{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T03:25:16Z","timestamp":1791429916858,"version":"4.3.3"},"reference-count":42,"publisher":"American Chemical Society (ACS)","issue":"2","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"name":"Moffitt Radiology Pilot Award"},{"name":"NIH\/NCI SBIR Phase 1 Contract to Modulation Therapeutics"},{"name":"Melanoma Research Alliance Team Science Award"},{"name":"H. Lee Moffitt Cancer Center & Research Institute an NCI designated Comprehensive Cancer Center","award":["P30-CA076292"],"award-info":[{"award-number":["P30-CA076292"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lipophilicity is explored in the biodistribution (BD), pharmacokinetics (PK), radiation dosimetry (RD), and toxicity of an internally administered targeted alpha-particle therapy (TAT) under development for the treatment of metastatic melanoma. The TAT conjugate is comprised of the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), conjugated to melanocortin receptor 1 specific peptidic ligand (MC1RL) using a linker moiety and chelation of the 225Ac radiometal. A set of conjugates were prepared with a range of lipophilicities (log D7.4 values) by varying the chemical properties of the linker. Reported are the observations that higher log D7.4 values are associated with decreased kidney uptake, decreased absorbed radiation dose, and decreased kidney toxicity of the TAT, and the inverse is observed for lower log D7.4 values. Animals administered TATs with lower lipophilicities exhibited acute nephropathy and death, whereas animals administered the highest activity TATs with higher lipophilicities lived for the duration of the 7 month study and exhibited chronic progressive nephropathy. Changes in TAT lipophilicity were not associated with changes in liver uptake, dose, or toxicity. Significant observations include that lipophilicity correlates with kidney BD, the kidney-to-liver BD ratio, and weight loss and that blood urea nitrogen (BUN) levels correlated with kidney uptake. Furthermore, BUN was identified as having higher sensitivity and specificity of detection of kidney pathology, and the liver enzyme alkaline phosphatase (ALKP) had high sensitivity and specificity for detection of liver damage associated with the TAT. These findings suggest that tuning radiopharmaceutical lipophilicity can effectively modulate the level of kidney uptake to reduce morbidity and improve both safety and efficacy.<\/jats:p>","DOI":"10.1021\/acsptsci.1c00035","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T13:52:18Z","timestamp":1615557138000},"page":"953-965","source":"Crossref","is-referenced-by-count":35,"title":["Lipophilicity Determines Routes of Uptake and Clearance,\nand Toxicity of an Alpha-Particle-Emitting Peptide Receptor Radiotherapy"],"prefix":"10.1021","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2680-319X","authenticated-orcid":true,"given":"Narges\nK.","family":"Tafreshi","sequence":"first","affiliation":[{"name":"H. 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Lee Moffitt Cancer Center & Research Institute , , , ,","place":["Tampa, Florida, United States, 33612"]},{"name":"University of South Florida , , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1920-7485","authenticated-orcid":true,"given":"Michael L.","family":"Doligalski","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center & Research Institute , , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikalai M.","family":"Budzevich","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center & Research Institute , , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nella C.","family":"Delva","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center & Research Institute , , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1145-3262","authenticated-orcid":true,"given":"Michael L.","family":"Langsen","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center & Research Institute , , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Vallas","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center & Research Institute , , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Boulware","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center & Research Institute , , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W.","family":"Engelman","sequence":"additional","affiliation":[{"name":"University of South Florida , , , ,","place":["Tampa, Florida, United\nStates, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth L.","family":"Gage","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center & Research Institute , , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo G.","family":"Moros","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center & Research Institute , , , ,","place":["Tampa, Florida, United States, 33612"]},{"name":"H. Lee Moffitt Cancer Center & Research Institute , , , ,","place":["Tampa, Florida, United States, 33612"]},{"name":"University of South Florida , , , ,","place":["Tampa, Florida, United States, 33612"]},{"name":"University of South Florida , , , ,","place":["Tampa, Florida, United\nStates, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9913-0336","authenticated-orcid":true,"given":"Thaddeus J","family":"Wadas","sequence":"additional","affiliation":[{"name":"University of Iowa Health Care , , , ,","place":["Iowa City, Iowa, United\nStates, 52242"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark L.","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"West Virginia University, Health Sciences Center , , , ,","place":["Morgantown, West Virginia, United States, 26506"]},{"name":"Modulation Therapeutics, Inc. , , ,","place":["Morgantown, West Virginia, United States, 26506"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Morse","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center & Research Institute , , , ,","place":["Tampa, Florida, United States, 33612"]},{"name":"University of South Florida , , , ,","place":["Tampa, Florida, United States, 33612"]},{"name":"H. Lee Moffitt Cancer Center & Research Institute , , , ,","place":["Tampa, Florida, United States, 33612"]},{"name":"University of South Florida , , , ,","place":["Tampa, Florida, United\nStates, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"issue":"2","key":"2026081904090189000_cit1","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.drudis.2017.10.007","article-title":"Medicinal chemistry in drug discovery\nin big pharma: past, present and future","volume":"23","author":"Campbell","year":"2018","journal-title":"Drug\nDiscovery Today"},{"issue":"1","key":"2026081904090189000_cit2","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.drudis.2014.10.003","article-title":"Peptide therapeutics: current status\nand future directions","volume":"20","author":"Fosgerau","year":"2015","journal-title":"Drug Discovery Today"},{"issue":"3","key":"2026081904090189000_cit3","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1517\/17460441.2015.1006195","article-title":"Multitasking models for quantitative structure-biological\neffect relationships: current status and future perspectives to speed\nup drug discovery","volume":"10","author":"Speck-Planche","year":"2015","journal-title":"Expert Opin. 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