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Embryonic Stem Cells-Derived Exosomes Endowed with Targeting Properties as Chemotherapeutics Delivery Vehicles for Glioblastoma Therapy.

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.

SUBMITTER: Zhu Q

PROVIDER: S-EPMC6425428 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Embryonic Stem Cells-Derived Exosomes Endowed with Targeting Properties as Chemotherapeutics Delivery Vehicles for Glioblastoma Therapy.

Zhu Qingwei Q Ling Xiaozheng X Yang Yunlong Y Zhang Juntao J Li Qing Q Niu Xin X Hu Guowen G Chen Bi B Li Haiyan H Wang Yang Y Deng Zhifeng Z

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20190201 6

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 ...[more]

PMID: 30937268

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Project description:ObjectiveGlioblastoma is a highly aggressive primary brain tumor that is resistant to radiotherapy and chemotherapy. Natural killer (NK) cells have been used to treat incurable cancers. Recent studies have investigated the effectiveness of NK-cell-derived exosomes (NK-Exo) for treating incurable cancers such as melanoma, leukemia, and neuroblastoma; however, NK-Exo have not been used to treat glioblastoma. In the present study, we investigated the antitumor effects of NK-Exo against aggressive glioblastoma both in vitro and in vivo and determined the tumor-targeting ability of NK-Exo by performing fluorescence imaging.MethodsU87/MG cells were transfected with the enhanced firefly luciferase (effluc) and thy1.1 genes; thy1.1-positive cells were selected using microbeads. U87/MG/F cells were assessed by reverse transcription polymerase chain reaction (RT-PCR), western blotting, and luciferase-activity assays. NK-Exo were isolated by ultracentrifugation, purified by density gradient centrifugation, and characterized by transmission electron microscopy, dynamic light scattering (DLS), nanoparticle-tracking analysis (NTA), and western blotting. Cytokine levels in NK-Exo were compared to those in NK cells and NK-cell medium by performing an enzyme-linked immunosorbent assay (ELISA). NK-Exo-induced apoptosis of cancer cells was confirmed by flow cytometry and western blotting. In vivo therapeutic effects and specificity of NK-Exo against glioblastoma were assessed in a xenograft mouse model by fluorescence imaging. Xenograft mice were treated with NK-Exo, which was administered seven times through the tail vein. Tumor growth was monitored by bioluminescence imaging (BLI), and tumor volume was measured by ultrasound imaging. The mice were intraperitoneally injected with dextran sulfate 2 h before NK-Exo injection to decrease the liver uptake and increase the tumor specificity of NK-Exo.ResultsRT-PCR and western blotting confirmed the gene and protein expression of effluc in U87/MG/F cells, with the bioluminescence activity of U87/MG/F cells increasing with an increase in cell number. NTA and DLS results indicated that the size of NK-Exo was ~100 nm, and the western blot results confirmed that NK-Exo expressed exosome markers CD63 and Alix. We confirmed the in vitro cytotoxic effects of NK-Exo on U87/MG/F cells by performing BLI, and the killing effect on U87/MG and U87MG/F cells was measured by CCK-8 and MTT assays (p < 0.001). ELISA results indicated that NK-Exo contained tumor necrosis factor-α and granzyme B. In vivo NK-Exo treatment inhibited tumor growth compared to in control mice (p < 0.001), and pretreatment of xenograft mice with dextran sulfate 2 h before NK-Exo treatment increased the antitumor effect of NK-Exo (p < 0.01) compared to in control and NK-Exo-alone-treated mice.ConclusionNK-Exo targeted and exerted antitumor effects on glioblastoma cells both in vitro and in vivo, suggesting their utility in treating incurable glioblastoma.

Dataset Information

Embryonic Stem Cells-Derived Exosomes Endowed with Targeting Properties as Chemotherapeutics Delivery Vehicles for Glioblastoma Therapy.

Publications

Embryonic Stem Cells-Derived Exosomes Endowed with Targeting Properties as Chemotherapeutics Delivery Vehicles for Glioblastoma Therapy.

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