title: Fibrin degradation by rtPA enhances the delivery of nanotherapeutics to A549 tumors in nude mice.
abstract: Effective drug delivery to a tumor depends on favorable blood perfusion within the tumor. As an important component of tumor extracellular matrix, fibrin is abundant near tumor vessels. Inspired by the distinct distribution pattern and vessel-dependent production of fibrin, we hypothesized that fibrin depletion in tumors decompresses tumor vessels to improve tumor blood perfusion and accordingly enhance drug delivery to tumors rich in vessels. In the present study, we attempted to employ a clinically used thrombolytic drug, recombinant tissue plasminogen activator (rtPA), to modulate fibrin deposition in tumors. We then combined this drug with a nanoparticle drug delivery system for tumor therapy. RtPA treatment (25 mg/kg/d i. p. administration for two weeks) successfully depleted fibrin deposition and enhanced blood perfusion within A549 tumor xenografts. Furthermore, rtPA treatment also improved the in vivo delivery of 115-nm nanoparticles to tumor tissues. Finally, rtPA combined with therapeutic agent-loaded nanoparticles resulted in the most effective shrinkage of A549 tumor xenografts compared with the control groups. Overall, the present study provides a new strategy to enhance the delivery of nanotherapeutics to tumors rich in vessels.
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, 430022, PR 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, PR 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, PR 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, PR 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, PR China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, 430022, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Deng
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, 430022, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, 430022, PR China; Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, PR China.
authors.forename: Heng
authors.initials: H
authors.lastname: Mei
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, 430022, PR China; Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, PR China. Electronic address: dr_huyu@126.com.
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, PR China. Electronic address: zqpang@fudan.edu.cn.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Pang
authors.affiliation: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, PR China.
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D016503:Drug Delivery Systems; D005337:Fibrin / Q000378:metabolism*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D059748:Proteolysis; D011994:Recombinant Proteins / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D011994:Recombinant Proteins; D005337:Fibrin; D010959:Tissue Plasminogen Activator; D017239:Paclitaxel
keywords: Fibrin; Nanoparticle; Tumor therapy; Tumor vessels; rtPA