rate of prodrug elimination.","is_dataset_classified":null,"base_score":3.4339872044851463,"endowment":3.4339872044851463,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"31321449","pmcid":null,"openalex_id":"https://openalex.org/W2963075201","authors":[],"funders":[],"total_grants":0,"fwci":0.8934,"citation_percentile":0.75694229,"influential_citations":0,"citation_trend":[{"year":2019,"count":1},{"year":2020,"count":4},{"year":2021,"count":3},{"year":2022,"count":2},{"year":2023,"count":8},{"year":2024,"count":6},{"year":2025,"count":5},{"year":2026,"count":1}],"oa_status":"closed","license":"http://www.springer.com/tdm","oa_locations":[{"url":"http://link.springer.com/content/pdf/10.1007/s00280-019-03903-5.pdf","host_type":"publisher"},{"url":"http://link.springer.com/article/10.1007/s00280-019-03903-5/fulltext.html","host_type":"publisher"},{"url":"https://doi.org/10.1007/s00280-019-03903-5","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/31321449","host_type":"repository"}],"fields_of_study":["PARP inhibition in cancer therapy","Microtubule and mitosis dynamics","DNA Repair Mechanisms"],"mesh_terms":["Irinotecan","Animals","Antineoplastic Agents","Drug Carriers","Half-Life","Metabolic Clearance Rate","Polyethylene Glycols","Prodrugs","Drug Delivery Systems","Xenograft Model Antitumor Assays","Macromolecular Substances","Mice","Topoisomerase I Inhibitors","Triple Negative Breast Neoplasms","Drug Liberation"],"keywords":["Prodrug","Pharmacokinetics","Conjugate","PEG ratio","Pharmacology","Drug","Chemistry","Medicine","Drug Delivery","Half-life Extension","Top1","Pegylated Prodrugs"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Zero hunger"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-04T05:39:54.261221Z","pmid":null,"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":[]}