title: Accumulation of arginine-rich cell-penetrating peptides in tumors and the potential for anticancer drug delivery in vivo.
abstract: We investigated the biodistribution of arginine-rich cell-penetrating peptides (CPPs) in tumor-xenografted nude mice after intravenous injection of fluorescently labeled CPPs using in vivo imaging. The CPPs used included HIV-1 Tat (48-60), penetratin, and the L- and D-enantiomers of oligoarginines (8, 12, and 16 residues), all of which are reported to have high cell penetration. Among the tested peptides, high accumulation in tumors was observed for the D-form of octaarginine (r8), and glycosaminoglycans played a key role. Injection of an r8-doxorubicin conjugate (4mg doxorubicin/kg) effectively suppressed tumor proliferation, with no significant decrease in mouse weight, whereas administration of doxorubicin itself (6mg/kg), yielding a similar degree of tumor-growth suppression, resulted in significant weight loss. These results suggest the potential of r8 as a prototypic tumor-targeting vector.
authors.affiliation: Institute for Chemical Research, Kyoto University, Kyoto 611-0011, Japan.
authors.forename: Ikuhiko
authors.initials: I
authors.lastname: Nakase
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Konishi
authors.forename: Masashi
authors.initials: M
authors.lastname: Ueda
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
authors.forename: Shiroh
authors.initials: S
authors.lastname: Futaki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016466:CHO Cells; D002352:Carrier Proteins / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000493:pharmacokinetics*; D006224:Cricetinae; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009842:Oligopeptides / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry; D013237:Stereoisomerism; D013997:Time Factors; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D009842:Oligopeptides; D010446:Peptide Fragments; C500307:octa-arginine peptide; D054322:tat Gene Products, Human Immunodeficiency Virus; C422951:tat peptide (48-60), Human immunodeficiency virus 1; D004317:Doxorubicin; C414409:penetratin