期刊
BIOMEDICINES
卷 10, 期 1, 页码 -出版社
MDPI
DOI: 10.3390/biomedicines10010130
关键词
glioblastoma; targeted delivery; monoclonal antibody-directed extracellular vesicle; natural compound verrucarin A
资金
- USA National Institute of Health (NIH) [1R01CA238273-01A1, R21CA226491-01A1]
This study developed and evaluated a new targeted therapy using highly potent natural compound verrucarin A (Ver-A) delivered with monoclonal antibody-directed extracellular vesicle (mAb-EV). The results showed that mAb-EV can penetrate the blood-brain barrier, target glioblastoma, and deliver drugs intracellularly. In vivo studies demonstrated that EGFR mAb-EV-Ver-A effectively inhibited glioblastoma growth.
Glioblastomas, accounting for approximately 50% of gliomas, comprise the most aggressive, highly heterogeneous, and malignant brain tumors. The objective of this study was to develop and evaluate a new targeted therapy, i.e., highly potent natural compound verrucarin A (Ver-A), delivered with monoclonal antibody-directed extracellular vesicle (mAb-EV). First, the high surface expression of epidermal growth factor receptor (EGFR) in glioblastoma patient tissue and cell lines was confirmed using immunohistochemistry staining, flow cytometry, and Western blotting. mAb-EV-Ver-A was constructed by packing Ver-A and tagging anti-EGFR mAb to EV generated from HEK293F culture. Confocal microscopy and the In Vivo Imaging System demonstrated that mAb-EV could penetrate the blood-brain barrier, target intracranial glioblastoma xenografts, and deliver drug intracellularly. The in vitro cytotoxicity study showed IC50 values of 2-12 nM of Ver-A. The hematoxylin and eosin staining of major organs in the tolerated dose study indicated minimal systemic toxicity of mAb-EV-Ver-A. Finally, the in vivo anti-tumor efficacy study in intracranial xenograft models demonstrated that EGFR mAb-EV-Ver-A effectively inhibited glioblastoma growth, but the combination with VEGF mAb did not improve the therapeutic efficacy. This study suggested that mAb-EV is an effective drug delivery vehicle and natural Ver-A has great potential to treat glioblastoma.
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