177 Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice
Abstract
Prostate-specific membrane antigen (PSMA) continues to be an active biomarker for small-molecule PSMA-targeted imaging and therapeutic agents for prostate cancer and various non-prostatic tumors that are characterized by PSMA expression on their neovasculature. One of the challenges for small-molecule PSMA inhibitors with respect to delivering therapeutic payloads is their rapid renal clearance. In order to overcome this pharmacokinetic challenge, we outfitted a 177Lu-labeled phosphoramidate-based PSMA inhibitor (CTT1298) with an albumin-binding motif (CTT1403) and compared its in vivo performance with that of an analogous compound lacking the albumin-binding motif (CTT1401). The radiolabeling of CTT1401 and CTT1403 was achieved using click chemistry to connect 177Lu-DOTA-N3 to the dibenzocyclooctyne (DBCO)-bearing CTT1298 inhibitor cores. A direct comparison in vitro and in vivo performance was made for CTT1401 and CTT1403; the specificity and efficacy by means of cellular uptake and internalization, biodistribution, and therapeutic efficacy were determined for both compounds. And while both compounds displayed excellent uptake and rapid internalization in PSMA+ PC3-PIP cells, the albumin binding moiety in CTT1403 conferred clear advantages to the PSMA-inhibitor scaffold including increased circulating half-life and prostate tumor uptake that continued to increase up to 168 h post-injection. This then increased tumor uptake translated into superior therapeutic efficacy ofmore »
- Authors:
-
- Cancer Targeted Technology, Woodinville, WA (United States)
- Univ. of Pittsburgh, PA (United States). Dept. of Medicine
- Univ. of Pittsburgh, PA (United States). Dept. of Medicine, Dept. of Radiology, Dept. of Bioengineering, Dept. of Pharmacology and Chemical Biology
- Publication Date:
- Research Org.:
- Univ. of Pittsburgh, PA (United States)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH)
- OSTI Identifier:
- 1393445
- Grant/Contract Number:
- SC0008833; HHSN261201500074C
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Theranostics
- Additional Journal Information:
- Journal Volume: 7; Journal Issue: 7; Journal ID: ISSN 1838-7640
- Publisher:
- Ivyspring
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; PSMA; albumin; phosphoramidate; 177Lu; radiotherapy
Citation Formats
Choy, Cindy J., Ling, Xiaoxi, Geruntho, Jonathan J., Beyer, Sophia K., Latoche, Joseph D., Langton-Webster, Beatrice, Anderson, Carolyn J., and Berkman, Clifford E. 177 Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice. United States: N. p., 2017.
Web. doi:10.7150/thno.18719.
Choy, Cindy J., Ling, Xiaoxi, Geruntho, Jonathan J., Beyer, Sophia K., Latoche, Joseph D., Langton-Webster, Beatrice, Anderson, Carolyn J., & Berkman, Clifford E. 177 Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice. United States. https://doi.org/10.7150/thno.18719
Choy, Cindy J., Ling, Xiaoxi, Geruntho, Jonathan J., Beyer, Sophia K., Latoche, Joseph D., Langton-Webster, Beatrice, Anderson, Carolyn J., and Berkman, Clifford E. Thu .
"177 Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice". United States. https://doi.org/10.7150/thno.18719. https://www.osti.gov/servlets/purl/1393445.
@article{osti_1393445,
title = {177 Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice},
author = {Choy, Cindy J. and Ling, Xiaoxi and Geruntho, Jonathan J. and Beyer, Sophia K. and Latoche, Joseph D. and Langton-Webster, Beatrice and Anderson, Carolyn J. and Berkman, Clifford E.},
abstractNote = {Prostate-specific membrane antigen (PSMA) continues to be an active biomarker for small-molecule PSMA-targeted imaging and therapeutic agents for prostate cancer and various non-prostatic tumors that are characterized by PSMA expression on their neovasculature. One of the challenges for small-molecule PSMA inhibitors with respect to delivering therapeutic payloads is their rapid renal clearance. In order to overcome this pharmacokinetic challenge, we outfitted a 177Lu-labeled phosphoramidate-based PSMA inhibitor (CTT1298) with an albumin-binding motif (CTT1403) and compared its in vivo performance with that of an analogous compound lacking the albumin-binding motif (CTT1401). The radiolabeling of CTT1401 and CTT1403 was achieved using click chemistry to connect 177Lu-DOTA-N3 to the dibenzocyclooctyne (DBCO)-bearing CTT1298 inhibitor cores. A direct comparison in vitro and in vivo performance was made for CTT1401 and CTT1403; the specificity and efficacy by means of cellular uptake and internalization, biodistribution, and therapeutic efficacy were determined for both compounds. And while both compounds displayed excellent uptake and rapid internalization in PSMA+ PC3-PIP cells, the albumin binding moiety in CTT1403 conferred clear advantages to the PSMA-inhibitor scaffold including increased circulating half-life and prostate tumor uptake that continued to increase up to 168 h post-injection. This then increased tumor uptake translated into superior therapeutic efficacy of CTT1403 in PSMA+ PC3-PIP human xenograft tumors.},
doi = {10.7150/thno.18719},
journal = {Theranostics},
number = 7,
volume = 7,
place = {United States},
year = {2017},
month = {4}
}
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Works referencing / citing this record:
177Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy
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- European Journal of Nuclear Medicine and Molecular Imaging, Vol. 46, Issue 12
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Preclinical Dosimetry, Imaging, and Targeted Radionuclide Therapy Studies of Lu-177-Labeled Albumin-Binding, PSMA-Targeted CTT1403
journal, July 2019
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Synthesis and in vitro and in vivo evaluation of urea-based PSMA inhibitors with increased lipophilicity
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The Future of PSMA-Targeted Radionuclide Therapy: An Overview of Recent Preclinical Research
journal, October 2019
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Alpha-PET for Prostate Cancer: Preclinical investigation using 149Tb-PSMA-617
text, January 2019
- Umbricht, Christoph A.; Köster, Ulli; Bernhardt, Peter
- ETH Zurich