title: The augmentation of intracellular delivery of peptide therapeutics by artificial protein transduction domains.
abstract: Protein transduction domains (PTDs), such as HIV-derived Tat, have been successfully used as functional biomaterials for intracellular delivery of anti-cancer macromolecular drugs (protein, peptides, and oligonucleotides). Although there were therefore great expectations regarding the therapeutic potential of PTDs for the development of anti-cancer therapeutics, their clinical application so far has been extremely limited because of the relatively high concentrations required to mediate any effects on cancer cells in vitro or in vivo. In this context, improving the transduction efficiency of PTDs using phage display-based molecular evolution techniques may be useful for creating artificial PTDs with high efficiency and safety. Here, we report an evaluation of transduction efficiency and toxicity of such artificial PTDs (designated mT02 and mT03) compared with Tat. The internalization of mT02 was the most rapid and efficient by a mechanism different from the usual macropinocytosis. Furthermore, we found that artificial PTDs fused with survivin antagonistic peptide potentiate tumor cell-cytostatic activity. Thus, the results of this work provide new insights for designing new-generation peptide therapeutics for a wide variety of cancers as well as those expressing survivin.
authors.affiliation: Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Toshiki
authors.initials: T
authors.lastname: Sugita
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mukai
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Abe
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Kamada
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsunoda
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tsutsumi
mesh_terms: D000595:Amino Acid Sequence; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D015638:Cytochalasin D / Q000378:metabolism; D054697:Cytostatic Agents / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D010873:Pinocytosis / Q000502:physiology; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D014161:Transduction, Genetic / Q000379:methods*; D047392:beta-Cyclodextrins / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D054697:Cytostatic Agents; D004337:Drug Carriers; D010446:Peptide Fragments; D010455:Peptides; D011993:Recombinant Fusion Proteins; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; C503112:shepherdin; D054322:tat Gene Products, Human Immunodeficiency Virus; D015638:Cytochalasin D