TUMOR-SELECTIVE RADIOPHARMACEUTICAL TARGETING VIA RECEPTOR-MEDIATED ENDOCYTOSIS OF GALLIUM-67-DEFEROXAMINE-FOLATE

The receptor-mediated endocytosis uptake pathway for the vitamin folat e was investigated as a target for tumor-selective radiopharmaceutical delivery. The molecular target for this delivery mechanism is a membr ane-associated folate binding protein (FBP) that is overexpressed by a variety of malignant cell lines. Methods: The ability of a Ga-67-labe led deferoxamine-folate conjugate (Ga-67-DF-folate) to target tumor ce lls in vivo was examined using an athymic mouse tumor model. Subcutane ous inoculation of similar to 4 x 10(6) folate-receptor-positive KB (h uman nasopharyngeal carcinoma) cells into athymic mice yielded similar to 0.20 g tumors in 15 days, at which time either Ga-67-DF-folate, Ga -67-deferoxamine (Ga-67-DF) or Ga-67-citrate was administered by intra venous injection. Results: The Ga-67-DF-folate conjugate showed marked tumor-specific deposition in vivo, with 1.0 +/- 0.3% of the injected dose (%ID) in tumor at 4 hr postinjection (equating to 5.2 +/- 1.5 %ID /g tumor; n = 3 mice), Corresponding tumor-to-background ratios at 4 h r postinjection were: tumor/blood = 409 +/- 195, tumor/muscle = 124 +/ - 47; tumor/liver = 11 +/- 3; and tumor/kidney = 2.6 +/- 0.9. Tumor up take of Ga-67-DF-folate conjugate was effectively blocked by co-inject ion of 2.4 +/- 1.0 mg free folate. In control experiments, Ga-67-citra te exhibited tumor uptake of 2.2 +/- 0.4% of the injected dose (10.9 /- 0.2 %ID/g tumor), but very poor target-to-background contrast (tumo r/blood = 0.84 +/- 0.19; tumor/muscle = 5.4 +/- 0.7; tumor/liver = 2.3 +/- 0.2; and tumor/kidney = 2.4 +/- 0.3). Unconjugated Ga-67-deferoxa mine showed no tumor affinity. Conclusion: Receptor-mediated endocytos is of radiolabeled folate-conjugates may offer a suitable mechanism fo r selectively delivering radiopharmaceuticals to tumors for diagnostic imaging and/or radiation therapy.