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Targeted anticancer potential against glioma cells of thymoquinone delivered by mesoporous silica core-shell nanoformulations with pH-dependent release

Shahein, Samar A, Aboul-Enein, Ahmed M, Higazy, Iman M, Abou-Elella, Faten, Lojkowski, Witold, Ahmed, Esam R, Mousa, Shaker A, AbouAitah, Khaled·2019·International Journal of Nanomedicine
DOI 10.2147/ijn.s206899PMC PMC6650459
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Figure 1 Schematic representation of preparation steps and proposed anticancer mechanism. Notes: Synthesis of MSNs and nanoformulations for delivery of TQ (A) and proposed anticancer mechanism (B) for brain cell cancer treated with nanoformulations. Abbreviations: MSN, mesoporous silica nanoparticles; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; TQ, thymoquinone; CS-SA, mixture solution of chitosan and stearic acid polymers; WP-AG, mixture solution of whey protein and gum Arabic.
Figure 1 Schematic representation of preparation steps and proposed anticancer mechanism. Notes: Synthesis of MSNs and nanoformulations for delivery of TQ (A) and proposed anticancer mechanism (B) for brain cell cancer treated with nanoformulations. Abbreviations: MSN, mesoporous silica nanoparticles; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; TQ, thymoquinone; CS-SA, mixture solution of chitosan and stearic acid polymers; WP-AG, mixture solution of whey protein and gum Arabic.CC BY-NC · PubMed Central
Figure 2 HR-TEM images of synthesized MSNs before and after drug loading and coating with polymer shells. Notes: MSNs at 100 nm scale (A) and at 200 nm scale (B). The morphological structure differences at all stages of preparations are seen MSNs (C), MSNTQ (D), MSNTQ-CS (E), and MSNTQ-WA (F). Abbreviations: HR-TEM, high-resolution transmission electron microscopy; MSN, mesoporous silica nanoparticles; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic.
Figure 2 HR-TEM images of synthesized MSNs before and after drug loading and coating with polymer shells. Notes: MSNs at 100 nm scale (A) and at 200 nm scale (B). The morphological structure differences at all stages of preparations are seen MSNs (C), MSNTQ (D), MSNTQ-CS (E), and MSNTQ-WA (F). Abbreviations: HR-TEM, high-resolution transmission electron microscopy; MSN, mesoporous silica nanoparticles; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic.CC BY-NC · PubMed Central
Figure 3 FE-SEM images of MSNs before and after drug loading and coating with polymer shells. Notes: MSN (A), core MSNTQ (B), core-shell MSNTQ-CS (C), and core-shell MSNTQ-WA (D). Abbreviations: FE-SEM, field emission scanning electron microscopy; MSN, mesoporous silica nanoparticles; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic.
Figure 3 FE-SEM images of MSNs before and after drug loading and coating with polymer shells. Notes: MSN (A), core MSNTQ (B), core-shell MSNTQ-CS (C), and core-shell MSNTQ-WA (D). Abbreviations: FE-SEM, field emission scanning electron microscopy; MSN, mesoporous silica nanoparticles; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic.CC BY-NC · PubMed Central
Figure 4 Nitrogen adsorption–desorption isotherms and pore size distributions measurements of all materials. Notes: The N2 adsorption-desorption isotherms of MSN, MSNTQ, MSNTQ-CS, and MSNTQ-WA (A). The pore diameter distribution for materials before and after TQ loading and coating with shells for nanoformulations (B). Abbreviations: MSN, mesoporous silica nanoparticles; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; TQ, thymoquinone; dVp/dD, pore volume distribtion; STP, standard temperature and pressure.
