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Targeted delivery of doxorubicin to HER2 positive tumor models

Gomari, Hosna, Forouzandeh Moghadam, Mehdi, Soleimani, Masoud, Ghavami, Mahlegha, Khodashenas, Shabanali·2019·International Journal of Nanomedicine
DOI 10.2147/ijn.s210731PMC PMC6662522
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Figure 1 MSCs transduction with viral GFP. (A) Fluorescent and phase contrast images were merged. (B) Fluorescent image of the same frame. Low efficiency of transduction can be observed. Abbreviations: MSCs, mesenchymal stem cells; GFP, green fluorescent protein.
Figure 1 MSCs transduction with viral GFP. (A) Fluorescent and phase contrast images were merged. (B) Fluorescent image of the same frame. Low efficiency of transduction can be observed. Abbreviations: MSCs, mesenchymal stem cells; GFP, green fluorescent protein.CC BY-NC · PubMed Central
Figure 2 Characterization of exosomes. (A) TEM images of exosomes. Typical structure of exosomes was shown in this image (scale bar 200 nm). (B) Characterization of exosomes by ECL Western blotting. Exosome preparations were negative for endoplasmic reticulum marker (calnexin) in lane 1; lane 2 is the cell lysate which is positive for calnexin. The positive results for exosomal markers are displayed in lane 3 (CD81), lane 4 (CD63), and lane 5 (CD9). (C) Size distribution of exosomes was measured by a zeta-sizer. The peak diameter was about 100 nm. Abbreviations: ECL, enhanced chemiluminescence; TEM, transmission electron microscopy.
Figure 2 Characterization of exosomes. (A) TEM images of exosomes. Typical structure of exosomes was shown in this image (scale bar 200 nm). (B) Characterization of exosomes by ECL Western blotting. Exosome preparations were negative for endoplasmic reticulum marker (calnexin) in lane 1; lane 2 is the cell lysate which is positive for calnexin. The positive results for exosomal markers are displayed in lane 3 (CD81), lane 4 (CD63), and lane 5 (CD9). (C) Size distribution of exosomes was measured by a zeta-sizer. The peak diameter was about 100 nm. Abbreviations: ECL, enhanced chemiluminescence; TEM, transmission electron microscopy.CC BY-NC · PubMed Central
Figure 3 Fluorimetry and flow cytometry analysis of binding ability of targeted and untargeted exosomes. Binding of PKH-67 labeled targeted and untargeted exosomes to (A) coated HER2 protein and (B) HER2-positive SKBR3 cells with different concentrations. Fluorescence of each well was assessed by fluorimetry after removing unbound exosomes. BSA and PBS were used as controls. (B) Binding of PKH-67 labeled targeted and untargeted exosomes to HER2-positive SKBR3 cells. There were significant differences both in HER2 protein and HER2-positive cell immobilization; yet, no significant difference was observed at 0.2 µg/µL in binding to SKBR3 cells. (C) Binding and entrance of targeted labeled exosomes were quantified by flow cytometry. The results show a significant increase in binding of targeted exosomes to TUBO cells (46.05%) as HER2-positive murine cells compared to 4T1 cells (13.9%). Targeted exosomes showed significantly higher binding to HER2-positive cells compared to HER2-negative cells. Each error bar represents the mean±SD of three replicates. *P<0.05. Abbreviations: RFU, relative fluorescence units; BSA, bovine serum albumin.
