Inhibition of in vivo tumor angiogenesis and growth via systemic delivery of an angiopoietin 2-specific RNA aptamer.

Abstract

BACKGROUND:

Cellular events mediated by the Tie2 receptor are important to tumor neovascularization. Despite the complex interplay of the best-characterized Tie2 ligands, angiopoietins 1 and 2, Ang2 is purportedly "proangiogenic" in the presence of vascular endothelial growth factor. We examined whether in vivo administration of an RNA aptamer that specifically blocks Ang 2 would inhibit tumor angiogenesis and growth.

METHODS:

Ang2-mediated Tie2 receptor phosphorylation was assessed in vitro in the absence and presence of aptamer coupled to polyethylene glycol. IN VIVO ANGIOGENESIS ASSAY: CT26 murine colon carcinoma cells expressing green fluorescent protein were delivered into mouse dorsal skinfold window chambers. Animals received daily intraperitoneal injections of phosphate-buffered saline, low-dose (Ang2 aptamer-LD; 1 mg/kg/d), or high-dose aptamer (Ang2 aptamer-HD; 10 mg/kg/d). Vascular length density was measured under fluorescence microscopy. PRIMARY TUMOR GROWTH: CT26 cells expressing luciferase were injected into flanks of BALB/c mice to allow tumor growth monitoring by bioluminescence imaging. Animals received continuous phosphate-buffered saline or aptamer (1 mg/kg/d) via ALZET pumps. Tumors were assessed for CD31/PECAM-1 immunostaining and Hoechst dye uptake.

RESULTS:

Pegylated aptamer inhibited Tie2 phosphorylation. Systemic aptamer administration reduced vascular length density (P < or = 0.03) and decreased bioluminescence emission (P < 0.04), corresponding to 50% decrease in tumor volume (P = 0.04). Control tumors displayed abundant vascular marker staining, in contrast to tumors from aptamer-treated animals.

CONCLUSIONS:

in vivo administration of a clinically relevant, pegylated RNA aptamer specifically designed against Ang2 inhibited tumor angiogenesis and growth. These findings support targeted Ang2 inhibition as a relevant anti-angiogenic, anti-neoplastic strategy.

• Authors: Shiva Sarraf-Yazdi, Jing Mi, Benjamin J Moeller, Xilin Niu, Rebekah R White, Christopher D Kontos, Bruce A Sullenger, Mark W Dewhirst, Bryan M Clary
• Journal: The Journal of surgical research (J Surg Res) Vol. 146 Issue 1 Pg. 16-23 (May 01 2008) ISSN: 0022-4804 [Print] United States
• PMID: 17950331 (Publication Type: Journal Article)

Chemical References

• Angiopoietin-2
• Aptamers, Nucleotide
• Receptor, TIE-2

Topics

• Angiopoietin-2 (pharmacology, therapeutic use)
• Animals
• Aptamers, Nucleotide (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colonic Neoplasms (blood supply, pathology)
• Dose-Response Relationship, Drug
• Female
• Mice
• Mice, Inbred BALB C
• Neovascularization, Pathologic (drug therapy, pathology)
• Phosphorylation (drug effects)
• Receptor, TIE-2 (drug effects)
• Xenograft Model Antitumor Assays