A tissue factor-cascade-targeted strategy to tumor vasculature: a combination of EGFP-EGF1 conjugation nanoparticles with photodynamic therapy

// Wei Shi 1,2,* , Yanxue Yin 1,2,* , Yao Wang 3,* , Bo Zhang 1,2 , Pei Tan 1,2 , Ting Jiang 1,2 , Heng Mei 1,2 , Jun Deng 1,2 , Huafang Wang 1,2 , Tao Guo 1,2 , Zhiqing Pang 3 and Yu Hu 1,2 1 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China 2 Targeted Biotherapy Key Laboratory of Ministry of Education, Wuhan, Hubei, China 3 Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China 4 Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, China * These authors have contributed equally to this work Correspondence to: Tao Guo, email: // Zhiqing Pang, email: // Yu Hu, email: // Keywords : EGFP-EGF1, tissue factor, TF-cascade-targeted drug delivery system, photodynamic therapy Received : July 18, 2016 Accepted : October 22, 2016 Published : October 26, 2016 Abstract Tumor requires tumor vasculature to supply oxygen and nutrients so as to support its continued growth, as well as provide a main route for metastatic spread. In this study, a TF-cascade-targeted strategy aiming to disrupt tumor blood vessels was developed by combination of TF-targeted HMME-loaded drug delivery system and PDT. PDT is a promising new modality in the treatment of cancers, which employs the interaction between a tumor-localizing photosensitizer and light of an appropriate wavelength to bring about ROS-induced cell death. In vitro results showed that protein EGFP-EGF1modification could significantly contribute to the uptake of nanoparticles by TF over-expressed BCECs. In vivo multispectral fluorescent imaging, the EGFP-EGF1 conjugated nanoparticles showed significantly higher accumulation in tumor tissues than non-conjugated ones. Tumor tissue slides further presented that EGFP-EGF1 conjugated nanoparticles showed significantly higher accumulation in tumor vasculature than non-conjugated ones. In vitro study demonstrated that PDT increased TF expression of BCECs. In vivo imaging, ex vivo imaging and tumor tissue slides showed that PDT further contribute EGFP-EGF1-NP accumulation in tumor. These promising results indicated that PDT enhanced EGFP-EGF1modified PEG-PLGA nanoparticle accumulation in tumor vaculature. Considering that EGFP-EGF1 conjugation enhanced nanoparticles uptake by TF over-expressed endothelium and PDT increased endothelium TF expression. We conclude that PDT triggered a TF cascade targeted effect. A combination of both EGFP-EGF1 modification and PDT provided a positive feed-back target effect to tumor vessels and might have a great potential for tumor therapy.