Targeting the tumor-associated folate receptor with an 111In-DTPA conjugate of pteroic acid.

Abstract

The cell membrane folate receptor is a potential molecular target for tumor-selective drug delivery. To probe structural requirements for folate receptor targeting with low molecular weight radiometal chelates, specifically the role of the amino acid fragment of folic acid (pteroylglutamic acid) in mediating targeting selectivity, the amide-linked conjugate pteroyl-NHCH(2)CH(2)OCH(2)CH(2)OCH(2)CH(2)NH-DTPA was prepared by a three-step procedure from pteroic acid, 2,2'-(ethylenedioxy)-bis(ethylamine), and t-Bu-protected DTPA. This conjugate, 1-{2-[2-[(2-(biscarboxymethyl-amino)ethyl)-carboxymethyl-amino]ethyl]-carboxymethyl-amino}-acetylamino-3,6-dioxa-8-pteroylamino-octane (1), was employed for synthesis of the corresponding (111)In(III) radiopharmaceutical. Following intravenous administration to athymic mice, the (111)In complex of 1 was found to selectively localize in folate receptor-positive human KB tumor xenografts and to afford prolonged tumor retention of the (111)In radiolabel (5.4 +/- 0.8, 5.6 +/- 1.1, and 3.6 +/- 0.6% of the injected dose per gram of tumor at 1, 4, and 24 h, respectively). The observed tumor localization was effectively blocked by co-administration of folic acid with the (111)In-1 complex, consistent with a folate receptor-mediated targeting process. In control studies, tumor targeting with this pteroic acid conjugate appears as effective as that seen using (111)In-DTPA-folate, a radiopharmaceutical that has progressed to clinical trials for detection of folate receptor-expressing gynecological tumors.

• Authors: Chun-Yen Ke, Carla J Mathias, Mark A Green
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 127 Issue 20 Pg. 7421-6 (May 25 2005) ISSN: 0002-7863 [Print] United States
• PMID: 15898791 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carrier Proteins
• Folate Receptors, GPI-Anchored
• Indium Radioisotopes
• Pterins
• Radiopharmaceuticals
• Receptors, Cell Surface
• Pentetic Acid
• pteroic acid

Topics

• Animals
• Carrier Proteins (metabolism)
• Folate Receptors, GPI-Anchored
• Humans
• Indium Radioisotopes
• KB Cells
• Mice
• Mice, Nude
• Neoplasms (diagnostic imaging, metabolism)
• Pentetic Acid (analogs & derivatives, chemistry, pharmacokinetics)
• Pterins (chemistry, pharmacokinetics)
• Radionuclide Imaging
• Radiopharmaceuticals (chemistry, pharmacokinetics)
• Receptors, Cell Surface (metabolism)
• Tissue Distribution