Evaluation of chemical, physical, and biologic properties of tumor-targeting radioiodinated quinazolinone derivative.
Our group is developing a novel technology, enzyme-mediated cancer imaging and therapy (EMCIT), that aims to entrap radioiodinated compounds within solid tumors for noninvasive tumor detection and therapy. In this approach, a water-soluble, radioiodinated prodrug is hydrolyzed in vivo to a highly water-insoluble compound by an enzyme overexpressed extracellularly by tumor cells. We have synthesized and characterized the water-soluble prodrug, 2-(2'-phosphoryloxyphenyl)-6-[(125)I]iodo-4-(3H)-quinazolinone [(125)I]5, which is readily hydrolyzed by alkaline phosphatase, an enzyme expressed by many tumor cell lines, to a water-insoluble drug, 2-(2'-hydroxyphenyl)-6-[(125)I]iodo-4-(3H)-quinazolinone [(125)I]1. In the course of our study, we discovered that ammonium 2-(2'-phosphoryloxyphenyl)-6-tributylstannyl-4-(3H)-quinazolinone, an intermediate in the radioiodination of the prodrug, exists as two isomers (3 and 4) whose radioiodination leads, respectively, to [(125)I]6 and [(125)I]5. These prodrugs have different in vitro and in vivo biologic activities. Compound 6 is not hydrolyzed by alkaline phosphatase (ALP), whereas 5 is highly soluble (mg/mL) in aqueous solution and is rapidly dephosphorylated in the presence of ALP to 1, a water-insoluble molecule (ng/mL). Mouse biodistribution studies indicate that [(125)I]6 has high uptake in kidney and liver and [(125)I]5 has very low uptake in all normal organs. Compounds 3 and 6 are converted, respectively, to 4 and 5 after incubation in DMSO. The stability of 5 in human serum is high. The minimum ALP concentration needed to hydrolyze 5 is much greater than the ALP level in the blood of patients with cancer, and the latter should not affect the pharmacokinetics of the compound. Incubation of 5 with viable human and mouse tumor-cell lines--but not with normal human cells and mouse tissues--leads to its hydrolysis and the formation of large crystals of 1. We expect that 5 will also be hydrolyzed in vivo by tumor cells that express phosphatase activity extracellularly and anticipate the specific precipitation of radioiodinated 1 within tumor cell clusters. This should lead to high tumor-to-normal-tissue ratios and enable imaging (SPECT/PET) and radionuclide therapy of solid tumors.
Wang
Ketai
K
Harvard Medical School, Department of Radiology, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.
Kirichian
Agop M
AM
Aowad
Ayman F Al
AF
Adelstein
S James
SJ
Kassis
Amin I
AI
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D006868:Hydrolysis; D007457:Iodine Radioisotopes / Q000737:chemistry; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000532:radiotherapy; D010755:Organophosphates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D012995:Solubility; D014018:Tissue Distribution
C522258:2-(2'-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone; D007457:Iodine Radioisotopes; D010755:Organophosphates; D011355:Prodrugs; D052999:Quinazolinones; D000469:Alkaline Phosphatase