title: Family of pH (low) insertion peptides for tumor targeting.
abstract: Cancer is a complex disease with a range of genetic and biochemical markers within and among tumors, but a general tumor characteristic is extracellular acidity, which is associated with tumor growth and development. Acidosis could be a universal marker for cancer imaging and the delivery of therapeutic molecules, but its promise as a cancer biomarker has not been fully realized in the clinic. We have discovered a unique approach for the targeting of acidic tissue using the pH-sensitive folding and transmembrane insertion of pH (low) insertion peptide (pHLIP). The essence of the molecular mechanism has been elucidated, but the principles of design need to be understood for optimal clinical applications. Here, we report on a library of 16 rationally designed pHLIP variants. We show how the tuning of the biophysical properties of peptide-lipid bilayer interactions alters tumor targeting, distribution in organs, and blood clearance. Lead compounds for PET/single photon emission computed tomography and fluorescence imaging/MRI were identified, and targeting specificity was shown by use of noninserting variants. Finally, we present our current understanding of the main principles of pHLIP design.
authors.affiliation: Physics Department, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Dhammika
authors.initials: D
authors.lastname: Weerakkody
authors.forename: Anna
authors.initials: A
authors.lastname: Moshnikova
authors.forename: Mak S
authors.initials: MS
authors.lastname: Thakur
authors.forename: Valentina
authors.initials: V
authors.lastname: Moshnikova
authors.forename: Jennifer
authors.initials: J
authors.lastname: Daniels
authors.forename: Donald M
authors.initials: DM
authors.lastname: Engelman
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Andreev
authors.forename: Yana K
authors.initials: YK
authors.lastname: Reshetnyak
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008051:Lipid Bilayers / Q000737:chemistry; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000737:chemistry*; D017510:Protein Folding; D013816:Thermodynamics; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D008051:Lipid Bilayers; D008565:Membrane Proteins; D010455:Peptides; C533201:pHLIP protein; D049452:Green Fluorescent Proteins