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Research Articles: Therapeutics, Targets, and Development

Enhancement of antitumor properties of TRAIL by targeted delivery to the tumor neovasculature

The State Key Laboratory of Pharmaceutical Biotechnology and Department of Biochemistry, College of Life Sciences, Nanjing University, Nanjing, Jiangsu, People's Republic of China

Requests for reprints: Zi-Chun Hua, The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, Jiangsu, People's Republic of China. Phone: 86-25-83324605; Fax: 86-25-83324605. E-mail: zchua{at}nju.edu.cn

Abstract

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent with tumor-selective apoptotic activity. TRAIL plays a role in the innate and adaptive immune response and autoimmune disease and may also be involved in hepatic cell death and inflammation. For these reasons, chronic exposure to TRAIL may have deleterious side effects in patients as a cancer therapeutic. In this study, we have improved the antitumor activity of TRAIL by targeted delivery to the tumor vasculature, leading to dramatic enhancement of its therapeutic properties. TRAIL was fused to the ACDCRGDCFC peptide (named RGD-L-TRAIL), a ligand of _Vβ₃ and _Vβ₅ integrins. Biological activity was evaluated in vitro and antitumor efficacy was investigated in vivo as a single agent and in combination with irinotecan hydrochloride (CPT-11). The fusion protein RGD-L-TRAIL, but not TRAIL or RGE-L-TRAIL, specifically bound to microvascular endothelial cells in a dose-dependent manner and showed enhanced apoptosis-inducing activity (caspase-3 and caspase-8 activation) in _Vβ₃ and _Vβ₅ integrin-positive cancer cells. In addition, RGD-L-TRAIL was more effective in suppressing tumor growth of COLO-205 tumor-bearing mice than an equivalent dose of TRAIL. The antitumor effect of RGD-L-TRAIL was further enhanced by combination with CPT-11 in both TRAIL-sensitive COLO-205 and TRAIL-resistive HT-29 tumor xenograft models. Our findings suggest that the novel fusion protein RGD-L-TRAIL can directly target tumor endothelial cells as well as _Vβ₃ and _Vβ₅ integrin-positive tumor cells. The tumor-targeted delivery of TRAIL derivatives, such as RGD-L-TRAIL, may prove to be a promising lead candidate for cancer therapy. [Mol Cancer Ther 2008;7(4):851–61]

Grant support: Chinese National Nature Sciences Foundation grants 30330530 and 30425009 and Jiangsu Provincial Nature Sciences Foundation grant BK2007715.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/ 5/07; revised 12/19/07; accepted 2/21/08.