Research Papers:
pHLIP-mediated targeting of truncated tissue factor to tumor vessels causes vascular occlusion and impairs tumor growth
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Abstract
Suping Li1,*, Yanhua Tian2,*, Ying Zhao1, Yinlong Zhang1, Shishuai Su1, Jing Wang1, Meiyu Wu1, Quanwei Shi1, Gregory J. Anderson3, Johannes Thomsen4, Ruifang Zhao1, Tianjiao Ji1, Jie Wang5, Guangjun Nie1,*
1CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, China, Beijing 100190, China
2Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
3QIMR Berghofer Medical Research Institute, Brisbane QLD 4006, Australia
4Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing 100190, China
5Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China
*These authors have contributed equally to this work
Correspondence to:
Guangjun Nie, e-mail: [email protected]
Keywords: pH low insertion peptide (pHLIP), truncated tissue factor (tTF), tumor vessel targeting, thrombosis
Received: April 24, 2015 Accepted: June 13, 2015 Published: June 25, 2015
ABSTRACT
Occluding tumor blood supply by delivering the extracellular domain of coagulation-inducing protein tissue factor (truncated tissue factor, tTF) to tumor vasculature has enormous potential to eliminate solid tumors. Yet few of the delivery technologies are moved into clinical practice due to their non-specific tissue biodistribution and rapid clearance by the reticuloendothelial system. Here we introduced a novel tTF delivery method by generating a fusion protein (tTF-pHLIP) consisting of tTF fused with a peptide with a low pH-induced transmembrane structure (pHLIP). This protein targets the acidic tumor vascular endothelium and effectively induces local blood coagulation. tTF-pHLIP, wherein pHLIP is cleverly designed to mimic the natural tissue factor transmembrane domain, triggered thrombogenic activity of the tTF by locating it to the endothelial cell surface, as demonstrated by coagulation assays and confocal microscopy. Systemic administration of tTF-pHLIP into tumor-bearing mice selectively induced thrombotic occlusion of tumor vessels, reducing tumor perfusion and impairing tumor growth without overt side effects. Our work introduces a promising strategy for using tTF as an anti-cancer drug, which has great potential value for clinical applications.
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