title: pHLIP-mediated targeting of truncated tissue factor to tumor vessels causes vascular occlusion and impairs tumor growth.
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.
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, China, Beijing 100190, China.
authors.forename: Suping
authors.initials: S
authors.lastname: Li
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Tian
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, China, Beijing 100190, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, China, Beijing 100190, China.
authors.forename: Yinlong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, China, Beijing 100190, China.
authors.forename: Shishuai
authors.initials: S
authors.lastname: Su
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, China, Beijing 100190, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, China, Beijing 100190, China.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Wu
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, China, Beijing 100190, China.
authors.forename: Quanwei
authors.initials: Q
authors.lastname: Shi
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane QLD 4006, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Anderson
authors.affiliation: Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Johannes
authors.initials: J
authors.lastname: Thomsen
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, China, Beijing 100190, China.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, China, Beijing 100190, China.
authors.forename: Tianjiao
authors.initials: T
authors.lastname: Ji
authors.affiliation: Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, China, Beijing 100190, China.
authors.forename: Guangjun
authors.initials: G
authors.lastname: Nie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001777:Blood Coagulation; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D005170:Factor X / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry; D008546:Melanoma, Experimental; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010477:Perfusion; D017434:Protein Structure, Tertiary; D013925:Thromboplastin / Q000494:pharmacology*; D013927:Thrombosis / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D008051:Lipid Bilayers; D008565:Membrane Proteins; C533201:pHLIP protein; D005170:Factor X; D013925:Thromboplastin
keywords: pH low insertion peptide (pHLIP); thrombosis; truncated tissue factor (tTF); tumor vessel targeting