Advanced cancer therapy by integrative antitumor actions via systemic administration of miR-499.

Abstract

Previously, we developed tetraethylenepentamine-based polycation liposomes (TEPA-PCL) as a vector for the delivery of small RNAs. In the present research, we attempted tumor-targeted delivery of miR-499 via systemic administration and evaluated the potency of this system as a therapeutic strategy to treat cancer. Lipoplexes were formed by mixing cholesterol-grafted miR-499 (miR-499-C) with TEPA-PCL. Firstly, human umbilical endothelial cells (HUVECs) and Colon 26 NL-17 mouse carcinoma cells were transfected with these lipoplexes in vitro. The results showed that miR-499 had antiangiogenic effects on the HUVECs and suppressed the secretion of vascular endothelial growth factor (VEGF) from the Colon 26 NL-17 cells. In addition, the growth of the latter cells was inhibited by transfection with miR-499-C/TEPA-PCL. For in vivo delivery of miR-499 to tumors via systemic injection, miR-499-C/TEPA-PCL were decorated with Ala-Pro-Arg-Pro-Gly (APRPG) peptide-conjugated polyethylene glycol (PEG) to prepare APRPG-PEG-modified lipoplexes carrying miR-499 (APRPG-miR-499). APRPG-miR-499 were injected into tumor-bearing mice via a tail vein, and these lipoplexes accumulated sufficiently in both angiogenic vessels and cancer cells. In addition, the expression of miR-499-target proteins and VEGF in the tumor cells was clearly suppressed by the treatment with APRPG-miR-499. Finally, the therapeutic effect of miR-499 on tumor growth was evaluated in mice. The tumor growth was significantly inhibited by the intravenous injection of APRPG-miR-499 at such a low dose as 0.5mg/kg. These results suggest that miR-499 delivered by the present system has excellent potency to treat cancer via integrative anticancer actions.

• Authors: Hidenori Ando, Tomohiro Asai, Hiroyuki Koide, Ayaka Okamoto, Noriyuki Maeda, Koji Tomita, Takehisa Dewa, Tetsuo Minamino, Naoto Oku
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 181 Pg. 32-9 (May 10 2014) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 24593893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Drug Carriers
• Ethylenediamines
• Liposomes
• MIRN499 microRNA, human
• MicroRNAs
• Oligopeptides
• Vascular Endothelial Growth Factor A
• alanyl-prolyl-arginyl-prolyl-glycine
• vascular endothelial growth factor A, mouse
• tetraethylenepentamine

Topics

• Angiogenesis Inhibitors (administration & dosage, genetics, therapeutic use)
• Animals
• Cell Line, Tumor
• Drug Carriers (chemistry)
• Ethylenediamines (chemistry)
• Gene Silencing
• Gene Transfer Techniques
• Human Umbilical Vein Endothelial Cells
• Humans
• Injections, Intravenous
• Liposomes
• Mice
• MicroRNAs (administration & dosage, genetics, therapeutic use)
• Neoplasm Invasiveness
• Neoplasms, Experimental (genetics, pathology, therapy)
• Oligopeptides (chemistry)
• Tissue Distribution
• Transfection
• Vascular Endothelial Growth Factor A (antagonists & inhibitors)