Double Methotrexate-Modified Neuropeptide Y Analogues Express Increased Toxicity and Overcome Drug Resistance in Breast Cancer Cells

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• 作者：David Böhme ; Jan Krieghoff ; Annette G. Beck-Sickinger
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3409-3417
• 全文大小：498K
• 年卷期：0
• ISSN：1520-4804

文摘

Bioconjugates containing the neuropeptide Y (NPY) analogue [F⁷,P³⁴]-NPY as targeting moiety are able to deliver toxic agents specifically to breast cancer cells that overexpress the human Y₁-receptor (hY₁R). To increase their activity, multiple toxophores can be attached to one peptide. Herein, synthesis and characterization of [F⁷,P³⁴]-NPY conjugates containing two methotrexate (MTX) molecules are presented. First, carboxytetramethylrhodamine was linked to [F⁷,P³⁴]-NPY by amide or enzymatic linkage. The conjugate containing the enzymatic cleavage site showed high extracellular stability and fast intracellular release. Then, MTX was introduced at positions four and 22 of [F⁷,P³⁴]-NPY, connected by enzymatic or amide linkage. The toxicity of the analogues on breast cancer cells was hY₁R-mediated and dependent on the used linkage and amount of toxophores. Furthermore, conjugates revealed higher potency than MTX on MTX-resistant cells. These results emphasize that peptide–drug conjugates can overcome drug resistance and that the attachment of multiple cleavable toxophores enhances the efficiency of this smart delivery system.