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. 2017 Apr 27;7(7):1928-1939.
doi: 10.7150/thno.18719. eCollection 2017.

177Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice

Cindy J Choy  1 , Xiaoxi Ling  2 , Jonathan J Geruntho  2 , Sophia K Beyer  1 , Joseph D Latoche  2 , Beatrice Langton-Webster  1 , Carolyn J Anderson  2   3   4   5 , Clifford E Berkman  1
Affiliations

177Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice

Cindy J Choy et al. Theranostics. .

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. 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 increased tumor uptake translated into superior therapeutic efficacy of CTT1403 in PSMA+ PC3-PIP human xenograft tumors.

Keywords: 177Lu; PSMA; albumin; phosphoramidate; radiotherapy..

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Conflict of interest statement

Competing Interests: Dr. Langton-Webster serves as the Chief Executive Officer for Cancer Targeted Technology. Dr. Berkman serves at the Chief Science Officer for Cancer Targeted Technology and is the inventor of the CTT1298 PSMA inhibitor scaffold.

Figures

Scheme 1
Scheme 1
Modular assembly of CTT1401 and CTT1403.
Figure 1
Figure 1
Uptake of CTT1401 (A) and CTT1403 (B) in PC3-PIP and PC3-WT cells.
Figure 2
Figure 2
Biodistribution of 177Lu-labeled CTT1401 (A, B) and CTT1403 (C, D) in PC3-PIP tumor-bearing mice. Pre-injection of 2-PMPA 30 min prior to the 177Lu-labeled agents showed significant decreases in tumor and kidney. Data are presented as % injected dose per gram of tissue (n=5 per group, except n=10 for CTT1403 72 h group; mean +/- sd).
Figure 3
Figure 3
Biodistribution of 177Lu-labeled CTT1401 (A) and CTT1403 (B) in in key PSMA+ (tumor, kidneys) and non-target tissues (blood, muscle) at 1, 4, 24, 28 and 72 h showing uptake and clearance. Data are presented as % injected dose per gram of tissue (n=5 per group, except n=10 for CTT1403 72 h group; mean +/- sd).
Figure 4
Figure 4
Tumor:non-tumor ratios for CTT1401 (panels A, C, E, G) and CTT1403 (panels B, D, F, H) in PC3-PIP tumor-bearing mice. (n=5 per group, except n=10 for CTT1403 72 h group; mean +/- sd).
Figure 5
Figure 5
Therapeutic efficacy of CTT1401 and CTT1403. (A) Comparison of the therapeutic efficacy in the mice groups treated with a single dose of CTT1401 or CTT1403 in comparison to the control group (untreated). (B) Average tumor growth for mice treated with a single dose of CTT1401 or CTT1403 in comparison to the control group (untreated). (C) Survival data for mice treated with a single dose of CTT1401 or CTT1403 in comparison to the control group (untreated).
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