title: Angiopep-2 and activatable cell-penetrating peptide dual-functionalized nanoparticles for systemic glioma-targeting delivery.
abstract: Gliomas are hard to treat because of the two barriers involved: the blood-brain barrier and blood-tumor barrier. In this study, a dual-targeting ligand, angiopep-2, and an activatable cell-penetrating peptide (ACP) were functionalized onto nanoparticles for glioma-targeting delivery. The ACP was constructed by conjugating RRRRRRRR (R8) with EEEEEEEE through a matrix metalloproteinase-2 (MMP-2)-sensitive linker. ACP modification effectively enhanced the C6 cellular uptake because of the high expression of MMP-2 on C6 cells. The uptake was inhibited by batimastat, an MMP-2 inhibitor, suggesting that the cell-penetrating property of the ACP was activated by MMP-2. By combining the dual-targeting delivery effect of angiopep-2 and activatable cell-penetrating property of the ACP, the dual-modified nanoparticles (AnACNPs) displayed higher glioma localization than that of single ligand-modified nanoparticles. After loading with docetaxel, a common chemotherapeutic, AnACNPs showed the most favorable antiglioma effect both in vitro and in vivo. In conclusion, a novel drug delivery system was developed for glioma dual targeting and glioma penetrating. The results demonstrated that the system effectively targeted gliomas and provided the most favorable antiglioma effect.
authors.affiliation: Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics Sciences, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Huile
authors.initials: H
authors.lastname: Gao
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.forename: Shijie
authors.initials: S
authors.lastname: Cao
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yang
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Pang
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D057846:Cell-Penetrating Peptides / Q000737:chemistry*; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000737:chemistry; D005910:Glioma / Q000188:drug therapy*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology / Q000379:methods*; D010455:Peptides / Q000737:chemistry*
chemical_list: C531860:Angiopep-2; D057846:Cell-Penetrating Peptides; D004791:Enzyme Inhibitors; D008024:Ligands; D010455:Peptides; D020778:Matrix Metalloproteinase 2