Research Article: Embryonic Stem Cells‐Derived Exosomes Endowed with Targeting Properties as Chemotherapeutics Delivery Vehicles for Glioblastoma Therapy

Date Published: February 01, 2019

Publisher: John Wiley and Sons Inc.

Author(s): Qingwei Zhu, Xiaozheng Ling, Yunlong Yang, Juntao Zhang, Qing Li, Xin Niu, Guowen Hu, Bi Chen, Haiyan Li, Yang Wang, Zhifeng Deng.

http://doi.org/10.1002/advs.201801899

Abstract

Exosomes are nanosized membrane vesicles (30–100 nm) that can easily penetrate the blood–brain barrier, safely deliver therapeutic drugs, and be modified with target ligands. Embryonic stem cells (ESCs) provide abundant exosome sources for clinical application due to their almost unlimited self‐renewal. Previous studies show that exosomes secreted by ESCs (ESC‐exos) have antitumor properties. However, it is not known whether ESC‐exos inhibit glioblastoma (GBM) growth. In this study, the anti‐GBM effect of ESC‐exos is confirmed and then c(RGDyK)‐modified and paclitaxel (PTX)‐loaded ESC‐exos, named cRGD‐Exo‐PTX are prepared. It is then investigated whether the engineered exosomes deliver more efficiently to GBM cells versus free drug alone and drug‐loaded ESC‐exos using an in vitro GBM model and in vivo subcutaneous and orthotopic xenografts model. The results show that cRGD‐Exo‐PTX significantly improves the curative effects of PTX in GBM via enhanced targeting. These data indicate that ESC‐exos are potentially powerful therapeutic carriers for GBM and could have utility in many other diseases.

Partial Text

Glioblastoma (GBM) is the most common primary malignant tumor of central nervous system with high mortality and disability rate.1, 2 Despite the high drug resistance of GBM, another pivotal reason for this poor prognosis is that blood–brain barrier (BBB) limits the efficacy of chemotherapy drugs to reach the tumor region.3, 4, 5 Hence, developing well‐designed drug delivery strategy to overcome BBB is an urgent demand in achieving efficient therapy of GBM.

In summary, we confirmed the GBM inhibitory effect of ESC‐exos in vitro and in vivo. Then ESC‐exos were conjugated with tumor‐targeted c(RGDyK) peptide and loaded with PTX synchronously. The engineered exosomes, named cRGD‐Exo‐PTX, were demonstrated to possess excellent GBM‐targeting ability and improve the curative efficacy of PTX in GBM models. Collectively, our research designs a new type of GBM‐targeting exosomes, and provides a powerful tool for brain tumor therapy.

Cell Culture: ESCs (H9; provided by the Institute of Biochemistry and Cell Biology of Chinese Academy of Sciences) were routinely cultured in mTeSR1 media (Stem Cell Technologies, Vancouver, Canada) on Matrigel‐coated plates and passaged every 4–5 days. The human GBM cell lines U87 and U251, lung cancer cell line A549, HCC cell line HepG2, melanoma cell line B16, breast cancer cell line MDA‐MB‐231, and prostatic cancer cell line DU145 were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China) and propagated in Dulbecco’s modified Eagle medium containing 10% fetal bovine serum (Gibco Grand Island, USA). All cell lines were incubated at 37 °C in humidified atmosphere of 5% CO2.

The authors declare no conflict of interest.

 

Source:

http://doi.org/10.1002/advs.201801899

 

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