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.
Highlights
One major obstacle to the development of coagulation therapy for cancer is the inability to target vascular occluding agents to tumor blood vessels, thereby limiting their therapeutic effect and causing adverse side effects
Unlike other current delivery strategies wherein tTF was delivered by targeted ligands [1,2,3,4,5,6], pH (low) membrane insertion peptide (pHLIP)-directed membrane insertion under acidic conditions could allow tTF to adopt a state which is close to the native extracellular domain of TF on membrane surfaces, maintaining its maximum coagulation activity
The chimeric protein tTF-pHLIP was generated by fusing the N-terminus of pHLIP to the C-terminus of the extracellular domain of tissue factor (1–218 amino acids)
Summary
One major obstacle to the development of coagulation therapy for cancer is the inability to target vascular occluding agents to tumor blood vessels, thereby limiting their therapeutic effect and causing adverse side effects. Over the past two decades, approaches to targeted coagulation therapy in vivo have largely focused on selective delivery of the extracellular domain of the coagulation-inducing protein tissue factor (truncated tissue factor, tTF, the initiator of the extrinsic pathway of blood coagulation) to tumor vessels, by using antibody or peptide ligands that recognize various tumor endothelial markers [1,2,3,4,5,6,7]. Unlike other current delivery strategies wherein tTF was delivered by targeted ligands [1,2,3,4,5,6], pHLIP-directed membrane insertion under acidic conditions could allow tTF to adopt a state which is close to the native extracellular domain of TF on membrane surfaces, maintaining its maximum coagulation activity
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