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Engineering blood exosomes for tumor-targeting efficient gene/chemo combination therapy

Zhan, Qi, Yi, Kaikai, Qi, Hongzhao, Li, Sidi, Li, Xueping, Wang, Qixue, Wang, Yunfei, Liu, Chaoyong, Qiu, Mingzhe, Yuan, Xubo, Zhao, Jin, Hou, Xin, Kang, Chunsheng·2020·Theranostics
DOI 10.7150/thno.45028PMC PMC7359100
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Scheme 1 Schematic representation of engineered blood exosomes for effective gene/chemo combined antitumor therapy. Taking full use of the structure and properties of the exosome membrane, such blood exosome-based co-delivery nanosystem tactfully integrates three moieties: co-loading of drugs and nucleic acids with high-payloads, tumor targeting and endosomal escaping. After intravenous injection, the engineered exosomes can accumulate at the tumor site with high-efficiency under an external magnetic field, following cellular uptake, the presence of endosomolytic peptide facilitates the effective release of therapeutic RNAs and chemotherapeutic drugs, resulting in a significantly improved gene/chemo combination antitumor effect.
Scheme 1 Schematic representation of engineered blood exosomes for effective gene/chemo combined antitumor therapy. Taking full use of the structure and properties of the exosome membrane, such blood exosome-based co-delivery nanosystem tactfully integrates three moieties: co-loading of drugs and nucleic acids with high-payloads, tumor targeting and endosomal escaping. After intravenous injection, the engineered exosomes can accumulate at the tumor site with high-efficiency under an external magnetic field, following cellular uptake, the presence of endosomolytic peptide facilitates the effective release of therapeutic RNAs and chemotherapeutic drugs, resulting in a significantly improved gene/chemo combination antitumor effect.CC BY · PubMed Central
Figure 1 Characterization of D-Exos/miR21i-L17E. (A, B) The particle size distribution and representative TEM images of SMNC-Exos and D-Exos/miR21i-L17E, respectively. (scale bar: 20 nm) (C) Western blots analysis of specific Tf receptors and exosome marker proteins (CD63, CD81 and CD9) of SMNC-Exos, D-Exos/miR21i and D-Exos/miR21i-L17E. (D) Detection of fluorescent signals in purified SMNC-Exos, D-Exos, D-Exos/miR21i and D-Exos/miR21i-L17E at different excitation/emission (Ex/Em) wavelength. The SMNC-Exos and chol-miR21i contained in each sample were labeled by FITC and Cy5, respectively. (E) UV-vis spectra of the SMNC-Exos, Dox, chol-miR21i-Cy5, L17E and D-Exos/miR21i-L17E. The inset shows the magnified UV-vis spectra from 600 to 700 nm. (F) Gel retention assay of D-Exos/miR21i prepared with D-Exos and varied concentrations of cholesterol-conjugated miR-21i or non-cholesterol-conjugated miR-21i. The Cy5-labeled miR-21i bands are displayed. (G) Schematic of the methods for confirming the localization of chol-miR21i on D-Exos/miR21i. Cy5-labeled miR-21 is complementary to chol-miR21i on D-Exos/miR21i. If miR-21i is completely display on the surface of exosomes, Cy5-miR21 will bind to D-Exos/miR21i, otherwise it will not. (H) Analysis for the binding of Cy5-miR21 to D-Exos/miR21i by gel electrophoresis. The Cy5-labeled miR-21 bands are displayed here. (I) Release profiles of Dox from D-Exos/miR21i-L17E in PBS (pH=7.4) and acetate buffer (pH=5.0) for 24 h. Data in (I) are presented as the mean ± standard deviation (SD) from three independent experiments (n=3).
