Effect of Angiopep-2-functionalized bacterial extracellular vesicles system on glioblastoma
10.12206/j.issn.2097-2024.202506017
- VernacularTitle:Angiopep-2修饰的细菌外囊泡载药系统治疗胶质母细胞瘤效果研究
- Author:
Bo SUN
1
;
Zongqiang LYU
2
;
Ning LUO
3
;
Rong LI
3
;
Hongxiang WANG
3
;
Juxiang CHEN
3
Author Information
1. Department of Neurosurgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China;Department of Neurosurgery, General Hospital of Central Theater Command, PLA, Wuhan 430070, China.
2. Department of Neurosurgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China;Department of Neurosurgery, No. 901 Hospital of The Joint Service Support Force, Hefei 230031, China.
3. Department of Neurosurgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China.
- Publication Type:Originalarticles
- Keywords:
glioblastoma;
blood brain barrier;
bacterial extracellular vesicles;
Angiopep-2;
Dox
- From:
Journal of Pharmaceutical Practice and Service
2025;43(10):481-490
- CountryChina
- Language:Chinese
-
Abstract:
Objective To construct a targeted drug delivery system, Ang-BEVs@Dox, based on Angiopep-2 peptide-modified bacterial extracellular vesicles （BEVs） loaded with doxorubicin （Dox）, overcome the challenges of blood-brain barrier （BBB） penetration and systemic toxicity in chemotherapy for glioblastoma （GBM）, enhance drug targeting to brain tumors and reduce its toxic side effects. Methods BEVs derived from Escherichia coli were isolated using ultracentrifugation. The targeting ligand Angiopep-2, specific for the LRP-1 receptor, was conjugated onto the surface of BEVs to construct the targeted carrier （Ang-BEVs）. Dox was loaded into Ang-BEVs using low-frequency sonication to form Ang-BEVs@Dox. The physicochemical properties （morphology and size） of the carriers were characterized by transmission electron microscopy （TEM） and dynamic light scattering （DLS）. The BBB-penetrating capability, in vitro/in vivo anti-tumor efficacy, and biosafety of the system were evaluated using cellular uptake assays, 3D tumor spheroid models, and orthotopic tumor-bearing mouse models. Results ① Carrier characterization and in vitro efficacy: Ang-BEVs@Dox exhibited a particle size of approximately 100 nm and maintained structural stability after Dox loading. It significantly enhanced cellular uptake efficiency in U87MG cells and achieved deep penetration within 3D tumor spheroids. Cytotoxicity assays demonstrated synergistic anti-tumor effects between the BEVs and Dox in the Ang-BEVs@Dox system. ② In vivo targeting and anti-tumor efficacy: In orthotopic tumor-bearing mouse models, Ang-BEVs@Dox effectively penetrated the BBB and significantly inhibited tumor growth, extending the median survival time of tumor-bearing mice to 33.5 days （compared to 23.5 days in the blank control group, P<0.001）. Immunohistochemical analysis revealed significant suppression of the tumor cell proliferation marker Ki-67 and enhancement of the apoptosis marker TUNEL staining signals. ③ Biosafety: Major organs from mice in the Ang-BEVs@Dox treatment group showed no observable pathological damage, indicating good biosafety. Conclusion This study successfully constructed an Angiopep-2 peptide-modified engineered BEVs delivery system （Ang-BEVs@Dox）. Through Angiopep-2-mediated BBB penetration and tumor targeting, it significantly enhanced the accumulation and therapeutic efficacy of BEVs at the GBM site. This method combined efficient delivery, low systemic toxicity, and clinical translation potential, which provided an innovative solution to overcome the therapeutic bottleneck in GBM treatment.
