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Computational Modeling and Experimental Evaluation of a Novel Prodrug for Targeting the Extracellular Space of Prostate Tumors

¹ Department of Radiology, Harvard Medical School, Boston, Massachusetts and ² Bauer Center for Genomics Research, Harvard University, Cambridge, Massachusetts

Requests for reprints: Amin I. Kassis, Department of Radiology, Harvard Medical School, Armenise Building, Room D2-137, 200 Longwood Avenue, Boston, MA 02115. Phone: 617-432-7777; Fax: 617-432-2419; E-mail: amin_kassis{at}hms.harvard.edu.

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 -benzylaminobenzylphosphonic acid. When ¹²⁵IQ_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-[¹²⁵I]iodo-4-(3H)-quinazolinone (¹²⁵IQ_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 ¹²⁵IQ_2-P showed accumulation of radioactive grains (¹²⁵IQ_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. [Cancer Res 2007;67(5):2197–205]