Computational modeling and experimental evaluation of a novel prodrug for targeting the extracellular space of prostate tumors.
We are developing a noninvasive approach for targeting imaging and therapeutic radionuclides to prostate cancer. Our method, Enzyme-Mediated Cancer Imaging and Therapy (EMCIT), aims to use enzyme-dependent, site-specific, in vivo precipitation of a radioactive molecule within the extracellular space of solid tumors. Advanced methods for data mining of the literature, protein databases, and knowledge bases (IT. Omics LSGraph and Ingenuity Systems) identified prostatic acid phosphatase (PAP) as an enzyme overexpressed in prostate cancer and secreted in the extracellular space. Using AutoDock 3.0 software, the prodrug ammonium 2-(2'-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ(2-P)) was docked in silico into the X-ray structure of PAP. The data indicate that IQ(2-P) docked into the PAP active site with a calculated inhibition constant (K(i)) more favorable than that of the PAP inhibitor alpha-benzylaminobenzylphosphonic acid. When (125)IQ(2-P), the radioiodinated form of the water-soluble prodrug, was incubated with PAP, rapid hydrolysis of the compound was observed as exemplified by formation of the water-insoluble 2-(2'-hydroxyphenyl)-6-[(125)I]iodo-4-(3H)-quinazolinone ((125)IQ(2-OH)). Similarly, the incubation of IQ(2-P) with human LNCaP, PC-3, and 22Rv1 prostate tumor cells resulted in the formation of large fluorescent IQ(2-OH) crystals. No hydrolysis was seen in the presence of normal human cells. Autoradiography of tumor cells incubated with (125)IQ(2-P) showed accumulation of radioactive grains ((125)IQ(2-OH)) around the cells. We anticipate that the EMCIT approach will enable the active in vivo entrapment of radioimaging and radiotherapeutic compounds within the extracellular spaces of primary prostate tumors and their metastases.
Pospisil
Pavel
P
Department of Radiology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Wang
Ketai
K
Al Aowad
Ayman F
AF
Iyer
Lakshmanan K
LK
Adelstein
S James
SJ
Kassis
Amin I
AI
D000135:Acid Phosphatase; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D003198:Computer Simulation; D016503:Drug Delivery Systems; D005110:Extracellular Space / Q000187:drug effects*; D006801:Humans; D007457:Iodine Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008954:Models, Biological; D008958:Models, Molecular; D011355:Prodrugs / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D052999:Quinazolinones / Q000008:administration & dosage / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
D007457:Iodine Radioisotopes; D011355:Prodrugs; D000644:Quaternary Ammonium Compounds; D052999:Quinazolinones; C460023:ammonium 2-(2'-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases