Development of melanoma-targeted polymer micelles by conjugation of a melanocortin 1 receptor (MC1R) specific ligand

Natalie M. Barkey, Narges K. Tafreshi, Jatinder S. Josan, Channa R. De Silva, Kevin N. Sill, Victor J Hruby, Robert J. Gillies, David L. Morse, Josef Vagner

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The incidence of malignant melanoma is rising faster than that of any other cancer in the United States. Because of its high expression on the surface of melanomas, MC1R has been investigated as a target for selective imaging and therapeutic agents against melanoma. Eight ligands were screened against cell lines engineered to overexpress MC1R, MC4R, or MC5R. Of these, compound 1 (4-phenylbutyryl-His-dPhe-Arg-Trp-NH 2) exhibited high (0.2 nM) binding affinity for MC1R and low (high nanomolar) affinities for MC4R and MC5R. Functionalization of the ligand at the C-terminus with an alkyne for use in Cu-catalyzed click chemistry was shown not to affect the binding affinity. Finally, formation of the targeted polymer, as well as the targeted micelle formulation, also resulted in constructs with low nanomolar binding affinity.

Original languageEnglish (US)
Pages (from-to)8078-8084
Number of pages7
JournalJournal of Medicinal Chemistry
Volume54
Issue number23
DOIs
StatePublished - Dec 8 2011

Fingerprint

Receptor, Melanocortin, Type 1
Micelles
Melanoma
Polymers
Ligands
Click Chemistry
Alkynes
Cell Line
Incidence
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Development of melanoma-targeted polymer micelles by conjugation of a melanocortin 1 receptor (MC1R) specific ligand. / Barkey, Natalie M.; Tafreshi, Narges K.; Josan, Jatinder S.; De Silva, Channa R.; Sill, Kevin N.; Hruby, Victor J; Gillies, Robert J.; Morse, David L.; Vagner, Josef.

In: Journal of Medicinal Chemistry, Vol. 54, No. 23, 08.12.2011, p. 8078-8084.

Research output: Contribution to journalArticle

Barkey, Natalie M. ; Tafreshi, Narges K. ; Josan, Jatinder S. ; De Silva, Channa R. ; Sill, Kevin N. ; Hruby, Victor J ; Gillies, Robert J. ; Morse, David L. ; Vagner, Josef. / Development of melanoma-targeted polymer micelles by conjugation of a melanocortin 1 receptor (MC1R) specific ligand. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 23. pp. 8078-8084.
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AU - De Silva, Channa R.

AU - Sill, Kevin N.

AU - Hruby, Victor J

AU - Gillies, Robert J.

AU - Morse, David L.

AU - Vagner, Josef

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AB - The incidence of malignant melanoma is rising faster than that of any other cancer in the United States. Because of its high expression on the surface of melanomas, MC1R has been investigated as a target for selective imaging and therapeutic agents against melanoma. Eight ligands were screened against cell lines engineered to overexpress MC1R, MC4R, or MC5R. Of these, compound 1 (4-phenylbutyryl-His-dPhe-Arg-Trp-NH 2) exhibited high (0.2 nM) binding affinity for MC1R and low (high nanomolar) affinities for MC4R and MC5R. Functionalization of the ligand at the C-terminus with an alkyne for use in Cu-catalyzed click chemistry was shown not to affect the binding affinity. Finally, formation of the targeted polymer, as well as the targeted micelle formulation, also resulted in constructs with low nanomolar binding affinity.

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