title: Cyclic RGD-linked polymeric micelles for targeted delivery of platinum anticancer drugs to glioblastoma through the blood-brain tumor barrier.
abstract: Ligand-mediated drug delivery systems have enormous potential for improving the efficacy of cancer treatment. In particular, Arg-Gly-Asp peptides are promising ligand molecules for targeting αvβ3/αvβ5 integrins, which are overexpressed in angiogenic sites and tumors, such as intractable human glioblastoma (U87MG). We here achieved highly efficient drug delivery to U87MG tumors by using a platinum anticancer drug-incorporating polymeric micelle (PM) with cyclic Arg-Gly-Asp (cRGD) ligand molecules. Intravital confocal laser scanning microscopy revealed that the cRGD-linked polymeric micelles (cRGD/m) accumulated rapidly and had high permeability from vessels into the tumor parenchyma compared with the PM having nontargeted ligand, "cyclic-Arg-Ala-Asp" (cRAD). As both cRGD/m- and cRAD-linked polymeric micelles have similar characteristics, including their size, surface charge, and the amount of incorporated drugs, it is likely that the selective and accelerated accumulation of cRGD/m into tumors occurred via an active internalization pathway, possibly transcytosis, thereby producing significant antitumor effects in an orthotopic mouse model of U87MG human glioblastoma.
authors.affiliation: Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miura
authors.forename: Tomoya
authors.initials: T
authors.lastname: Takenaka
authors.forename: Kazuko
authors.initials: K
authors.lastname: Toh
authors.forename: Shourong
authors.initials: S
authors.lastname: Wu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishihara
authors.forename: Mitsunobu R
authors.initials: MR
authors.lastname: Kano
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ino
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nomoto
authors.forename: Yu
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koyama
authors.forename: Horacio
authors.initials: H
authors.lastname: Cabral
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010456:Peptides, Cyclic / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D016023:Integrins; D008823:Micelles; D009944:Organoplatinum Compounds; D010456:Peptides, Cyclic; D011108:Polymers; C507169:cyclic arginine-glycine-aspartic acid peptide