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: Yutaka Miura, Tomoya Takenaka, Kazuko Toh, Shourong Wu, Hiroshi Nishihara, Mitsunobu R Kano, Yasushi Ino, Takahiro Nomoto, Yu Matsumoto, Hiroyuki Koyama, Horacio Cabral, Nobuhiro Nishiyama, Kazunori Kataoka
• Journal: ACS nano (ACS Nano) Vol. 7 Issue 10 Pg. 8583-92 (Oct 22 2013) ISSN: 1936-086X [Electronic] United States
• PMID: 24028526 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, 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, pharmacokinetics, therapeutic use)
• Peptides, Cyclic (chemistry)
• Polymers (chemistry)