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Title: 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 » CTT1403 in PSMA+ PC3-PIP human xenograft tumors.« less

Authors:
 [1];  [2];  [2];  [1];  [2];  [1];  [3];  [1]
+ Show Author Affiliations
  1. Cancer Targeted Technology, Woodinville, WA (United States)
  2. Univ. of Pittsburgh, PA (United States). Dept. of Medicine
  3. 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.
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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
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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.
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@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 = {Thu Apr 27 00:00:00 EDT 2017},
month = {Thu Apr 27 00:00:00 EDT 2017}
}
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https://doi.org/10.7150/thno.18719
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    Development of a new class of PSMA radioligands comprising ibuprofen as an albumin-binding entity
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    Targeted alpha therapy in a systemic mouse model of prostate cancer - a feasibility study
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