Angiopep‑2 and Activatable Cell-Penetrating Peptide Dual-Functionalized Nanoparticles for Systemic Glioma-Targeting Delivery

• Published in: Molecular pharmaceutics Vol. 11; no. 8; pp. 2755 - 2763
• Main Authors: Gao, Huile, Zhang, Shuang, Cao, Shijie, Yang, Zhi, Pang, Zhiqing, Jiang, Xinguo
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 04.08.2014
• Subjects: Animals; Apoptosis; Blood-Brain Barrier; Brain Neoplasms - drug therapy; Cell Line, Tumor; Cell Proliferation; Cell-Penetrating Peptides - chemistry; Drug Delivery Systems; Enzyme Inhibitors - chemistry; Glioma - drug therapy; Human Umbilical Vein Endothelial Cells - cytology; Humans; Inhibitory Concentration 50; Ligands; Matrix Metalloproteinase 2 - metabolism; Mice; Mice, Inbred BALB C; Nanoparticles - chemistry; Nanotechnology - methods; Peptides - chemistry; glioma; angiopep-2; activatable cell-penetrating peptide; systemic targeted delivery
• ISSN: 1543-8384; 1543-8392; 1543-8392
• DOI: 10.1021/mp500113p

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.