Theranostics 2017; 7(7):1928-1939. doi:10.7150/thno.18719

Research Paper

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

Cindy J. Choy1*, Xiaoxi Ling2*, Jonathan J. Geruntho2, Sophia K. Beyer1, Joseph D. Latoche2, Beatrice Langton-Webster1, Carolyn J. Anderson2, 3, 4, 5✉, Clifford E. Berkman1✉

1. Cancer Targeted Technology, Woodinville, WA;
2. Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15203;
3. Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15203;
4. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15203;
5. Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15203.
* Co-first authors

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: PSMA, albumin, phosphoramidate, 177Lu, radiotherapy.

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How to cite this article:
Choy CJ, Ling X, Geruntho JJ, Beyer SK, Latoche JD, Langton-Webster B, Anderson CJ, Berkman CE. 177Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice. Theranostics 2017; 7(7):1928-1939. doi:10.7150/thno.18719. Available from http://www.thno.org/v07p1928.htm