Journal
BIOCONJUGATE CHEMISTRY
Volume 20, Issue 11, Pages 2162-2168Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bc9003475
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Funding
- Southwest Melanoma SPORE Developmental Research Program
- Stranahan Foundation
- Oxnard Foundation
- DOD [W81XWH-09-1-0105]
- NIH [NM-INBRE P20RR-016480]
- W.M. Keck Foundation
- University of New Mexico Cancer Research and Treatment Center [NIH P30 CA118100]
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The purpose of this study was to examine the effect of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) position on melanoma targeting and pharmacokinetics of radiolabeled lactam bridge-cyclized alpha-melanocyte stimulating hormone (alpha-MSH) peptide. Method: A novel lactam bridge-cyclized alpha-MSH peptide, Ac-GluGlu-CycMSH[DOTA] {Ac-Glu-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Lys(DOTA)]}, was synthesized using standard 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry, DOTA was directly attached to the (X-amino group of Lys in the cyclic ring, while the N-terminus of the peptide was acetylated to generate Ac-GluGlu-CycMSH[DOTA]. The MC1 receptor binding affinity of Ac-GluGlu-CycMSH[DOTA] was determined in B16/F1 melanoma cells. Melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-In-111 were determined in B16/F1 melanoma-bearing C57 mice and compared to that of In-111-DOTA-Gly-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp] (In-111-DOTA-GlyGlu-CycMSH; DOTA was coupled to the N-terminus of the peptide). Results: Ac-GluGlu-CycMSH[DOTA] displayed 0.6 nM MC1 receptor binding affinity in B16/F1 cells. Ac-GluGlu-CycMSH[DOTA]-In-111 was readily prepared with greater than 95% radiolabeling yield. Ac-GluGlu-CycMSH[DOTA]-In-111 exhibited high tumor uptake (11.42 +/- 2.20% ID/g 2 h postinjection) and prolonged tumor retention (9.42 +/- 2.41% ID/g 4 h postinjection) in B16/F1 melanoma-bearing C57 mice. The uptake values for nontarget organs were generally low (<1.3% ID/g) except for the kidneys 2, 4, and 24 h postinjection. Conclusions: DOTA position exhibited profound effect on melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-In-111, providing a new insight into the design of lactam bridge-cyclized peptide for melanoma imaging and therapy.
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