Pharmacokinetic and Biodistribution Assessment of a Near Infrared-Labeled PSMA-Specific Small Molecule in Tumor-Bearing Mice

Abstract

Prostate cancer is the most frequently diagnosed cancer in men and often requires surgery. Use of near infrared (NIR) technologies to perform image-guided surgery may improve accurate delineation of tumor margins. To facilitate preclinical testing of such outcomes, here we developed and characterized a PSMA-targeted small molecule, YC-27. IRDye 800CW was conjugated to YC-27 or an anti-PSMA antibody used for reference. Human 22Rv1, PC3M-LN4, and/or LNCaP prostate tumor cells were exposed to the labeled compounds. In vivo targeting and clearance properties were determined in tumor-bearing mice. Organs and tumors were excised and imaged to assess probe localization. YC-27 exhibited a dose dependent increase in signal upon binding. Binding specificity and internalization were visualized by microscopy. In vitro and in vivo blocking studies confirmed YC-27 specificity. In vivo, YC-27 showed good tumor delineation and tissue contrast at doses as low as 0.25 nmole. YC-27 was cleared via the kidneys but bound the proximal tubules of the renal cortex and epididymis. Since PSMA is also broadly expressed on the neovasculature of most tumors, we expect YC-27 will have clinical utility for image-guided surgery and tumor resections.

A novel PSMA/GCPII‐deficient mouse model shows enlarged seminal vesicles upon aging

“…Additionally, we found that PSMA/GCPII is expressed throughout all parts of the mouse epididymis, as determined by immunohistochemistry. This agrees with previous findings, in which the researchers saw a strong signal in mouse epididymis after intravenous injection of a low‐molecular‐weight fluorescent agent targeting PSMA/GCPII . To investigate whether our observations may also be applicable to humans, we examined tissue sections of human epididymis.…”

“…This agrees with previous findings, in which the researchers saw a strong signal in mouse epididymis after intravenous injection of a low-molecular-weight fluorescent agent targeting PSMA/GCPII. 53,54 To investigate whether our observations may also be applicable to humans, we examined tissue sections of human epididymis. The presence of PSMA/GCPII mRNA in human epididymis has been reported.…”

Assessment of near-infrared fluorophores to study the biodistribution and tumor targeting of an IL13 receptor α2 antibody by fluorescence molecular tomography

“…Fluorophores such as IRDye800 ® CW, VT680 ® , XenoLight CF680 and XenoLight CF750 have been used to label proteins (albeit different proteins) via NHS chemistry and the protein quality can be ensured by thin layer chromatography, HPLC or immune-binding assays [ 6 , 23 – 27 ]. The DOL which represents the number of fluorophore molecules conjugated to each molecule of Ab is a critical parameter that should be balanced for good in vivo signal, at the same time retaining the properties of Ab.…”

PSMA-targeting agents for radio- and fluorescence-guided prostate cancer surgery

“…Kovar et al . described that YC-27-800CW showed good tissue contrast and tumor delineation at doses as low as 0.25 nmol 1. Subsequently, Neuman et al used a PCa murine model with subcutaneous PC3-PIP PSMA-expressing tumors to perform image-guided resection of tumor lesions 53.…”

“…Despite recent improvements in imaging and therapy, PCa remains the most frequently diagnosed cancer type in men and is estimated to be the second leading cause of cancer related deaths 1, 2. Currently, PCa treatment is dependent on the stage of the disease at initial diagnosis.…”