Design and Synthesis of [¹¹¹In]DTPA−Folate for Use as a Tumor-Targeted Radiopharmaceutical

Abstract

Folate-conjugated metal chelates have been proposed as potential imaging agents for cancers that overexpress folate receptors. In a previous study, folic acid was linked through its gamma-carboxyl group to deferoxamine (DF), and the 67Ga-labeled complex ([67Ga]DF-folate) was examined for in vivo tumor targeting efficiency in athymic mice with a human tumor cell implant. Although superb tumor-to-background contrast was obtained, slow hepatobiliary clearance would compromise imaging of abdominal tumors such as ovarian cancer. In the present study, folic acid was conjugated to an alternative chelator, diethylenetriaminepentaacetic acid (DTPA), via an ethylenediamine spacer. The desired DTPA-folate (gamma) regioisomer was synthesized by two different approaches, purified by reversed phase column chromatography, and characterized mainly by analytical HPLC, mass spectroscopy, and NMR. In cultured tumor cells, uptake of [111In]DTPA-folate (gamma) was found to be specific for folate receptor-bearing cells, and the kinetics of uptake were similar to those of free folate and other folate-conjugated molecules. In the normal rat, intravenously administered [111In]DTPA-folate (gamma) was found to be rapidly excreted into the urine, giving intestinal levels of radiotracer 10-fold lower than those observed with [67Ga]DF-folate (gamma) at 4 h. In a preliminary mouse imaging study, a folate receptor-positive KB cell tumor was readily visualized by gamma scintigraphy 1 h following intravenous administration of [111In]DTPA-folate (gamma).

Conjugation of Folate via Gelonin Carbohydrate Residues Retains Ribosomal-inactivating Properties of the Toxin and Permits Targeting to Folate Receptor Positive Cells

“…However, the receptors for these ligands are expressed on a range of neoplastic and non-neoplastic tissues. Therefore the use of these ligands may give rise to toxin uptake in non-target cells, a phenomenon not observed with folate-targeted conjugates (19,24,25).…”

“…Therefore it is possible that the conjugation of folate to gelonin carbohydrate residues will lead to an increase in the blood circulation of the conjugate compared with toxin alone. Intravenous administration of folate-targeted conjugates to mice has been shown to lead to tumor accumulation of the conjugates, with minimal accumulation in other tissues (24,25). Therefore folate-S-gelonin may be a suitable candidate as an intravenous administered cancer therapy.…”

Contrast Agents for Breast Cancer Diagnosis by Magnetic Resonance Imaging: Targeting the Folate Receptor

“…While a wide range of folate-drug conjugates and folate analogs have been examined as targeted therapeutics (Grüner and Weitman 1999), the targeting of diagnostic pharmaceuticals is only recently being explored (Reddy and Low 1998). Folate conjugates of '"In (Wang, Luo et al 1997;Mathias, Wang et al 1998), 67 Ga (Mathias, Wang et al 1996;Wang, Lee et al 1996), and " m Tc (Guo, Hinkle et al 1999) chelates have been synthesized and examined as targeted radiopharmaceuticals. An [ ul In]-DTPA-folate (DTPA = diethylenetriaminepentaacetic acid) agent was shown (Wang, Luo et al 1997;Mathias, Wang et al 1998) to be specific for folate-receptor-bearing cells with uptake kinetics similar to those of free folate.…”

“…Folate conjugates of '"In (Wang, Luo et al 1997;Mathias, Wang et al 1998), 67 Ga (Mathias, Wang et al 1996;Wang, Lee et al 1996), and " m Tc (Guo, Hinkle et al 1999) chelates have been synthesized and examined as targeted radiopharmaceuticals. An [ ul In]-DTPA-folate (DTPA = diethylenetriaminepentaacetic acid) agent was shown (Wang, Luo et al 1997;Mathias, Wang et al 1998) to be specific for folate-receptor-bearing cells with uptake kinetics similar to those of free folate. In a preliminary mouse study, y-scintigraphy allowed visualization of a folate receptor-positive KB cell tumor following i.v.…”

Isomeric Folate-Conjugated Polymeric Micelles Bind to Folate Receptors and Display Anticancer Effects

“…Nevertheless, the binding ability for α-and γ-folate regioisomers to FRs was disputed. Wang and colleagues showed that the cell surface FRs recognizes folate derivatives at the γ-but not α-carboxylate (Wang et al, 1996;Wang et al, 1997). In contrast, it was recently reported that both α-and γ-folate derivatives are able to bind to folate receptor-positive cells at virtually identical levels (Leamon et al, 1999;Bettio et al, 2006;Zong et al, 2012).…”