Figure 1 Characterization of D-Exos/miR21i-L17E. (A, B) The particle size distribution and representative TEM images of SMNC-Exos and D-Exos/miR21i-L17E, respectively. (scale bar: 20 nm) (C) Western blots analysis of specific Tf receptors and exosome marker proteins (CD63, CD81 and CD9) of SMNC-Exos, D-Exos/miR21i and D-Exos/miR21i-L17E. (D) Detection of fluorescent signals in purified SMNC-Exos, D-Exos, D-Exos/miR21i and D-Exos/miR21i-L17E at different excitation/emission (Ex/Em) wavelength. The SMNC-Exos and chol-miR21i contained in each sample were labeled by FITC and Cy5, respectively. (E) UV-vis spectra of the SMNC-Exos, Dox, chol-miR21i-Cy5, L17E and D-Exos/miR21i-L17E. The inset shows the magnified UV-vis spectra from 600 to 700 nm. (F) Gel retention assay of D-Exos/miR21i prepared with D-Exos and varied concentrations of cholesterol-conjugated miR-21i or non-cholesterol-conjugated miR-21i. The Cy5-labeled miR-21i bands are displayed. (G) Schematic of the methods for confirming the localization of chol-miR21i on D-Exos/miR21i. Cy5-labeled miR-21 is complementary to chol-miR21i on D-Exos/miR21i. If miR-21i is completely display on the surface of exosomes, Cy5-miR21 will bind to D-Exos/miR21i, otherwise it will not. (H) Analysis for the binding of Cy5-miR21 to D-Exos/miR21i by gel electrophoresis. The Cy5-labeled miR-21 bands are displayed here. (I) Release profiles of Dox from D-Exos/miR21i-L17E in PBS (pH=7.4) and acetate buffer (pH=5.0) for 24 h. Data in (I) are presented as the mean ± standard deviation (SD) from three independent experiments (n=3).CC BY · PubMed Central
Figure 2 RNA transfection ability of SMNC-Exos modified with L17E peptide. (A) Fluorescence images of U87-GFP cells transfected with SMNC-Exos or SMNC-Exos-L17E carrying GFP siRNA (siGFP). The nucleus were stained with Hoechst 33342 (blue). The scale bar is 100 μm. (B) Western blot analysis of GFP protein expression. (C) Schematic representation of the luciferase reporter system (luc-hPEST-miR21). Luc: Firefly luciferase; hPEST: Protein degradation sequence (human-proline, glutamic acid, serine and threonine). Once exogenous miR-21i are transfected into cells via different nanocarriers and released into the cytoplasm, they block miR-21 associated with the 3'UTR of luciferase, which leads to decreased luciferase activity. (D) The bioluminescence of U87 cells after transfection of miR-21i into cells stably expressing luc-hPEST-miR21 by PEI, SMNC-Exos and SMNC-Exos-L17E. The results are expressed as RLU / mg protein. (E) Cell viability of U87 cells after treatment with SMNC-Exos containing different concentrations of L17E peptides for 24 h and 48 h. All data in (D) and (E) are presented as the mean ± SD from three independent experiments (n=3). The significant levels are shown as * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 2 RNA transfection ability of SMNC-Exos modified with L17E peptide. (A) Fluorescence images of U87-GFP cells transfected with SMNC-Exos or SMNC-Exos-L17E carrying GFP siRNA (siGFP). The nucleus were stained with Hoechst 33342 (blue). The scale bar is 100 μm. (B) Western blot analysis of GFP protein expression. (C) Schematic representation of the luciferase reporter system (luc-hPEST-miR21). Luc: Firefly luciferase; hPEST: Protein degradation sequence (human-proline, glutamic acid, serine and threonine). Once exogenous miR-21i are transfected into cells via different nanocarriers and released into the cytoplasm, they block miR-21 associated with the 3'UTR of luciferase, which leads to decreased luciferase activity. (D) The bioluminescence of U87 cells after transfection of miR-21i into cells stably expressing luc-hPEST-miR21 by PEI, SMNC-Exos and SMNC-Exos-L17E. The results are expressed as RLU / mg protein. (E) Cell viability of U87 cells after treatment with SMNC-Exos containing different concentrations of L17E peptides for 24 h and 48 h. All data in (D) and (E) are presented as the mean ± SD from three independent experiments (n=3). The significant levels are shown as * p < 0.05, ** p < 0.01, *** p < 0.001.CC BY · PubMed Central
Figure 3 Cellular uptake and intracellular distribution of D-Exos/miR21i-L17E. (A) Confocal images of U87 cells incubated with D-Exos/miR21i and D-Exos/miR21i-L17E for different times (1 h, 2 h, 4 h). The fluorescence spots of Dox (red) and chol-miR21i-Cy5 (purple) were observed. The nucleus and endo/lysosome were stained with DAPI (blue) and Lysotracker Green (green), respectively. (B) Co-localization ratio of the miR-21i signals (purple) in D-Exos/miR21i and D-Exos/miR21i-L17E to endosome signals (green) at different time points. (C) Flow cytometry profile of U87 cells incubated with free Dox and chol-miR21i, D-Exos, Exos/miR21i, D-Exos/miR21i and D-Exos/miR21i-L17E for 4 h. The y-axis represents cell counts and the x-axis represents the Dox and chol-miR21i-Cy5 fluorescence intensity, respectively. Data in (B) are presented as the mean ± SD (n>50) from three independent experiments (n=3). The significant levels are shown as ** p < 0.01, *** p < 0.001.
