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. 2015 Jun;32(6):2003-14.
doi: 10.1007/s11095-014-1593-y. Epub 2015 Jan 22.

Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio

Tianzhi Yang  1 , Paige Martin, Brittany Fogarty, Alison Brown, Kayla Schurman, Roger Phipps, Viravuth P Yin, Paul Lockman, Shuhua Bai
Affiliations

Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio

Tianzhi Yang et al. Pharm Res. 2015 Jun.

Abstract

Purpose: The blood-brain barrier (BBB) essentially restricts therapeutic drugs from entering into the brain. This study tests the hypothesis that brain endothelial cell derived exosomes can deliver anticancer drug across the BBB for the treatment of brain cancer in a zebrafish (Danio rerio) model.

Materials and methods: Four types of exosomes were isolated from brain cell culture media and characterized by particle size, morphology, total protein, and transmembrane protein markers. Transport mechanism, cell uptake, and cytotoxicity of optimized exosome delivery system were tested. Brain distribution of exosome delivered anticancer drugs was evaluated using transgenic zebrafish TG (fli1: GFP) embryos and efficacies of optimized formations were examined in a xenotransplanted zebrafish model of brain cancer model.

Results: Four exosomes in 30-100 diameters showed different morphologies and exosomes derived from brain endothelial cells expressed more CD63 tetraspanins transmembrane proteins. Optimized exosomes increased the uptake of fluorescent marker via receptor mediated endocytosis and cytotoxicity of anticancer drugs in cancer cells. Images of the zebrafish showed exosome delivered anticancer drugs crossed the BBB and entered into the brain. In the brain cancer model, exosome delivered anticancer drugs significantly decreased fluorescent intensity of xenotransplanted cancer cells and tumor growth marker.

Conclusions: Brain endothelial cell derived exosomes could be potentially used as a carrier for brain delivery of anticancer drug for the treatment of brain cancer.

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Figures

Fig. 1
Fig. 1
Particle size (a) and scanning electron micrograph (b) of exosomes isolated from (1) brain endothelial bEND.3, (2) neuroectodermal tumor PFSK-1, (3) glioblastoma A-172, and (4) glioblastoma -astrocytoma U-87 MG cells (* Results are significantly different, p<0.05).
Fig. 2
Fig. 2
Western blots and ELISA results of (a) CD9, (b) CD63, and (c) CD81 in exosomes isolated from (1) bEND.3, (2) PFSK-1, (3) A-172, and (4) U-87 MG cells (* Results are significantly different, p<0.05).
Fig. 3
Fig. 3
Flow cytometric analysis of rhodamine 123 in bEND.3 cell incubated at (a) 37°C and (b) 4°C.
Fig. 4
Fig. 4
Uptake (a) and confocal imaging (b) of bEND.3 exosome delivered fluorescent marker in U-87 MG cells.
Fig. 5
Fig. 5
Cytotoxicity on U-87 MG cells treated by (a) doxorubicin with U-87 MG cell derived exosome, (b) doxorubicin with bEND.3 cell derived exosome, (c) paclitaxel with U-87 MG cell derived exosome, and (d) paclitaxel with bEND.3 cell derived exosome (1: 25 μM drug; 2. 100 μg/ml exosome; 3. 200 μg/ml exosome; 4. drug + 20 μg/ml exosome; 5. drug + 40 μg/ml exosome; 6. drug + 80 μg/ml exosome; 7. drug + 100 μg/ml exosome; 8. drug + 200 μg/ml exosome, * Results are significantly different, p<0.05).
Fig. 6
Fig. 6
In vivo brain imaging of exosome delivered rhodamine 123 in Tg (fli1:GFP) embryonic zebrafish. Rhodamine 123 (red) retained within vessels (green) after the injected formulations without exosome (a) and with exosomes isolated from (b) neuroectodermal tumor PFSK-1, (c) glioblastoma A-172, and (d) glioblastoma-astrocytoma U-87 MG. Rhodamine 123 (red) crossed out of vessels (green) after the injected formulation with exosomes isolated from (e) brain endothelial bEND.3 cells.
Fig. 7
Fig. 7
In vivo brain imaging of exosome delivered anticancer drugs in Tg (fli1:GFP) embryos. Doxorubicin (a) and fluorescence labelled paclitaxel (b) retained within vessels after the injected formulations without exosomes. Doxorubicin (c) and fluorescence labelled paclitaxel (d) (red) crossed out of vessels (green) after the injected formulations with brain endothelial bEND.3 cell derived exosomes.
Fig. 8
Fig. 8
Efficacy of bEND.3 exosome delivered doxorubicin on zebrafish cancer model. DiD labeled cancer cells were injected into the hindbrain ventricle of 2 dpf zebrafish and further visualized at (a) without treatment, (b) treated by PBS buffer, (c) doxorubicin, (d) doxorubicin loaded exosome at 7 dpf.
Fig. 9
Fig. 9
Inhibitory of VEGF in vivo using bEND.3 exosome delivered doxorubicin on zebrafish cancer model (* Results are significantly different, p<0.05).
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