title: Targeting fibronectins of glioma extracellular matrix by CLT1 peptide-conjugated nanoparticles.
abstract: The abundant extracellular matrix (ECM) in the glioma microenvironment play a critical role in the maintenance of glioma morphology, glioma cells differentiation and proliferation, but little has been done to understand the feasibility of ECM as the therapeutic target for glioma therapy. In this study, a drug delivery system targeting fibronectins (FNs), a prevailing component in the ECM of many solid tumors, was constructed for glioma therapy based on the interaction between the abundant FNs in glioma tissues and the FNs-targeting moiety CLT1 peptide. CLT1 peptide was successfully conjugated to PEG-PLA nanoparticles (CNP). FNs were demonstrated to be highly expressed in the ECM of glioma spheroids in vitro and glioma tissues in vivo. CLT1 modification favored targeting nanoparticles penetration into the core of glioma spheroids and consequently induced more severe inhibitive effects on glioma spheroids growth than traditional NP. In vivo imaging, ex vivo imaging and glioma tissue slides showed that CNP enhanced nanoparticles retention in glioma site, distributed more extensively and more deeply into glioma tissues than that of conventional NP, and mainly located in glioma cells rather than in extracellular matrix as conventional NP. Pharmacodynamics outcomes revealed that the median survival time of glioma-bearing mice models treated with paclitaxel-loaded CNP (CNP-PTX) was significantly prolonged when compared with that of any other group. TUNEL assay demonstrated that more extensive cell apoptosis was induced by CNP-PTX treatment compared with other treatments. Altogether, these promising results indicated that this ECM-targeting drug delivery system enhanced retention and glioma cell uptake of nanoparticles and might have a great potential for glioma therapy in clinical applications.
authors: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei 430022, PR China.
authors: Bo
authors: B
authors: Zhang
authors: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai 201203, PR China.
authors: Shun
authors: S
authors: Shen
authors: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai 201203, PR China.
authors: Ziwei
authors: Z
authors: Liao
authors: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei 430022, PR China.
authors: Wei
authors: W
authors: Shi
authors: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai 201203, PR China.
authors: Yu
authors: Y
authors: Wang
authors: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai 201203, PR China.
authors: Jingjing
authors: J
authors: Zhao
authors: College of Pharmacy, Jiamusi University, Jiamusi 154007, PR China.
authors: Yue
authors: Y
authors: Hu
authors: College of Pharmacy, Jiamusi University, Jiamusi 154007, PR China.
authors: Jiarong
authors: J
authors: Yang
authors: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai 201203, PR China.
authors: Jun
authors: J
authors: Chen
authors: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei 430022, PR China.
authors: Heng
authors: H
authors: Mei
authors: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei 430022, PR China. Electronic address: dr_huyu@126.com.
authors: Yu
authors: Y
authors: Hu
authors: 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: Zhiqing
authors: Z
authors: Pang
authors: School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai 201203, PR China.
authors: Xinguo
authors: X
authors: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000737:chemistry; D005353:Fibronectins / Q000737:chemistry*; D005910:Glioma / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000627:therapeutic use*; D051381:Rats
chemical_list: D005353:Fibronectins; D010456:Peptides, Cyclic; C510872:cyclo(cysteinyl-glycyl-leucyl-isoleucyl-isoleucyl-glutaminyl-lysyl-asparaginyl-glutamyl-cysteinyl)
keywords: Extracellular matrix; Fibronectin; Glioma; Nanoparticles; Retention; Targeting