title: pH-Selective Cytotoxicity of pHLIP-Antimicrobial Peptide Conjugates.
abstract: Positively charged antimicrobial peptides have become promising agents for the treatment of cancer by inducing apoptosis though their preferential binding and disruption of negatively charged membranes, such as the mitochondrial membrane. (KLAKLAK)2 is such a peptide but due to its polarity, it cannot cross the cellular membrane and therefore relies on the use of a delivery agent. For targeted delivery, previous studies have relied on cell penetrating peptides, nanoparticles or specific biomarkers. Herein, we investigated the first use of pHLIP to selectively target and directly translocate (KLAKLAK)2 into the cytoplasm of breast cancer cells, based on the acidic tumor micro-environment. With the goal of identifying a lead conjugate with optimized selective cytotoxicity towards cancer cells, we analyzed a family of (KLAKLAK)2 analogs with varying size, polarity and charge. We present a highly efficacious pHLIP conjugate that selectively induces concentration- and pH-dependent toxicity in breast cancer cells.
authors.affiliation: Department of Chemistry, Lehigh University, 06 East Packer Ave, Bethlehem, PA 18015, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Burns
authors.affiliation: Department of Chemistry, Lehigh University, 06 East Packer Ave, Bethlehem, PA 18015, USA.
authors.forename: Tanner P
authors.initials: TP
authors.lastname: McCleerey
authors.affiliation: Department of Chemistry, Lehigh University, 06 East Packer Ave, Bethlehem, PA 18015, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Thévenin
mesh_terms: D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008565:Membrane Proteins / Q000138:chemical synthesis / Q000737:chemistry*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D060327:Solid-Phase Synthesis Techniques
chemical_list: D023181:Antimicrobial Cationic Peptides; D004337:Drug Carriers; D008565:Membrane Proteins; C533201:pHLIP protein