The alpha(v)
beta(3) 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 alpha(v)
beta(3) 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 alpha(v)
beta(3) integrin. Because of selective expression of alpha(v)
beta(3) integrin in
tumors, radiolabeled RGD
peptides are attractive candidates for alpha(v)
beta(3) 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 (111)In/(90)Y and (99m)Tc, 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 ((111)In-
DOTA-E-[c(RGDfK)](2)) or 6.0%ID/g ((99m)Tc-HYNIC-E-[c(RGDfK)](2)) at 2 and 1 h postinjection, respectively.
Integrin alpha(v)beta(3) receptor binding specificity was demonstrated by reduced
tumor uptake after injection of the scrambled control
peptide (111)In-
DOTA-E-[c(RDKfD)](2) (0.28%ID/g at 2 h p.i.) and after coinjection of excess nonradioactive (115)In-
DOTA-E-[c(RGDfK)](2) (0.22%ID/g at 2 h p.i.). A single injection of (90)
Y-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 (90)Y-labeled scrambled
peptide or untreated mice (median survival of 54 versus 33.5 versus 19 days, respectively). In conclusion, the radiolabeled RGD
peptides (111)In-
DOTA-E-[c(RGDfK)](2) and (99m)Tc-HYNIC-E-[c(RGDfK)](2) demonstrated high and specific
tumor uptake in a human
tumor xenograft. Injection of (90)
Y-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.