Figure 3 Cellular uptake and intracellular distribution of D-Exos/miR21i-L17E. (A) Confocal images of U87 cells incubated with D-Exos/miR21i and D-Exos/miR21i-L17E for different times (1 h, 2 h, 4 h). The fluorescence spots of Dox (red) and chol-miR21i-Cy5 (purple) were observed. The nucleus and endo/lysosome were stained with DAPI (blue) and Lysotracker Green (green), respectively. (B) Co-localization ratio of the miR-21i signals (purple) in D-Exos/miR21i and D-Exos/miR21i-L17E to endosome signals (green) at different time points. (C) Flow cytometry profile of U87 cells incubated with free Dox and chol-miR21i, D-Exos, Exos/miR21i, D-Exos/miR21i and D-Exos/miR21i-L17E for 4 h. The y-axis represents cell counts and the x-axis represents the Dox and chol-miR21i-Cy5 fluorescence intensity, respectively. Data in (B) are presented as the mean ± SD (n>50) from three independent experiments (n=3). The significant levels are shown as ** p < 0.01, *** p < 0.001.CC BY · PubMed Central
Figure 4 In vitro gene/chemo combination anticancer activity. (A, B) Relative expression levels of miR-21 in U87 (A) and MDA-MB-231 (B) cells after treatment with different samples. (C, D) Western blot analysis of AKT, BCL-2 and Caspase-3 protein expression in U87 (C) and MDA-MB-231 (D) cells after incubating with PBS, SMNC-Exos, D-Exos, D-Exos/miR21i, and D-Exos/miR21-L17E, respectively. Cell cytoskeleton protein (β-Actin) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) are used as the loading control. (E) Cell apoptosis of U87 cells in each treatment group. Cell apoptosis ratios were assessed using flow cytometry. The data in (A, B) are presented as the mean ± SD from three independent experiments (n=3). The significance levels are shown as * p < 0.05, ** p < 0.01.
Figure 4 In vitro gene/chemo combination anticancer activity. (A, B) Relative expression levels of miR-21 in U87 (A) and MDA-MB-231 (B) cells after treatment with different samples. (C, D) Western blot analysis of AKT, BCL-2 and Caspase-3 protein expression in U87 (C) and MDA-MB-231 (D) cells after incubating with PBS, SMNC-Exos, D-Exos, D-Exos/miR21i, and D-Exos/miR21-L17E, respectively. Cell cytoskeleton protein (β-Actin) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) are used as the loading control. (E) Cell apoptosis of U87 cells in each treatment group. Cell apoptosis ratios were assessed using flow cytometry. The data in (A, B) are presented as the mean ± SD from three independent experiments (n=3). The significance levels are shown as * p < 0.05, ** p < 0.01.CC BY · PubMed Central
Figure 5 Tumor targeting efficiency of engineered exosomes in tumor-bearing mice in vivo. (A) In vivo NIRF imaging of U87 tumor-bearing nude mice after intravenous injection of Cy5.5-labeled D-Exos/miR21i-L17E with/without an external MF at 1 h, 4 h and 24 h post-injection. (B) Quantitative analysis of the tumor accumulation of the D-Exos/miR21i-L17E based on the fluorescence intensity from the in vivo images. (C) The accumulation of Dox and Cy5-miR21i in the tumor section, where red represents Dox, green represents miR21i and cell nucleus was stained by DAPI. The scale bar is 100 μm. Data in (B) are presented as the mean ± SD (n=5).
