The objective of this study was to examine radiopharmaceutica
ls that target the
lpha.gif" BORDER=0>3
le">1 integrin todetermine if these agents target tumors for diagnostic imaging and/or targeted radiotherapy of cancer.Prior studies had shown that residues 531-542 from the
lpha.gif" BORDER=0>1 chain of type IV co
llagen bind a varietyof tumor ce
ll lpha.gif" BORDER=0>3
le">1 integrins. A peptide mimic of this sequence containing a
ll D-amino acids (designated
D-Hep-III) was synthesized by so
lid-phase methods. The tetraazamacrocyc
lic che
lator, TETA, wasconjugated to the peptide whi
le it was resin-bound. TETA-
D-Hep-III and
D-Hep-III were radio
labe
ledwith
64Cu and
125I, respective
ly, in high specific activity and radiochemica
l purity. Hetero
logouscompetitive binding assays between
D-Hep-III and either
125I-
D-Hep-III or
64Cu-TETA-
D-Hep-IIIindicated
low micromo
lar affinity of
D-Hep-III. The biodistribution of each radio
labe
led ana
logue of
D-Hep-III was carried out in rats and tumor-bearing mice. Both ana
logues were rapid
ly c
leared fromthe b
lood in norma
l rats, with the kidneys receiving the highest accumu
lation of each.
SKOV3 humanovarian tumor ce
lls, known to strong
ly express
lpha.gif" BORDER=0>3
le">1, were xenografted in SCID mice. Loca
lization of
125I-
D-Hep III and
64Cu-TETA-
D-Hep III in the xenografts were
low (&
lt;2% ID/g), and in the case of
125I-
D-Hep III, not inhibited by a competitive dose of
D-Hep III. The
low tumor accumu
lation is
like
lynot due to receptor down-regu
lation, but rather due to the weak affinity of the radio
ligands for the
lpha.gif" BORDER=0>3
le">1 integrin.