title: Novel cleavable cell-penetrating peptide-drug conjugates: synthesis and characterization.
abstract: We report the first drug conjugate with a negatively charged amphipathic cell-penetrating peptide. Furthermore, we compare two different doxorubicin cell-penetrating peptide conjugates, which are both unique in their properties, due to their net charge at physiological pH, namely the positively charged octaarginine and the negatively charged proline-rich amphipathic peptide. These conjugates were prepared exploiting a novel heterobifunctional crosslinker to join the N-terminal cysteine residue of the peptides with the aliphatic ketone of doxorubicin. This small linker contains an activated thiol as well as aminooxy functionality, capable of generating a stable oxime bond with the C-13 carbonyl group of doxorubicin. The disulfide bond formed between the peptide and doxorubicin enables the release of the drug in the cytosol, as confirmed by drug-release studies performed in the presence of glutathione. Additionally, the cytotoxicity as well as the cellular uptake and distribution of this tripartite drug delivery system was investigated in MCF-7 and HT-29 cell lines.
authors.affiliation: Department of Synthetic Chemistry, Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Lelle
authors.forename: Stefanie U
authors.initials: SU
authors.lastname: Frick
authors.forename: Kerstin
authors.initials: K
authors.lastname: Steinbrink
authors.forename: Kalina
authors.initials: K
authors.lastname: Peneva
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D003600:Cytosol / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry* / Q000494:pharmacology; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D004317:Doxorubicin
keywords: anthracyclines; antitumor agents; drug delivery; peptides; synthesis