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Biochemistry and Biophysics |
-Melanocyte-stimulating Hormone Peptide Analogues1
Departments of Biochemistry [JQ. C., T. P. Q.] and Chemistry [Z. C., S. S. J.], University of Missouri-Columbia, Columbia, Missouri 65211, and Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri 65201 [T. J. H.]
Preliminary reports have demonstrated that 99mtechnetium
(Tc)-labeled cyclic [Cys3,4,10,
D-Phe7]
-MSH3–13 (CCMSH)
exhibits high tumor uptake and retention values in a murine melanoma
mouse model. In this report, the tumor targeting mechanism of
99mTc-CCMSH was studied and compared with four other
radiolabeled -melanocyte stimulating hormone (-MSH) peptide
analogues: 125I-(Tyr2)-[Nle4,
D-Phe7]-MSH
[125I-(Tyr2)-NDP];
99mTc-CGCG-NDP; 99mTc-Gly11-CCMSH;
and 99mTc-Nle11-CCMSH. In vitro
receptor binding, internalization, and cellular retention of
radiolabeled -MSH analogues in B16/F1 murine cell line demonstrated
that >70% of the receptor-bound radiolabeled analogues were
internalized together with the receptor. Ninety % of the internalized
125I-(Tyr2)-NDP, whereas only 36% of
internalized 99mTc-CCMSH, was released from the cells into
the medium during a 4-h incubation at 37°C. Two mouse models, C57
mice and severe combined immunodeficient (Scid) mice, inoculated s.c.
with B16/F1 murine and TXM-13 human melanoma cells were used for the
in vivo studies. Tumor uptake values of 11.32 and 2.39
[% injected dose (ID)/g] for 99mTc-CCMSH at 4 h
after injection, resulted in an uptake ratio of tumor:blood of 39.0 and
11.5 in murine melanoma-C57 and human melanoma-Scid mouse models,
respectively. Two strategies for decreasing the nonspecific kidney
uptake of 99mTc-CCMSH, substitution of Lys11 in
CCMSH with Gly11 or Nle11, and lysine
coinjection, were evaluated. The biodistribution data for the modified
peptides showed that Lys11 replacement dramatically
decreased the kidney uptake, whereas the tumor uptakes of
99mTc-Nle11- and
99mTc-Gly11-CCMSH were significantly lower than
that of 99mTc-CCMSH. Lysine coinjection significantly
decreased the kidney uptake (e.g., from 14.6% ID/g to
4.5% ID/g at 4 h after injection in murine melanoma-C57 mice)
without significantly changing the value of tumor uptake of
99mTc-CCMSH. In conclusion, the compact cyclic structure of
99mTc-CCMSH, its resistance to degradation, and its
enhanced intracellular retention are the major contributing factors to
the superior in vivo tumor targeting properties of
99mTc-CCMSH. Lys11 residue in
99mTc-CCMSH is critical to the tumor targeting in
vivo, and lysine coinjection rather than lysine replacement can
significantly decrease the nonspecific renal radioactivity accumulation
without impeding the high melanoma-targeting properties of
99mTc-CCMSH. The metal-cyclized CCMSH molecule displays
excellent potential for the development of melanoma-specific diagnostic
and therapeutic agents.
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