Improved tumor targeting of radiolabeled RGD peptides using rapid dose fractionation

Arginine-glycine-aspartic acid (RGD) peptides preferentially bind to alpha(v)beta(3) integrin, an integrin expressed on newly formed endothelial cells and on various tumor cells. When labeled with beta-emitting radionuclides, these peptides can be used for peptide-receptor radionuclide therapy of malignant tumors. These studies aimed to investigate whether tumor targeting and tumor therapy could be optimized by dose fractionation. The RGD-peptide DOTA-E-[c(RGDfK)](2) was labeled with In-111 for biodistribution experiments and with Y-90 for therapy experiments. In mice with NIH:OVCAR-3 ovarian carcinoma xenografts, optimal tumor uptake was obtained at peptide doses up to 1.0 mug (4.8 %ID/g). A peptide dose of 5 mug, required to administer the maximum tolerable dose (MTD) Y-90-DOTA-E-[c(RGDfK)](2), was administered as 5 portions of 1.0 mug. Tumor uptake of the fifth portion was significantly higher than that of the single 5.0 mug portion (3.3 %ID/g versus 2.1 %ID/g). The therapeutic efficacy of 37 MBq Y-90-DOTA-E-[c(RGDfK)](2) (1 X 5.0 mug) was compared with that of 37 MBq administered in five equal portions (5 X 1.0 mug). No difference in tumor growth between the fractionated and the nonfractionated therapy was observed. In conclusion, dose fractionation resulted in higher radiation doses. However, therapeutic efficacy of the radiolabeled peptide was not significantly improved by dose fractionation.