Cyclic RGD-linked polymeric micelles for targeted delivery of platinum anticancer drugs to glioblastoma through the blood-brain tumor barrier

ACS Nano. 2013 Oct 22;7(10):8583-92. doi: 10.1021/nn402662d. Epub 2013 Sep 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Blood-Brain Barrier*
  • Brain Neoplasms / drug therapy*
  • Cell Line, Tumor
  • Flow Cytometry
  • Glioblastoma / drug therapy*
  • Humans
  • Integrins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Micelles*
  • Organoplatinum Compounds / administration & dosage*
  • Organoplatinum Compounds / pharmacokinetics
  • Organoplatinum Compounds / therapeutic use
  • Peptides, Cyclic / chemistry*
  • Polymers / chemistry*

Substances

  • Antineoplastic Agents
  • Integrins
  • Micelles
  • Organoplatinum Compounds
  • Peptides, Cyclic
  • Polymers
  • cyclic arginine-glycine-aspartic acid peptide