Theranostic Agents for Photodynamic Therapy of Prostate Cancer by Targeting Prostate-Specific Membrane Antigen.

Xinning Wang,Ping Zhang,James P Basilion,Lee Ponsky,Gopolakrishnan Ramamurthy,Joseph Meyers,Malcolm E Kenney,Brian Tsui,Jonathan Kiechle

doi:10.1158/1535-7163.mct-15-0722

Abstract

Prostatectomy has been the mainstay treatment for men with localized prostate cancer. Surgery, however, often can result in major side effects, which are caused from damage and removal of nerves and muscles surrounding the prostate. A technology that can help surgeons more precisely identify and remove prostate cancer resulting in a more complete prostatectomy is needed. Prostate-specific membrane antigen (PSMA), a type II membrane antigen highly expressed in prostate cancer, has been an attractive target for imaging and therapy. The objective of this study is to develop low molecular weight PSMA-targeted photodynamic therapy (PDT) agents, which would provide image guidance for prostate tumor resection and allow for subsequent PDT to eliminate unresectable or remaining cancer cells. On the basis of our highly negatively charged, urea-based PSMA ligand PSMA-1, we synthesized two PSMA-targeting PDT conjugates named PSMA-1-Pc413 and PSMA-1-IR700. In in vitro cellular uptake experiments and in vivo animal imaging experiments, the two conjugates demonstrated selective and specific uptake in PSMA-positive PC3pip cells/tumors, but not in PSMA-negative PC3flu cells/tumors. Further in vivo photodynamic treatment proved that the two PSMA-1-PDT conjugates can effectively inhibit PC3pip tumor progression. The two PSMA-1-PDT conjugates reported here may have the potential to aid in the detection and resection of prostate cancers. It may also allow for the identification of unresectable cancer tissue and PDT ablation of such tissue after surgical resection with potentially less damage to surrounding tissues. Mol Cancer Ther; 15(8); 1834-44. ©2016 AACR.

Highlights

PSA testing has allowed significantly more men to be diagnosed and treated for prostate cancer
Synthesis The synthesis and characterization of Prostate-specific membrane antigen (PSMA)-1-Pc413 and PSMA-1-IR700 is shown in Supplementary Figs
PSMA-1-IR700 was synthesized by reaction of PSMA-1 with commercially available IRDye700DX NHS ester in PBS (Supplementary Fig. S4A)

Summary

Introduction

PSA testing has allowed significantly more men to be diagnosed and treated for prostate cancer. 220,800 new diagnoses and 27,540 deaths from the disease are projected in 2015 in the United States [1]. Over 90% of men have localized tumors at initial screenings and are candidates for radical prostatectomies [2]. At surgery, cancer has been shown to extend outside the prostate (pathologic stage C) in 20% to 42% of patients [3], surgery fails to halt the disease in approximately 20% of the patients who undergo radical prostatectomy, and recurrence rate of this disease is more than 60% [4,5,6]. Surgeons have difficulty accessing prostate cancer invasion; many malignant nodules escape detection, leading to disease recurrence.

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