title: Enhanced Antitumor Activity of EGFP-EGF1-Conjugated Nanoparticles by a Multitargeting Strategy.
abstract: Tumor stromal cells have been increasingly recognized to interact with tumor parenchyma cells and promote tumor growth. Therefore, we speculated that therapeutics delivery to both parenchyma cells and stromal cells simultaneously might treat a tumor more effectively. Tissue factor (TF) was shown to be extensively located in a tumor and was abundantly sited in both tumor parenchyma cells and stromal cells including neo-vascular cells, tumor-associated fibroblasts, and tumor-associated macrophages, indicating it might function as a favorable target for drug delivery to multiple cell types simultaneously. EGFP-EGF1 is a fusion protein derived from factor VII, the natural ligand of TF. It retains the specific TF binding capability but does not cause coagulation. In the present study, a nanoparticle modified with EGFP-EGF1 (ENP) was constructed as a multitargeting drug delivery system. The protein binding experiment showed EGFP-EGF1 could bind well to A549 tumor cells and other stromal cells including neo-vascular cells, tumor-associated fibroblasts, and tumor-associated macrophages. Compared with unmodified nanoparticles (NP), ENP uptake by A549 cells and those stromal cells was significantly enhanced but inhibited by excessive free EGFP-EGF1. In addition, ENP induced more A549 tumor cell apoptosis than Taxol and NP when paclitaxel (PTX) was loaded. In vivo, ENP accumulated more specially in TF-overexpressed A549 tumors by in vivo imaging, mainly regions unoccupied by factor VII and targeted tumor parenchyma cells as well as different types of stromal cells by immunofluorescence staining. Treatment with PTX-loaded ENP (ENP-PTX) significantly reduced the A549 tumor growth in nude mice while NP-PTX- and Taxol-treated mice had lower response to the therapy. Furthermore, H&E and TUNEL staining revealed that ENP-PTX induced more severe tumor necrosis and more extensive cell apoptosis. Altogether, the present study demonstrated that ENP could target multiple key cell types in tumors through TF, which could be utilized to improve the therapeutic effect of anticancer drugs.
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology , Wuhan, Hubei 430022, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology , Wuhan, Hubei 430022, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Jiang
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ling
authors.affiliation: Instrumental Analysis Center of School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Zhonglian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Tuo
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: She
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Shen
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology , Wuhan, Hubei 430022, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Pang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects; D016503:Drug Delivery Systems; D049452:Green Fluorescent Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D024101:Mitochondrial Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000008:administration & dosage / Q000737:chemistry; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry; D020653:Peptide Elongation Factor G / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D011485:Protein Binding; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology
chemical_list: C441680:GFM1 protein, human; D024101:Mitochondrial Proteins; D015514:Oncogene Proteins, Fusion; D020653:Peptide Elongation Factor G; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D017239:Paclitaxel
keywords: EGFP-EGF1; TF; multitargeting; nanoparticle; tumor