Glycosylated DOTA-alpha-melanocyte-stimulating hormone analogues for melanoma targeting: influence of the site of glycosylation on in vivo biodistribution.

Abstract

alpha-Melanocyte-stimulating hormone (alpha-MSH) is known to bind to the melanocortin receptor 1 (MC1R) which is overexpressed on melanotic and amelanotic melanoma cells. alpha-MSH analogues are potential candidates for specific targeting of melanoma metastases. Several linear and cyclic radiolabeled MSH peptides have been designed and tested in the past, showing both high affinity for the MC1R in vitro and good incorporation in tumor xenografts in vivo. However, considerable kidney reabsorption of the radiopeptides could not be avoided. With the aim to increase the tumor-to-kidney ratio, we synthesized six glycosylated derivatives of NAPamide, an alpha-MSH octapeptide analogue with high tumor selectivity and coupled them to the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). The peptides were evaluated in vitro for MC1R binding and bioactivity and, after labeling with (111)In, for in vitro cellular uptake and in vivo tissue distribution in mice carrying B16F1 melanoma tumors. The glycopeptides showed excellent binding affinities in the low nanomolar to subnanomolar range using both murine and human melanoma cell lines. However, five glycopeptides displayed lower selectivity in vivo than the parent DOTA-NAPamide, because of either a lower tumor uptake or a higher kidney uptake. In particular C-terminal extension of the amide group by a galactosyl moiety increased the kidney retention dramatically. By contrast, an N-terminally positioned galactose residue in DOTA-Gal-NAPamide improved the tumor-to-kidney ratio (4-48 h AUC of 1.34) by a factor of about 1.2 as compared to the parent DOTA-NAPamide (4-48 h AUC of 1.11), thus serving as new lead compound for MC1R-targeting molecules.

• Authors: Jean-Philippe Bapst, Martine Calame, Heidi Tanner, Alex N Eberle
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 20 Issue 5 Pg. 984-93 (May 20 2009) ISSN: 1520-4812 [Electronic] United States
• PMID: 19388674 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carbohydrates
• Glycopeptides
• Heterocyclic Compounds, 1-Ring
• Peptide Fragments
• Receptor, Melanocortin, Type 1
• alpha-MSH (4-11), acetyl0Nle(4)-Asp(5)-Phe(7)-
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• alpha-MSH

Topics

• Animals
• Binding Sites
• Biological Transport
• Carbohydrates (chemistry)
• Cell Line, Tumor
• Female
• Glycopeptides (chemistry, metabolism, pharmacokinetics, pharmacology)
• Glycosylation
• Heterocyclic Compounds, 1-Ring (chemistry)
• Humans
• Melanoma (metabolism)
• Mice
• Peptide Fragments (chemistry)
• Receptor, Melanocortin, Type 1 (metabolism)
• alpha-MSH (analogs & derivatives, chemistry)