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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]
  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. 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., & 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
journal, August 2019

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177Lu-DOTA-HYNIC-Lys(Nal)-Urea-Glu: synthesis and assessment of the ability to target the prostate specific membrane antigen
journal, October 2018

  • Hernández-Jiménez, Tania; Ferro-Flores, Guillermina; Ocampo-García, Blanca
  • Journal of Radioanalytical and Nuclear Chemistry, Vol. 318, Issue 3
  • DOI: 10.1007/s10967-018-6239-9

Synthesis and preclinical evaluation of the 99mTc-/177Lu-CXCR4-L theranostic pair for in vivo chemokine-4 receptor-specific targeting
journal, February 2020

  • Ávila-Sánchez, Marcela; Ferro-Flores, Guillermina; Jiménez-Mancilla, Nallely
  • Journal of Radioanalytical and Nuclear Chemistry, Vol. 324, Issue 1
  • DOI: 10.1007/s10967-020-07043-6

Preclinical Dosimetry, Imaging, and Targeted Radionuclide Therapy Studies of Lu-177-Labeled Albumin-Binding, PSMA-Targeted CTT1403
journal, July 2019

  • Ling, Xiaoxi; Latoche, Joseph D.; Choy, Cindy J.
  • Molecular Imaging and Biology, Vol. 22, Issue 2
  • DOI: 10.1007/s11307-019-01404-8

Alpha-PET for Prostate Cancer: Preclinical investigation using 149Tb-PSMA-617
journal, November 2019


Synthesis and in vitro and in vivo evaluation of urea-based PSMA inhibitors with increased lipophilicity
journal, August 2018


The Future of PSMA-Targeted Radionuclide Therapy: An Overview of Recent Preclinical Research
journal, October 2019