Controlling Toxicity of Peptide–Drug Conjugates by Different Chemical Linker Structures |
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| Authors: | David Böhme Prof. Dr. Annette G. Beck‐Sickinger |
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| Affiliation: | Institute of Biochemistry, Faculty of Biosciences, Pharmacy & Psychology, Universit?t Leipzig, Brüderstrasse 34, 04103 Leipzig (Germany) |
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| Abstract: | The side effects of chemotherapy can be overcome by linking toxic agents to tumor‐targeting peptides with cleavable linkers. Herein, this concept is demonstrated by addressing the human Y1 receptor (hY1R), overexpressed in breast tumors, with analogues of the hY1R‐preferring [F7,P34]NPY. First, carboxytetramethylrhodamine was connected to [F7,P34]NPY by an amide, ester, disulfide, or enzymatic linkage. Live imaging revealed hY1R‐mediated delivery and allowed visualization of time‐dependent intracellular release. Next, the fluorophore was replaced by the toxic agent methotrexate (MTX). In addition to linkage through the amide, ester, disulfide bond, or enzymatic cleavage site, a novel disulfide/ester linker was designed and coupled to [F7,P34]NPY by solid‐phase peptide synthesis. Internalization studies showed hY1R subtype selective uptake, and cell viability experiments demonstrated hY1R‐mediated toxicity that was clearly dependent on the linkage type. Fast release profiles for fluorophore‐[F7,P34]NPY analogues correlated with high toxicities of MTX conjugates carrying the same linker types and emphasize the relevance of new structures connecting the toxophore and the carrier. |
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| Keywords: | cancer cleavable linkers drug delivery neuropeptide Y peptide– drug conjugates |
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