Development of Melanoma-Targeted Polymer Micelles by Conjugation of a Melanocortin 1 Receptor (MC1R) Specific Ligand

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 8, 2011
• 年：2011
• 卷：54
• 期：23
• 页码：8078-8084
• 全文大小：258K
• 年卷期：v.54,no.23(December 8, 2011)
• ISSN：1520-4804

文摘

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-NH₂) 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.