Original Articles
Receptor-mediated targeting of 67Ga-Deferoxamine-Folate to folate-receptor-positive human kb tumor xenografts

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Abstract

The radiochemical synthesis and stability of 67Ga-deferoxamine-folate ([67Ga]Ga-DF-Folate) were examined as a function of DF-Folate concentration. Optimal labeling occurred at DF-Folate concentrations ≥2.5 μg/mL. To define the possible biological significance of variations in product formulation, the biodistribution of [67Ga]Ga-DF-Folate was examined as a function of administered deferoxamine-folate dose in an athymic mouse KB tumor model. The folate-receptor-positive KB tumors were found to concentrate the 67Ga radiolabel in a dose-dependent fashion, consistent with saturable involvement of the folate receptor in mediating tumor accumulation of the radiopharmaceutical.

Introduction

The tumor-cell-membrane-associated folate receptor is a potential molecular target for selective radiopharmaceutical delivery to ovarian, endometrial, and other human tumors known to overexpress folate binding protein (FBP) 1, 2. FBP is a glycosyl-phosphatidylinositol-linked cell membrane protein involved in cellular uptake of oxidized folates via endocytosis (4). Previous studies have shown that simple low-molecular-weight folate-chelate conjugates, such as 67Ga-deferoxamine-folate ([67Ga]Ga-DF-Folate; 6, 7, 8, 12) and 111In-DTPA-Folate 9, 10, 11, 13, are able to target this tumor receptor system both in vitro and in vivo. The present study was undertaken to better define optimal conditions for radiochemical synthesis of [67Ga]Ga-DF-Folate, and to define the effects of DF-Folate dose on [67Ga]Ga-DF-Folate biodistribution in a mouse tumor model.

Section snippets

General

The deferoxamine-folate(γ) conjugate (DF-Folate, Fig. 1) was prepared as described previously (12). No-carrier-added 67Ga-gallium chloride was obtained as an aqueous HCl solution from Mallinckrodt Medical, Inc. (Maryland Heights, MO). Folate-deficient rodent chow was obtained commercially (ICN Biomedicals, Costa Mesa, CA) and ultraviolet (UV) irradiated prior to use. The KB cells, a human oral epidermoid carcinoma cell line, were cultured and prepared for implantation as described previously 6

Results and discussion

Radiochemical purity of the [67Ga]Ga-DF-Folate product after 24 h incubation was found to exceed 95%, except at the two lowest DF-Folate conjugate concentrations (≤0.25 μg/mL), in which labeling yields remained below 60% at 24 h (Table 1 and Fig. 2). At DF-Folate concentrations of 0.0025–2.75 mg/mL, radiolabeling yields always exceeded 80% by 10 min following DF-Folate addition to the [67Ga]Ga-acetylacetonate solution (Table 1).

The biodistribution of [67Ga]Ga-DF-Folate was determined in

Conclusions

These data support our previous findings 6, 7 of saturable, receptor-mediated, uptake of [67Ga]Ga-DF-Folate in folate-receptor-positive KB tumor xenografts.

Acknowledgements

This work was supported in part by The Walther Cancer Institute, a “Jump-Start” Grant awarded by the Purdue Cancer Center, and a grant from the National Cancer Institute (RO1-CA70845).

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