Tumor-selective radiopharmaceutical targeting via receptor-mediated endocytosis of gallium-67-deferoxamine-folate.
The receptor-mediated endocytosis uptake pathway for the vitamin folate was investigated as a target for tumor-selective radiopharmaceutical delivery. The molecular target for this delivery mechanism is a membrane-associated folate binding protein (FBP) that is overexpressed by a variety of malignant cell lines.


METHODS
The ability of a 67Ga-labeled deferoxamine-folate conjugate (67Ga-DF-folate) to target tumor cells in vivo was examined using an athymic mouse tumor model. Subcutaneous inoculation of approximately 4 X 10(6) folate-receptor-positive KB (human nasopharyngeal carcinoma) cells into athymic mice yielded approximately 0.20 g tumors in 15 days, at which time either 67Ga-DF-folate, 67Ga-deferoxamine (67Ga-DF) or 67Ga-citrate was administered by intravenous injection.


RESULTS
The 67Ga-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 hr postinjection were: tumor/blood = 409 +/- 195; tumor/muscle = 124 +/- 47; tumor/liver = 11 +/- 3; and tumor/kidney = 2.6+/-0.9. Tumor uptake of 67Ga-DF-folate conjugate was effectively blocked by co-injection of 2.4+/-1.0 mg free folate. In control experiments, 67Ga-citrate 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 (tumor/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 67Ga-deferoxamine showed no tumor affinity.


CONCLUSIONS
Receptor-mediated endocytosis of radiolabeled folate-conjugates may offer a suitable mechanism for selectively delivering radiopharmaceuticals to tumors for diagnostic imaging and/or radiation therapy.
Mathias
C J
CJ
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907-1333, USA.
Wang
S
S
Lee
R J
RJ
Waters
D J
DJ
Low
P S
PS
Green
M A
MA
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D003676:Deferoxamine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics; D004705:Endocytosis; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000378:metabolism; D011877:Radionuclide Imaging; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000378:metabolism
D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; C099574:deferoxamine-gamma-folate conjugate; D005492:Folic Acid; D003676:Deferoxamine