Targeted Extracellular Vesicles Delivered Verrucarin A to Treat Glioblastoma.

Kai Chen,Taehyun Kim,Zhuoxin Zhou,Xiaoguang Liu,Lufang Zhou,Seulhee Kim,Jia-Shiung Guan,Liang Shan,Christopher D Willey,Yingnan Si

doi:10.3390/biomedicines10010130

Kai Chen, Taehyun Kim + Show 8 more

Open Access

https://doi.org/10.3390/biomedicines10010130

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Journal: Biomedicines	Publication Date: Jan 7, 2022
Citations: 10	License type: CC BY 4.0

Affiliation: University of Alabama at Birmingham

Abstract

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.

Highlights

Gliomas are the most prevalent primary intracranial cancer, including the highly malignant, aggressive, heterogeneous, and angiogenetic glioblastomas (GBM, WHO grade IV), which account for the majority of gliomas [1]
Our study showed that the anti-epidermal growth factor receptor (EGFR) monoclonal antibody-directed extracellular vesicle (mAb-extracellular vesicle (EV))-verrucarin A (Ver-A) can effectively target
These data indicated that the EGFR-targeted EV-drug could cover >53% patients with malignant GBM

Summary

Introduction

Gliomas are the most prevalent primary intracranial cancer, including the highly malignant, aggressive, heterogeneous, and angiogenetic glioblastomas (GBM, WHO grade IV), which account for the majority of gliomas [1]. Surgery followed by the combination of involved-field radiation therapy and the DNA alkylating agent chemotherapy temozolomide (TMZ) is the current standard treatment strategy for newly diagnosed GBM in clinics [2,3]. Due to the stem-like cells, blood–brain barrier (BBB), or hypoxia, GBMs are usually resistant to conventional therapies with a high recurrence rate. Food and Drug Administration has approved bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb), to treat recurrent GBM. The current standard care only provides a median survival of 14.6 months for GBM patients [4].

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