Enhancement of antitumor properties of TRAIL by targeted delivery to the tumor neovasculature.
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 alpha(V)beta(3) and alpha(V)beta(5) 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 alpha(V)beta(3) and alpha(V)beta(5) 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 alpha(V)beta(3) and alpha(V)beta(5) 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.
Cao
Lin
L
The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, Jiangsu, People's Republic of China.
Du
Pan
P
Jiang
Shu-Han
SH
Jin
Guang-Hui
GH
Huang
Qi-Lai
QL
Hua
Zi-Chun
ZC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D019030:Receptors, Vitronectin / Q000378:metabolism; D012867:Skin / Q000098:blood supply / Q000378:metabolism; D015996:Survival Rate; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019030:Receptors, Vitronectin; D053221:TNF-Related Apoptosis-Inducing Ligand; C064660:integrin alphaVbeta5; C047981:arginyl-glycyl-aspartic acid; D053148:Caspase 3; D053181:Caspase 8