A prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile

Abstract Prostate-specific membrane antigen (PSMA) is a promising target for the treatment of advanced prostate cancer (PC) and various solid tumors. Although PSMA-targeted radiopharmaceutical therapy (RPT) has enabled significant imaging and prostate-specific antigen (PSA) responses, accumulating c...

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Autores principales:	Srikanth Boinapally, Hye-Hyun Ahn, Bei Cheng, Mary Brummet, Hwanhee Nam, Kathleen L. Gabrielson, Sangeeta R. Banerjee, Il Minn, Martin G. Pomper
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/66509369cb3640a3b49a1ee996b47027
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spelling	oai:doaj.org-article:66509369cb3640a3b49a1ee996b470272021-12-02T18:17:53ZA prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile10.1038/s41598-021-86551-12045-2322https://doaj.org/article/66509369cb3640a3b49a1ee996b470272021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86551-1https://doaj.org/toc/2045-2322Abstract Prostate-specific membrane antigen (PSMA) is a promising target for the treatment of advanced prostate cancer (PC) and various solid tumors. Although PSMA-targeted radiopharmaceutical therapy (RPT) has enabled significant imaging and prostate-specific antigen (PSA) responses, accumulating clinical data are beginning to reveal certain limitations, including a subgroup of non-responders, relapse, radiation-induced toxicity, and the need for specialized facilities for its administration. To date non-radioactive attempts to leverage PSMA to treat PC with antibodies, nanomedicines or cell-based therapies have met with modest success. We developed a non-radioactive prodrug, SBPD-1, composed of a small-molecule PSMA-targeting moiety, a cancer-selective cleavable linker, and the microtubule inhibitor monomethyl auristatin E (MMAE). SBPD-1 demonstrated high binding affinity to PSMA (K i = 8.84 nM) and selective cytotoxicity to PSMA-expressing PC cell lines (IC50 = 3.90 nM). SBPD-1 demonstrated a significant survival benefit in two murine models of human PC relative to controls. The highest dose tested did not induce toxicity in immunocompetent mice. The high specific targeting ability of SBPD-1 to PSMA-expressing tumors and its favorable toxicity profile warrant its further development.Srikanth BoinapallyHye-Hyun AhnBei ChengMary BrummetHwanhee NamKathleen L. GabrielsonSangeeta R. BanerjeeIl MinnMartin G. PomperNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Srikanth Boinapally Hye-Hyun Ahn Bei Cheng Mary Brummet Hwanhee Nam Kathleen L. Gabrielson Sangeeta R. Banerjee Il Minn Martin G. Pomper A prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile
description	Abstract Prostate-specific membrane antigen (PSMA) is a promising target for the treatment of advanced prostate cancer (PC) and various solid tumors. Although PSMA-targeted radiopharmaceutical therapy (RPT) has enabled significant imaging and prostate-specific antigen (PSA) responses, accumulating clinical data are beginning to reveal certain limitations, including a subgroup of non-responders, relapse, radiation-induced toxicity, and the need for specialized facilities for its administration. To date non-radioactive attempts to leverage PSMA to treat PC with antibodies, nanomedicines or cell-based therapies have met with modest success. We developed a non-radioactive prodrug, SBPD-1, composed of a small-molecule PSMA-targeting moiety, a cancer-selective cleavable linker, and the microtubule inhibitor monomethyl auristatin E (MMAE). SBPD-1 demonstrated high binding affinity to PSMA (K i = 8.84 nM) and selective cytotoxicity to PSMA-expressing PC cell lines (IC50 = 3.90 nM). SBPD-1 demonstrated a significant survival benefit in two murine models of human PC relative to controls. The highest dose tested did not induce toxicity in immunocompetent mice. The high specific targeting ability of SBPD-1 to PSMA-expressing tumors and its favorable toxicity profile warrant its further development.
format	article
author	Srikanth Boinapally Hye-Hyun Ahn Bei Cheng Mary Brummet Hwanhee Nam Kathleen L. Gabrielson Sangeeta R. Banerjee Il Minn Martin G. Pomper
author_facet	Srikanth Boinapally Hye-Hyun Ahn Bei Cheng Mary Brummet Hwanhee Nam Kathleen L. Gabrielson Sangeeta R. Banerjee Il Minn Martin G. Pomper
author_sort	Srikanth Boinapally
title	A prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile
title_short	A prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile
title_full	A prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile
title_fullStr	A prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile
title_full_unstemmed	A prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile
title_sort	prostate-specific membrane antigen (psma)-targeted prodrug with a favorable in vivo toxicity profile
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/66509369cb3640a3b49a1ee996b47027
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A prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile

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