PSMA-Activated Imaging Agents for Prostate Cancer
Abstract
In preliminary studies, a potent TG analog (12ADT) was coupled to a series of pentapeptides composed of varying combinations of Asp and Glu to create PSMA-activated prodrugs. One of these prodrugs with the sequence 12ADT-Asp-Glu*Glu*Glu*Glu was efficiently hydrolyzed by PSMA and resulted in accumulation of high levels of the cleaved product in tumor tissue compared to normal tissue. The goal of this study is to take advantage of this selective accumulation of the TG analog to make a prostate cancer specific PSMA targeted imaging agent. Specific Aims: The specific aims of the study are: (1) To synthesize and characterize the cytotoxicity of a series of Iodide labeled Asp- or Glu-containing TG analogs. (2) To synthesize iodinated PSMA prodrugs and characterize PSMA-selective activation and cytotoxicity to PSMA-producing prostate cancer cells. (3) To determine the in vivo efficacy toxicity, pharmacokinetics and biodistribution of 125-I labeled PSMA-activated prodrugs in non-tumor bearing mice and mice bearing PSMA positive tumor human prostate cancer xenografts; (4) To evaluate added therapeutic efficacy produced by 131-I labeling of the PSMA-activated prodrug in vivo against PSMA producing xenografts. Progress: Over the past year we have developed a 14-step synthesis to generate precursor phenolic TG analog. We documented the analogs ability to bind to the SERCA pump target. We then developed methods to couple the analog to the carrier peptide and confirmed cleavage by PSMA. Finally we developed methods to synthesize and purify the iodinated PSMA-activated agent. This compound is now under evaluation in vivo in biodistribution and imaging studies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2008
- Accession Number
- ADA491146
Entities
People
- Samuel Denmeade
Organizations
- Johns Hopkins Hospital