科研之友
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摘要
Our concept of enzyme-mediated cancer imaging and therapy aims to use radiolabeled compounds to target hydrolases over-expressed on the extracellular surface of solid tumors. A data mining approach identified extracellular sulfatase 1 (SULF1) as an enzyme expressed on the surface of pancreatic cancer cells. We designed, synthesized, and characterized 2-(2'-sulfooxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ2-S) as well as its radioiodinated form (125IQ2-S) as a prodrug with potential for hydrolysis by SULF1. IQ2-S was successfully docked in silico into three enzymes homolog of SULF1, alkaline phosphatase, and prostatic acid phosphatase. The incubation of 125IQ2-S and 125IQ2-P with the three enzymes in solution confirms the docking results and enzyme selectivity for the analogs. The hydrolysis of both radioactive compounds produces the water-insoluble, fluorescent product 2-(2'-hydroxyphenyl)-6-[125I]iodo-4-(3H)-quinazolinone (125IQ2-OH). The in vitro incubation of 127IQ2-S and 127IQ2-P with pancreatic, ovarian, and prostate cancer cells expressing studied hydrolases also results in their hydrolysis and the precipitation of 127IQ2-OH fluorescent crystals on the cell surface. To our knowledge, these findings are the first to report the targeting of a radioactive substrate to SULF1 and that this prodrug may be potentially useful in the imaging (123I/124I/131I) and radiotherapy (131I) of pancreatic cancer.
- 出版日期2012-6
