pHLIP-mediated targeting of truncated tissue factor to tumor vessels causes vascular occlusion and impairs tumor growth.

// Suping Li 1, * , Yanhua Tian 2, * , Ying Zhao 1 , Yinlong Zhang 1 , Shishuai Su 1 , Jing Wang 1 , Meiyu Wu 1 , Quanwei Shi 1 , Gregory J. Anderson 3 , Johannes Thomsen 4 , Ruifang Zhao 1 , Tianjiao Ji 1 , Jie Wang 5 , Guangjun Nie 1, * 1 CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, China, Beijing 100190, China 2 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China 3 QIMR Berghofer Medical Research Institute, Brisbane QLD 4006, Australia 4 Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing 100190, China 5 Department 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: niegj@nanoctr.cn 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.