Introduction: Because of the restricted expression in normal tissues and its abundant expression in various types of tumors, Ξ± v Ξ² 3 integrin is considered a suitable receptor for tumor-targeting. RGD peptides contain the Arg-Gly-Asp sequence and preferentially bind to the Ξ± v Ξ² 3 integrin receptor. In previous studies, we have shown that radiolabeled cyclic RGD peptides specifically accumulated in subcutaneously growing tumors in nude mice. Here we studied the tumor-targeting potential of an 111 In-labeled cyclic DOTA-E-c[RGDfK] in athymic mice with intraperitoneally (ip) growing ovarian carcinoma tumors. Furthermore, the therapeutic potential of the 177 Lu-labeled RGD peptide was investigated.
Experimental: DOTA-E-c(RGDfK) was labeled with 111 In at a specific activity of 10 GBq/ΞΌmol. Specific activity with Lu-177 was 162 GBq/ΞΌmol. Tumor targeting of the 111 In-labeled compound was studied in athymic mice with i.p. growing NIH:OVCAR-3 xenografts. The optimal peptide dose of 111 In-DOTA-E-c(RGDfK) in this model was determined. In addition, the biodistribution at optimal dose was determined at various time points. The effect of the route of administration was studied (ip vs iv). The therapeutic potential was investigated, one group of mice (n=7) with ip OVCAR-3 tumors received 37 MBq/mouse 177 Lu-DOTA-E-c(RGDfK), while a control group did not receive any treatment.
Results and Discussion: Optimal tumor uptake of 111 In-DOTA-E-c(RGDfK) was observed at peptide doses ranging from 0.03 ΞΌg to 0.1 ΞΌg (20.6 Β± 9.7% ID/g and 18.5 Β± 5.9% ID/g, respectively). At 2 h pi, the tumor-to-blood ratio at a peptide dose of 0.1 ΞΌg was 133 Β± 46. At higher peptide doses the uptake in the tumor was significantly lower, indicating receptor saturation. At a peptide dose of 0.1 ΞΌg, tumor uptake peaked at 4 h pi (38.8 Β± 2.7% ID/g) and gradually decreased with time. Blood levels were 0.98 Β± 0.20% ID/g at 0.5 h pi and rapidly decreased to 0.006 Β± 0.001% ID/g at 72 hr pi, resulting in extremely high tumor-to-blood ratios (3216 Β± 120). At 2 h pi, tumor uptake after ip injection was 35.2 Β± 3.8% ID/g whereas after iv injection, the tumor uptake was only 0.98 Β± 0.26% ID/g. Mice that received 37 MBq 177 Lu-DOTA-E-c(RGDfK) ip showed a significant longer survival than the mice that received no treatment (p = 0.017). Median survival of mice that were treated with the 177 Lu labeled RGD peptide was 21 wks, whereas that for the untreated mice was 5 wks.
Conclusion:
We showed that 111 In-DOTA-E-c(RGDfK) has high and specific uptake in mice with i.p. growing OVCAR-3 tumors. PRRT experiments in this model of ovarian cancer indicated that ip tumor growth can be inhibited significantly by a therapeutic dose of 177 Lu-DOTA-E-c(RGDfK).