title: Targeting acidity in diseased tissues: mechanism and applications of the membrane-inserting peptide, pHLIP.
abstract: pHLIPs are a family of soluble ∼36 amino acid peptides, which bind to membrane surfaces. If the environment is acidic, a pHLIP folds and inserts across the membrane to form a stable transmembrane helix, thus preferentially locating itself in acidic tissues. Since tumors and other disease tissues are acidic, pHLIPs' low-pH targeting behavior leads to applications as carriers for diagnostic and surgical imaging agents. The energy of membrane insertion can also be used to promote the insertion of modestly polar, normally cell-impermeable cargos across the cell membrane into the cytosol of targeted cells, leading to applications in tumor-targeted delivery of therapeutic molecules. We review the biochemical and biophysical basis of pHLIPs' unique properties, diagnostic and therapeutic applications, and the principles upon which translational applications are being developed.
authors.affiliation: Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Deacon
authors.affiliation: Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Engelman
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA. Electronic address: fbarrera@utk.edu.
authors.forename: Francisco N
authors.initials: FN
authors.lastname: Barrera
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D002463:Cell Membrane Permeability / Q000187:drug effects*; D016503:Drug Delivery Systems; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008565:Membrane Proteins / Q000737:chemistry / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017433:Protein Structure, Secondary
chemical_list: D008565:Membrane Proteins; C533201:pHLIP protein
keywords: Membrane insertion; Transmembrane; Tumor microenvironment; Tumor targeting