pH-Responsive Liposomes Loaded with Targeting Procoagulant Proteins as Potential Embolic Agents for Solid Tumor-Targeted Therapy

Selectively inducing tumor thrombosis and subsequent necrosis is a novel and promising antitumor strategy. We have previouslydesigned a targeting procoagulant protein, called tTF-EG3287, which is afusion of a truncated tissue factor (tTF) with EG3287, a short peptideagainst the neuropilin-1 (NRP1) binding site of vascular endothelialgrowth factor-A 165 (VEGF-A 165). However, off-target effects andhigh-dose requirements limit the further use of tTF-EG3287 in antitumortherapy. Therefore, we encapsulated tTF-EG3287 into poly(2-ethyl-2-oxazoline)-distearoyl phosphatidyl ethanolamine (PEOz-DSPE)-modi-fied liposomes to construct pH-responsive liposomes as a novel vascularembolization agent, called tTF-EG3287@Liposomes. The liposomes hadan average particle size of about 100 nm and showed considerable drug-loading capacity, encapsulation efficiency, and biocompatibility. Underthe stimulation of acidic microenvironments (pH 6.5), the lipid membrane of tTF-EG3287@Liposomes collapsed, and thecumulative drug release rate within 72 h was 83 +/- 1.26%. When administered to a mouse model of hepatocellular carcinoma(HCC), tTF-EG3287@Liposomes showed prolonged retention and enhanced accumulation in the tumor as well as a superiorantitumor effec, compared with tTF-EG3287. This study demonstrates the potential of tTF-EG3287@Liposomes as a novel embolicagent for solid tumors and provides a new strategy for tumor-targeted infarction therapy