title: Cell penetrating peptides improve tumor delivery of cargos through neuropilin-1-dependent extravasation.
abstract: Cell-penetrating peptides (CPPs), also referred to as protein transduction domains (PTDs), can mediate the cellular uptake of a wide range of macromolecules including peptides, proteins, oligonucleotides, and nanoparticles, and thus have received considerable attention as a promising method for drug delivery in vivo. Here, we report that CPP/PTDs facilitate the extravasation of fused proteins by binding to neuropilin-1 (NRP1), a vascular endothelial growth factor (VEGF) co-receptor expressed on the surface of endothelial and some tumor cells. In this study, we examined the capacity of the amphipathic and cationic CPP/PTDs, PTD-3 and TAT-PTD, respectively, to bind cells in vitro and accumulate in xenograft tumors in vivo. Notably, these functions were significantly suppressed by pre-treatment with NRP1-neutralizing Ab. Furthermore, co-injection of iRGD, a cyclic peptide known to increase NRP1-dependent vascular permeability, significantly reduced CPP/PTD tumor delivery. This data demonstrates a mechanism by which NRP1 promotes the extravasation of CPP/PTDs that may open new avenues for the development of more efficient CPP/PTD delivery systems.
authors.affiliation: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kadonosono
authors.affiliation: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamano
authors.affiliation: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Goto
authors.affiliation: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Tsubaki
authors.affiliation: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Niibori
authors.affiliation: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kuchimaru
authors.affiliation: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan. Electronic address: skondoh@bio.titech.ac.jp.
authors.forename: Shinae
authors.initials: S
authors.lastname: Kizaka-Kondoh
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D015696:Gene Products, tat / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000378:metabolism*; D039942:Neuropilin-1 / Q000378:metabolism*; D009842:Oligopeptides / Q000008:administration & dosage; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D057846:Cell-Penetrating Peptides; D015696:Gene Products, tat; C569656:N-end cysteine peptide tumor-homing peptide; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D039942:Neuropilin-1
keywords: Cell penetrating peptide; Drug delivery; Extravasation; Neuropilin-1; Protein transduction domain