Figure 3 Fluorimetry and flow cytometry analysis of binding ability of targeted and untargeted exosomes. Binding of PKH-67 labeled targeted and untargeted exosomes to (A) coated HER2 protein and (B) HER2-positive SKBR3 cells with different concentrations. Fluorescence of each well was assessed by fluorimetry after removing unbound exosomes. BSA and PBS were used as controls. (B) Binding of PKH-67 labeled targeted and untargeted exosomes to HER2-positive SKBR3 cells. There were significant differences both in HER2 protein and HER2-positive cell immobilization; yet, no significant difference was observed at 0.2 µg/µL in binding to SKBR3 cells. (C) Binding and entrance of targeted labeled exosomes were quantified by flow cytometry. The results show a significant increase in binding of targeted exosomes to TUBO cells (46.05%) as HER2-positive murine cells compared to 4T1 cells (13.9%). Targeted exosomes showed significantly higher binding to HER2-positive cells compared to HER2-negative cells. Each error bar represents the mean±SD of three replicates. *P<0.05. Abbreviations: RFU, relative fluorescence units; BSA, bovine serum albumin.CC BY-NC · PubMed Central
Figure 4 Binding of PKH-67 labeled exosomes to TUBO cells. Exosomes isolated from MSCs were labeled with PKH-67 and incubated with TUBO cells for 24 hours. (A) Fluorescent image of binding of PKH-67 targeted exosomes which showed significantly higher binding compared to PKH-67 untargeted exosomes. (B) Merged fluorescent image of DAPI, PKH-67, and phase contrast. (C) Merged bright field and PKH-67 fluorescent images of TUBO cells. (D) Fluorescent image of untargeted exosomes. (E) Merged DAPI, PKH-67, and bright field image of untargeted exosomes. (F) Merged bright field and PKH-67 fluorescent image of untargeted exosomes binding to TUBO cells. Labeled exosomes were colored green and nuclei colored by DAPI were observed in blue. Abbreviation: MSCs, mesenchymal stem cells.
Figure 4 Binding of PKH-67 labeled exosomes to TUBO cells. Exosomes isolated from MSCs were labeled with PKH-67 and incubated with TUBO cells for 24 hours. (A) Fluorescent image of binding of PKH-67 targeted exosomes which showed significantly higher binding compared to PKH-67 untargeted exosomes. (B) Merged fluorescent image of DAPI, PKH-67, and phase contrast. (C) Merged bright field and PKH-67 fluorescent images of TUBO cells. (D) Fluorescent image of untargeted exosomes. (E) Merged DAPI, PKH-67, and bright field image of untargeted exosomes. (F) Merged bright field and PKH-67 fluorescent image of untargeted exosomes binding to TUBO cells. Labeled exosomes were colored green and nuclei colored by DAPI were observed in blue. Abbreviation: MSCs, mesenchymal stem cells.CC BY-NC · PubMed Central
Figure 5 DOX delivery to TUBO cells and in vitro cellular cytotoxicity. (A) TUBO cells were incubated with 200 nM of exo-DOX for 4 hours. (B) TUBO cells were incubated with free DOX, targeted and untargeted exo-DOX for 24 hours, 48 hours, and 72 hours. Cell cytotoxicity was assessed using MTT assay. Exo-Dox showed similar cytotoxicity with free Dox after24 hours and 48 hours, with more cytotoxicity at 72 hours. The Student’s t-test was used to assess the significance of difference in cytotoxicity of the tested groups. Each error bar represents the mean±SD of three replicates. *P<0.05. Abbreviations: DOX, doxorubicin; exo-DOX, doxorubicin-loaded exosome.
Figure 5 DOX delivery to TUBO cells and in vitro cellular cytotoxicity. (A) TUBO cells were incubated with 200 nM of exo-DOX for 4 hours. (B) TUBO cells were incubated with free DOX, targeted and untargeted exo-DOX for 24 hours, 48 hours, and 72 hours. Cell cytotoxicity was assessed using MTT assay. Exo-Dox showed similar cytotoxicity with free Dox after24 hours and 48 hours, with more cytotoxicity at 72 hours. The Student’s t-test was used to assess the significance of difference in cytotoxicity of the tested groups. Each error bar represents the mean±SD of three replicates. *P<0.05. Abbreviations: DOX, doxorubicin; exo-DOX, doxorubicin-loaded exosome.CC BY-NC · PubMed Central
Figure 6 Immunohistochemistry of the TUBO tumor. (A) Brown colors indicate the HER2 receptor on the cell surface, (B) H&E staining of TUBO tumor.
