Theranostic Agents for Photodynamic Therapy of Prostate Cancer by Targeting Prostate-Specific Membrane Antigen.
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.
Department of Radiology and NFCR Center for Molecular Imaging, Case Western Reserve University, Cleveland, Ohio.
Xinning
X
Wang
School of Medicine, Case Western Reserve University, Cleveland, Ohio.
Brian
B
Tsui
Department of Radiology and NFCR Center for Molecular Imaging, Case Western Reserve University, Cleveland, Ohio.
Gopolakrishnan
G
Ramamurthy
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio.
Ping
P
Zhang
Department of Radiology and NFCR Center for Molecular Imaging, Case Western Reserve University, Cleveland, Ohio.
Joseph
J
Meyers
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio.
Malcolm E
ME
Kenney
Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio.
Jonathan
J
Kiechle
Urology Institute, University Hospitals Case Medical Center, Cleveland, Ohio.
Lee
L
Ponsky
Department of Radiology and NFCR Center for Molecular Imaging, Case Western Reserve University, Cleveland, Ohio. Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio. jxb206@case.edu.
James P
JP
Basilion
D000595:Amino Acid Sequence; D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D057054:Molecular Imaging; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D010778:Photochemotherapy; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000068936:Theranostic Nanomedicine; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D000954:Antigens, Surface; D000970:Antineoplastic Agents; D008024:Ligands; D010446:Peptide Fragments; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II