title: Tumor targeting of a cell penetrating peptide by fusing with a pH-sensitive histidine-glutamate co-oligopeptide.
abstract: Cell penetrating peptides (CPPs) have been well established as potential carriers for intracellular delivery of protein/peptide therapeutics. However, their lack of selectivity impedes their application in vivo. In order to increase their specificity, a highly pH-sensitive histidine-glutamate (HE) co-oligopeptide was fused with a CPP, i.e. model amphipathic peptide (MAP), and was expressed as a fusion protein with glutathione S-transferase (GST) acting as a cargo protein. Compared with two other fusion proteins containing either HE or MAP, only the fused peptide (HE-MAP) could effectively deliver the cargo GST protein to cells at pH 6.5 or below, while maintaining low delivery to cells at pH 7.0 and above. Using a xenograft mouse model of human breast cancer, fluorescent imaging showed that only HE-MAP could effectively target GST to the tumor site, while reducing non-specific association of MAP in other organs. The data presented in this report demonstrate the diagnostic and/or therapeutic potential of the fused peptide, HE-MAP, for targeting the acidic tumor microenvironment. The concise design for this pH-sensitive peptide offers a simple way to overcome CPP's lack of selectivity, which could lead to increased application of CPPs and macromolecular therapeutics.
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA 90033, USA.
authors: Likun
authors: L
authors: Fei
authors: Molecular Imaging Center, Department of Radiology, Keck School of Medicine, University of Southern California, 2250 Alcazar Street, CSC 103, CA 90033, USA.
authors: Li-Peng
authors: LP
authors: Yap
authors: Molecular Imaging Center, Department of Radiology, Keck School of Medicine, University of Southern California, 2250 Alcazar Street, CSC 103, CA 90033, USA.
authors: Peter S
authors: PS
authors: Conti
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA 90033, USA.
authors: Wei-Chiang
authors: WC
authors: Shen
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA 90033, USA. Electronic address: zaro@usc.edu.
authors: Jennica L
authors: JL
authors: Zaro
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy; D002460:Cell Line; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D018698:Glutamic Acid / Q000737:chemistry*; D005982:Glutathione Transferase / Q000008:administration & dosage* / Q000627:therapeutic use*; D006367:HeLa Cells; D006639:Histidine / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D023041:Xenograft Model Antitumor Assays
chemical_list: D057846:Cell-Penetrating Peptides; D018698:Glutamic Acid; D006639:Histidine; D005982:Glutathione Transferase
keywords: Drug delivery; Image analysis; Peptide; Recombinant protein; pH-sensitive activation