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Pharmacokinetic and Biodistribution Assessment of a Near Infrared-Labeled PSMA-Specific Small Molecule in
Joy L Kovar1, Lael L Cheung1, Melanie A Simpson2
1Translational Research, LI-COR Biosciences, 4647 Superior Street, Lincoln, NE 68504, USA.
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.
Insights
A novel prostate-specific membrane antigen (PSMA)-targeted molecule, YC-27, effectively delineates prostate tumors for image-guided surgery. Preclinical studies show YC-27 provides good tumor contrast, aiding surgical precision.
Area of Science:
- Oncology
- Medical Imaging
- Molecular Imaging
Background:
- Prostate cancer is a leading cancer diagnosis in men, frequently necessitating surgical intervention.
- Image-guided surgery using near-infrared (NIR) technologies offers potential for improved tumor margin delineation.
- Developing targeted probes is crucial for advancing preclinical testing of image-guided surgical techniques.
Purpose of the Study:
- To develop and characterize a novel PSMA-targeted small molecule, YC-27, for preclinical evaluation in prostate cancer.
- To assess the in vitro and in vivo targeting, specificity, and clearance properties of YC-27.
- To determine the utility of YC-27 for image-guided surgery by evaluating its tumor delineation capabilities.
Main Methods:
- YC-27 was synthesized and conjugated with IRDye 800CW, a near-infrared fluorescent dye.
- In vitro studies involved exposing prostate cancer cell lines (22Rv1, PC3M-LN4, LNCaP) to labeled YC-27 and an anti-PSMA antibody.
- In vivo experiments utilized tumor-bearing mice to assess YC-27's targeting, clearance, and tumor delineation efficacy through ex vivo imaging.
Main Results:
- YC-27 demonstrated dose-dependent signal increase upon binding to PSMA-expressing cells.
- Microscopy confirmed specific binding and internalization of YC-27.
- In vivo studies showed YC-27 provided effective tumor delineation and tissue contrast at low doses (0.25 nmole).
- YC-27 was primarily cleared by the kidneys, with observed binding in renal cortex proximal tubules and epididymis.
Conclusions:
- YC-27 is a promising PSMA-targeted small molecule for preclinical evaluation in prostate cancer.
- The probe exhibits specific binding and effective tumor visualization, supporting its potential in image-guided surgery.
- YC-27's ability to delineate tumor margins suggests clinical utility for improving surgical resection outcomes in prostate cancer.
