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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

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
 [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:
Grant/Contract Number:
SC0008833; HHSN261201500074C
Accepted Manuscript
Journal Name:
Additional Journal Information:
Journal Volume: 7; Journal Issue: 7; Journal ID: ISSN 1838-7640
Research Org:
Univ. of Pittsburgh, PA (United States)
Sponsoring Org:
USDOE; National Institutes of Health (NIH)
Country of Publication:
United States
60 APPLIED LIFE SCIENCES; PSMA; albumin; phosphoramidate; 177Lu; radiotherapy
OSTI Identifier: