Prostate Activated Prodrugs and Imaging Agents

摘要

The goal of this project is to demonstrate that enzymatically active PSA in the prostatic microenvironment can be used to locally activate either prodrugs or imaging systems. The substrate chosen was a 3 component system composed of a peptide sequence with affinity for PSA, an imaging agent / cytotoxic drug, and a deactivating bridge-linker, which electronically incapacitates the imaging agent /cytotoxin. On PSA mediated release, the peptide sequence is designed to uncouple from the bridge, which then undergoes spontaneous decomposition, releasing imaging agent /free cytoxoxin. The linker selected was 4-amino benzyl alcohol and proof of principle studies were conducted with a tyrosine derivative to which was coupled a series of three image contrast agents. Enzymatic release of imaging agents was achieved on exposure to PSA, however the conjugates were also substrates for the enzyme - chymotrypsin, limiting their usefulness for screening prostate cancer cells. Specificity for PSA was eventually achieved by conversion to a hexapeptide derivative which underwent selective activation by PSA, releasing imaging agent on exposure to enzyme or prostate cancer tissue.