title: Novel pH-Sensitive Cyclic Peptides.
abstract: A series of cyclic peptides containing a number of tryptophan (W) and glutamic acid (E) residues were synthesized and evaluated as pH-sensitive agents for targeting of acidic tissue and pH-dependent cytoplasmic delivery of molecules. Biophysical studies revealed the molecular mechanism of peptides action and localization within the lipid bilayer of the membrane at high and low pHs. The symmetric, c[(WE)4WC], and asymmetric, c[E4W5C], cyclic peptides translocated amanitin, a polar cargo molecule of similar size, across the lipid bilayer and induced cell death in a pH- and concentration-dependent manner. Fluorescently-labelled peptides were evaluated for targeting of acidic 4T1 mammary tumors in mice. The highest tumor to muscle ratio (5.6) was established for asymmetric cyclic peptide, c[E4W5C], at 24 hours after intravenous administration. pH-insensitive cyclic peptide c[R4W5C], where glutamic acid residues (E) were replaced by positively charged arginine residues (R), did not exhibit tumor targeting. We have introduced a novel class of cyclic peptides, which can be utilized as a new pH-sensitive tool in investigation or targeting of acidic tissue.
authors: Department of Physics, University of Rhode Island, Kingston, RI 02881, US.
authors: Dhammika
authors: D
authors: Weerakkody
authors: Department of Physics, University of Rhode Island, Kingston, RI 02881, US.
authors: Anna
authors: A
authors: Moshnikova
authors: Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, 9401 Jeronimo Road, Irvine, CA 92618, US.|Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road Kingston, RI 02881, US.|Cellulose and Paper Department, National Research Center, Dokki 12622, Cairo, Egypt.
authors: Naglaa Salem
authors: NS
authors: El-Sayed
authors: Department of Physics, University of Rhode Island, Kingston, RI 02881, US.
authors: Ramona-Cosmina
authors: RC
authors: Adochite
authors: Department of Physics, University of Rhode Island, Kingston, RI 02881, US.
authors: Gregory
authors: G
authors: Slaybaugh
authors: Department of Physics, University of Rhode Island, Kingston, RI 02881, US.
authors: Jovana
authors: J
authors: Golijanin
authors: Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, 9401 Jeronimo Road, Irvine, CA 92618, US.|Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road Kingston, RI 02881, US.
authors: Rakesh K
authors: RK
authors: Tiwari
authors: Department of Physics, University of Rhode Island, Kingston, RI 02881, US.
authors: Oleg A
authors: OA
authors: Andreev
authors: Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, 9401 Jeronimo Road, Irvine, CA 92618, US.|Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road Kingston, RI 02881, US.
authors: Keykavous
authors: K
authors: Parang
authors: Department of Physics, University of Rhode Island, Kingston, RI 02881, US.
authors: Yana K
authors: YK
authors: Reshetnyak
mesh_terms: D000546:Amanitins / Q000378:metabolism; D000818:Animals; D005260:Female; D018698:Glutamic Acid / Q000008:administration & dosage / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D014364:Tryptophan / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D000546:Amanitins; D008051:Lipid Bilayers; D010456:Peptides, Cyclic; D018698:Glutamic Acid; D014364:Tryptophan