Figure 6 Immunohistochemistry of the TUBO tumor. (A) Brown colors indicate the HER2 receptor on the cell surface, (B) H&E staining of TUBO tumor.CC BY-NC · PubMed Central
Figure 7 Biodistribution of exo-DOX in mice bearing TUBO tumor. In vivo targeting efficiency of targeted exo-DOX were assessed in a murine TUBO tumor model. These models were administered with a single 70-µg injection of targeted or untargeted exo-DOX. (A) In vivo fluorescent signals were recorded at 30 minutes and (B) 60 minutes post-injection. Fluorescence was detected at the tumor sites (black boxes), with gradual increasing in signal intensity at 60 minutes. Enhanced permeability and retention (EPR) effect causes accumulation of untargeted exo-DOX in tumor site, while it was lower in comparison to targeted exo-DOX. PBS was injected as blank and no fluorescence was detected in these mice. (C) Ex vivo fluorescent imaging of major organs of the tumor model after 60 minutes. Lanes 1, 2, and 3 were sequentially related to untargeted, targeted, and PBS intravenous injections. Accumulation of targeted and untargeted exo-DOX was mainly in the liver and lung, while, there was no accumulation in the heart after 60 minutes. Fluorescent intensity of untargeted exo-DOX was lower than targeted exo-DOX. Abbreviations: DOX, doxorubicin; exo-DOX, doxorubicin-loaded exosome DOX.
Figure 7 Biodistribution of exo-DOX in mice bearing TUBO tumor. In vivo targeting efficiency of targeted exo-DOX were assessed in a murine TUBO tumor model. These models were administered with a single 70-µg injection of targeted or untargeted exo-DOX. (A) In vivo fluorescent signals were recorded at 30 minutes and (B) 60 minutes post-injection. Fluorescence was detected at the tumor sites (black boxes), with gradual increasing in signal intensity at 60 minutes. Enhanced permeability and retention (EPR) effect causes accumulation of untargeted exo-DOX in tumor site, while it was lower in comparison to targeted exo-DOX. PBS was injected as blank and no fluorescence was detected in these mice. (C) Ex vivo fluorescent imaging of major organs of the tumor model after 60 minutes. Lanes 1, 2, and 3 were sequentially related to untargeted, targeted, and PBS intravenous injections. Accumulation of targeted and untargeted exo-DOX was mainly in the liver and lung, while, there was no accumulation in the heart after 60 minutes. Fluorescent intensity of untargeted exo-DOX was lower than targeted exo-DOX. Abbreviations: DOX, doxorubicin; exo-DOX, doxorubicin-loaded exosome DOX.CC BY-NC · PubMed Central
Figure 8 Therapeutic effects of exo-DOX in b6 nude mice bearing TUBO tumor. Mice bearing TUBO tumors (>100 mm3) were administrated intravenously with 1.5 mg/kg of different reagents (PBS, free DOX, targeted and untargeted exo-DOX), ttwice a week for a total of six injections. (A) Tumor growth was measured by digital caliper after each injection, and the antitumor activity of each group was assessed via tumor volume measurements. Targeted exo-DOX treatment dramatically reduced the rate of tumor growth compared to the control group (*P<0.05). At the experimental dose, free DOX and untargeted exo-DOX showed no significant effects on tumor growth (B) No significant difference was detected in body mass among the mice in these groups. Abbreviations: DOX, doxorubicin; exo-DOX, doxorubicin-loaded exosome DOX.
Figure 8 Therapeutic effects of exo-DOX in b6 nude mice bearing TUBO tumor. Mice bearing TUBO tumors (>100 mm3) were administrated intravenously with 1.5 mg/kg of different reagents (PBS, free DOX, targeted and untargeted exo-DOX), ttwice a week for a total of six injections. (A) Tumor growth was measured by digital caliper after each injection, and the antitumor activity of each group was assessed via tumor volume measurements. Targeted exo-DOX treatment dramatically reduced the rate of tumor growth compared to the control group (*P<0.05). At the experimental dose, free DOX and untargeted exo-DOX showed no significant effects on tumor growth (B) No significant difference was detected in body mass among the mice in these groups. Abbreviations: DOX, doxorubicin; exo-DOX, doxorubicin-loaded exosome DOX.CC BY-NC · PubMed Central

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Metadata

Authors
Gomari, H., Forouzandeh Moghadam, M., Soleimani, M., Ghavami, M., & Khodashenas, S.
Venue
International Journal of Nanomedicine
Publisher
Informa UK Limited
Published
2019-07
Volume
Volume 14
Pages
5679-5690
ISSN
1178-2013
DOI
10.2147/ijn.s210731
PMC
PMC6662522
Cited by
111
References
2
Language
en
Licence
creativecommons.org/licenses/by-nc/3.0/ (unspecified)

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