pteroic-acid and Neoplasms

The folate receptor (FR) is a very attractive target in oncological imaging as it is overexpressed by a variety of cancer types, whereas the expression in healthy tissue is very limited. The synthesis of regioisomeric pure folic acid derivatives normally requires a regioselective approach and does not allow the use of native folic acid (FA). As the pharmacophore of FA is assumed to be pteroic acid, its use without the glutamic acid moiety may enable the possibility to considerably simplify the synthesis of a positron emission tomography (PET) tracer for FR imaging. In this work, DO3A-EA-Pte was successfully synthesized and labeled with (68)Ga. It is stable for up to 3 h in PBS and against transchelation by transferrin. It also displays a lipophilicity that allows the assumption that it will show favorable in vivo characteristics for FR imaging via PET.

Topics: Drug Stability; Folate Receptors, GPI-Anchored; Gallium Radioisotopes; Humans; Isotope Labeling; Neoplasms; Positron-Emission Tomography; Pterins; Radiopharmaceuticals; Solubility

Nanoparticulate medicines offer the advantage of allowing delivery of large quantities of unmodified drug within the same particle. Nanoparticle uptake by cancer cells can, however, be compromised due to the large size and hydrophilicity of the particle. To circumvent cell penetration problems and simultaneously improve tumor specificity, nanoparticulate medicines have been linked to targeting ligands that bind to malignant cell surfaces and enter cells by receptor-mediated endocytosis. In this chapter, we summarize multiple methods for delivering nanoparticles into cancer cells by folate receptor-mediated endocytosis, devoting special emphasis to folate-targeted liposomes. Folate receptor-mediated endocytosis has emerged as an attractive strategy for nanoparticle delivery due to both overexpression of the folate receptor on cancer cells and the rapid internalization of the receptor by receptor-mediated endocytosis.

Topics: Animals; Carrier Proteins; Cell Line, Tumor; Diagnostic Imaging; Drug Delivery Systems; Female; Folate Receptors, GPI-Anchored; Folic Acid; Humans; Mice; Mice, Nude; Nanomedicine; Nanoparticles; Neoplasms; Phosphatidylethanolamines; Polyethylene Glycols; Pterins; Receptors, Cell Surface

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.

Topics: Animals; Carrier Proteins; Folate Receptors, GPI-Anchored; Humans; Indium Radioisotopes; KB Cells; Mice; Mice, Nude; Neoplasms; Pentetic Acid; Pterins; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Cell Surface; Tissue Distribution