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Tumor Targeting with Radiolabeled _vß₃ Integrin Binding Peptides in a Nude Mouse Model

Departments of Nuclear Medicine [M. L. J., I. D., W. J. O., C. F., F. H. C., O. C. B.] and Obstetrics and Gynecology [M. L. J., L. F. M., H. B.], University Medical Center Nijmegen, 6500 HB Nijmegen, the Netherlands, and Bristol-Myers Squibb, Billerica, Massachusetts 01862 [D. S. E., M. R.]

The _vß₃ integrin is expressed on proliferating endothelial cells such as those present in growing tumors, as well as on tumor cells of various origin. Tumor-induced angiogenesis can be blocked in vivo by antagonizing the _vß₃ integrin with small peptides containing the Arg-Gly-Asp (RGD) amino acid sequence. This tripeptidic sequence, naturally present in extracellular matrix proteins, is the primary binding site of the _vß₃ integrin. Because of selective expression of _vß₃ integrin in tumors, radiolabeled RGD peptides are attractive candidates for _vß₃ integrin targeting in tumors. We studied the in vivo behavior of the radiolabeled dimeric RGD peptide E-[c(RGDfK)]₂ in the NIH:OVCAR-3 s.c. ovarian carcinoma xenograft model in BALB/c nude mice. Conjugation of the 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA) and hydrazinonicotinamide (HYNIC) chelators enabled efficient radiolabeling with ¹¹¹In/⁹⁰Y and ^99mTc, respectively. The radiolabeled peptide was rapidly excreted renally. Uptake in nontarget organs such as liver and spleen was considerable. Tumor uptake peaked at 7.5% injected dose (ID)/g (¹¹¹In-DOTA-E-[c(RGDfK)]₂) or 6.0%ID/g (^99mTc-HYNIC-E-[c(RGDfK)]₂) at 2 and 1 h postinjection, respectively. Integrin _vß₃ receptor binding specificity was demonstrated by reduced tumor uptake after injection of the scrambled control peptide ¹¹¹In-DOTA-E-[c(RDKfD)]₂ (0.28%ID/g at 2 h p.i.) and after coinjection of excess nonradioactive ¹¹⁵In-DOTA-E-[c(RGDfK)]₂ (0.22%ID/g at 2 h p.i.). A single injection of ⁹⁰Y-DOTA-E-[c(RGDfK)]₂ at the maximum-tolerated dose (37 MBq) in mice with small s.c. tumors caused a significant growth delay as compared with mice treated with 37 MBq ⁹⁰Y-labeled scrambled peptide or untreated mice (median survival of 54 versus 33.5 versus 19 days, respectively). In conclusion, the radiolabeled RGD peptides ¹¹¹In-DOTA-E-[c(RGDfK)]₂ and ^99mTc-HYNIC-E-[c(RGDfK)]₂ demonstrated high and specific tumor uptake in a human tumor xenograft. Injection of ⁹⁰Y-DOTA-E-[c(RGDfK)]₂ induced a significant delay in tumor growth. Potentially, these peptides can be used for peptide receptor radionuclide imaging as well as therapy.

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