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Angiopep-2 and activatable cell-penetrating peptide dual-functionalized nanoparticles for systemic glioma-targeting
Huile Gao1, Shuang Zhang, Shijie Cao
1Key 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.
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.
Insights
This study developed novel nanoparticles for targeted glioma treatment, overcoming the blood-brain and blood-tumor barriers. These dual-modified nanoparticles effectively delivered chemotherapy, showing promising anti-glioma effects in vitro and in vivo.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Gliomas are challenging to treat due to the blood-brain and blood-tumor barriers.
- Effective drug delivery systems are crucial for improving glioma therapy outcomes.
Purpose of the Study:
- To develop dual-targeting nanoparticles for enhanced glioma delivery and treatment.
- To investigate the efficacy of angiopep-2 and an activatable cell-penetrating peptide (ACP) for glioma targeting.
Main Methods:
- Functionalized nanoparticles with angiopep-2 and an ACP (RRRRRRRR-MMP-2-sensitive linker-EEEEEEEE).
- Evaluated cellular uptake and MMP-2 sensitivity of the ACP.
- Assessed glioma localization and anti-glioma efficacy of dual-modified nanoparticles (AnACNPs) loaded with docetaxel in vitro and in vivo.
Main Results:
- ACP-modified nanoparticles showed enhanced C6 cell uptake, dependent on matrix metalloproteinase-2 (MMP-2) activity.
- Dual-modified AnACNPs exhibited superior glioma localization compared to single-ligand nanoparticles.
- Docetaxel-loaded AnACNPs demonstrated significant anti-glioma effects both in vitro and in vivo.
Conclusions:
- A novel dual-targeting and activatable cell-penetrating nanoparticle system was successfully developed for glioma treatment.
- The AnACNP system effectively targets gliomas and enhances therapeutic outcomes.
- This approach offers a promising strategy for overcoming drug delivery challenges in glioma therapy.
