title: Multi-targeting Peptide-Functionalized Nanoparticles Recognized Vasculogenic Mimicry, Tumor Neovasculature, and Glioma Cells for Enhanced Anti-glioma Therapy.
abstract: Chemotherapy failure of glioma, the most aggressive and devastating cancer, might be ascribed to the physiologic barriers of the tumor mainly including heterogeneous tumor perfusion and vascular permeability, which result in a limited penetration of chemotherapeutics. Besides, the vasculogenic mimicry (VM) channels, which are highly resistant to anti-angiogenic therapy and serve as a complement of angiogenesis, were abound in glioma and always associated with tumor recurrence. In order to enhance the therapy effect of anti-glioma, we developed a PEG-PLA-based nanodrug delivery system (nanoparticles, NP) in this study and modified its surface with CK peptide, which was composed of a human sonic hedgehog (SHH) targeting peptide (CVNHPAFAC) and a KDR targeting peptide (K237) through a GYG linker, for facilitating efficient VM channels, tumor neovasculature, and glioma cells multi-targeting delivery of paclitaxel. In vitro cellular assay showed that CK-NP-PTX not only exhibited the strongest antiproliferation effect on U87MG cells and HUVEC cells but also resulted in the most efficient destruction of VM channels when compared with CVNHPAFAC-NP, K237-NP, and the unmodified ones. Besides, CK-NP accumulated more selectively at the glioma site as demonstrated by in vivo and ex vivo imaging. As expected, the glioma-bearing mice treated with CK-NP-PTX achieved the longest median survival time compared to those treated with CVNHPAFAC-NP-PTX and K237-NP-PTX. These findings indicated that the multi-targeting therapy mediated by CK peptide might provide a promising way for glioblastoma therapy.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Xingye
authors.initials: X
authors.lastname: Feng
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine , 280 South Chongqing Road, Shanghai 200025, People's Republic of China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Gao
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Yixian
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Kang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Tianze
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Jingxian
authors.initials: J
authors.lastname: Feng
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D010455:Peptides
keywords: KDR receptors; glioblastoma; human sonic hedgehog; multi-targeting therapy; nanoparticle; tumor-homing peptide; vasculogenic mimicry channels