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

作者：Ando Hidenori; Asai Tomohiro; Koide Hiroyuki; Okamoto Ayaka; Maeda Noriyuki; Tomita Koji; Dewa Takehisa; Minamino Tetsuo; Oku Naoto^*

来源：Journal of Controlled Release, 2014, 181: 32-39.

DOI：10.1016/j.jconrel.2014.02.019

• MicroRNA
• miR-499
• Cancer therapy
• Gene delivery
• Liposomes
• Antiangiogenesis

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-graftedmiR-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 0.5 mg/kg. These results suggest that miR-499 delivered by the present system has excellent potency to treat cancer via integrative anticancer actions.

• 出版日期2014-5-10