Figure 5 Tumor targeting efficiency of engineered exosomes in tumor-bearing mice in vivo. (A) In vivo NIRF imaging of U87 tumor-bearing nude mice after intravenous injection of Cy5.5-labeled D-Exos/miR21i-L17E with/without an external MF at 1 h, 4 h and 24 h post-injection. (B) Quantitative analysis of the tumor accumulation of the D-Exos/miR21i-L17E based on the fluorescence intensity from the in vivo images. (C) The accumulation of Dox and Cy5-miR21i in the tumor section, where red represents Dox, green represents miR21i and cell nucleus was stained by DAPI. The scale bar is 100 μm. Data in (B) are presented as the mean ± SD (n=5).CC BY · PubMed Central
Figure 6 Gene/chemo combination antitumor efficacy of D-Exos/miR21i-L17E in vivo. (A) Tumor growth curves of U87 subcutaneous tumor in nude mice injected with PBS, SMNC-Exos, Dox, D-Exos, Exos/miR21i, D-Exos/miR21i and D-Exos/miR21i-L17E. Every mouse was applied with a MF of 1T. Tumor volume was examined every 3 days for 18 consecutive days. (B) Ex vivo photograph of the tumors from the treated mice at 18 days' post-injection. (C) Comparison of the weight of collected tumor tissues from the mice treated with different formulations. (D) Changes in body weight of the mice with different treatment. (E) RNA in situ hybridization presenting the expression of miR-21 in the tumor tissue from the mice of each treatment group. Nucleus is stained blue, and miR-21 is stained brown. The scale bar is 50 μm. (F) Immunohistochemistry analyses of the expression of p-Akt, Bcl-2 and Caspase-3 in each treatment group. Nuclei are stained blue, and the proteins are stained brown. The scale bar is 200 μm. (G) TUNEL analysis of the tumor tissues from the mice in each treatment group. Normal cell nuclei are stained blue, and apoptotic cell nuclei are stained red. The scale bar is 100 μm. Data in (A) are presented as the mean ± SEM, and data in (C, D) are presented as the mean ± SD (n=5). The significance levels are shown as * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 6 Gene/chemo combination antitumor efficacy of D-Exos/miR21i-L17E in vivo. (A) Tumor growth curves of U87 subcutaneous tumor in nude mice injected with PBS, SMNC-Exos, Dox, D-Exos, Exos/miR21i, D-Exos/miR21i and D-Exos/miR21i-L17E. Every mouse was applied with a MF of 1T. Tumor volume was examined every 3 days for 18 consecutive days. (B) Ex vivo photograph of the tumors from the treated mice at 18 days' post-injection. (C) Comparison of the weight of collected tumor tissues from the mice treated with different formulations. (D) Changes in body weight of the mice with different treatment. (E) RNA in situ hybridization presenting the expression of miR-21 in the tumor tissue from the mice of each treatment group. Nucleus is stained blue, and miR-21 is stained brown. The scale bar is 50 μm. (F) Immunohistochemistry analyses of the expression of p-Akt, Bcl-2 and Caspase-3 in each treatment group. Nuclei are stained blue, and the proteins are stained brown. The scale bar is 200 μm. (G) TUNEL analysis of the tumor tissues from the mice in each treatment group. Normal cell nuclei are stained blue, and apoptotic cell nuclei are stained red. The scale bar is 100 μm. Data in (A) are presented as the mean ± SEM, and data in (C, D) are presented as the mean ± SD (n=5). The significance levels are shown as * p < 0.05, ** p < 0.01, *** p < 0.001.CC BY · PubMed Central

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Metadata

Authors
Zhan, Q., Yi, K., Qi, H., Li, S., Li, X., Wang, Q., Wang, Y., Liu, C., Qiu, M., Yuan, X., Zhao, J., Hou, X., & Kang, C.
Venue
Theranostics
Publisher
Ivyspring International Publisher
Published
2020
Volume
10
Issue
17
Pages
7889-7905
ISSN
1838-7640
DOI
10.7150/thno.45028
PMC
PMC7359100
Cited by
168
References
5
Language
en

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Zhan, Q., Yi, K., Qi, H., Li, S., Li, X., Wang, Q., Wang, Y., Liu, C., Qiu, M., Yuan, X., Zhao, J., Hou, X., & Kang, C. (2020). Engineering blood exosomes for tumor-targeting efficient gene/chemo combination therapy. Theranostics. https://doi.org/10.7150/thno.45028