Figure 4 Nitrogen adsorption–desorption isotherms and pore size distributions measurements of all materials. Notes: The N2 adsorption-desorption isotherms of MSN, MSNTQ, MSNTQ-CS, and MSNTQ-WA (A). The pore diameter distribution for materials before and after TQ loading and coating with shells for nanoformulations (B). Abbreviations: MSN, mesoporous silica nanoparticles; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; TQ, thymoquinone; dVp/dD, pore volume distribtion; STP, standard temperature and pressure.CC BY-NC · PubMed Central
Figure 5 TGA and DSC measurements. Notes: TGA analysis of MSNs, TQ-loaded, and coated polymer nanoformulations (A). TQ (B). DSC profiles of MSNs, TQ-loaded, and coated polymer nanoformulations (C). TQ (D). Abbreviations: TGA, thermal gravimetric analysis; DSC, differential scanning calorimetry analysis; MSN, mesoporous silica nanoparticles; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; TQ, thymoquinone.
Figure 5 TGA and DSC measurements. Notes: TGA analysis of MSNs, TQ-loaded, and coated polymer nanoformulations (A). TQ (B). DSC profiles of MSNs, TQ-loaded, and coated polymer nanoformulations (C). TQ (D). Abbreviations: TGA, thermal gravimetric analysis; DSC, differential scanning calorimetry analysis; MSN, mesoporous silica nanoparticles; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; TQ, thymoquinone.CC BY-NC · PubMed Central
Figure 6 FTIR spectra of MSNs before and after loading, used polymers, and TQ. Notes: Orange arrows indicate the corresponding peaks to TQ for MSNTQ. Blue arrows specify peaks for chitosan. Green arrows specify peaks for whey protein and stearic acid. Black arrows indicate decreasing intensity of peaks corresponding to MSNTQ due to the shell for MSNTQ-WA due to used polymers and only the peak centered at 3,440 cm−1 MSNTQ-CS due to used polymers. Abbreviations: FTIR, Fourier transform infrared spectroscopy; MSN, mesoporous silica nanoparticles; TQ, thymoquinone; Cs, chitosan; AG, gum Arabic; SA, stearic acid; WP, whey protein; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic.
Figure 6 FTIR spectra of MSNs before and after loading, used polymers, and TQ. Notes: Orange arrows indicate the corresponding peaks to TQ for MSNTQ. Blue arrows specify peaks for chitosan. Green arrows specify peaks for whey protein and stearic acid. Black arrows indicate decreasing intensity of peaks corresponding to MSNTQ due to the shell for MSNTQ-WA due to used polymers and only the peak centered at 3,440 cm−1 MSNTQ-CS due to used polymers. Abbreviations: FTIR, Fourier transform infrared spectroscopy; MSN, mesoporous silica nanoparticles; TQ, thymoquinone; Cs, chitosan; AG, gum Arabic; SA, stearic acid; WP, whey protein; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic.CC BY-NC · PubMed Central
Figure 7 Release kinetic profiles of core nanoformulation (MSNTQ) and core-shell nanoformulations (MSNTQ-CS and MSNTQ-WA) at different pH conditions with PBS media. Notes: In vitro release profiles at pH 7.4 (A). In vitro release profiles at pH 6.8 (B). In vitro release profiles at pH 5.5 (C). The curves are expressed as mean ± SD (n=3), and error bars were created based on SD values. Abbreviations: MSNTQ, MSNs loaded with thymoquinone; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; PBS, phosphate-buffered saline; SD, standard deviation; n, number of replicates.
Figure 7 Release kinetic profiles of core nanoformulation (MSNTQ) and core-shell nanoformulations (MSNTQ-CS and MSNTQ-WA) at different pH conditions with PBS media. Notes: In vitro release profiles at pH 7.4 (A). In vitro release profiles at pH 6.8 (B). In vitro release profiles at pH 5.5 (C). The curves are expressed as mean ± SD (n=3), and error bars were created based on SD values. Abbreviations: MSNTQ, MSNs loaded with thymoquinone; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; PBS, phosphate-buffered saline; SD, standard deviation; n, number of replicates.CC BY-NC · PubMed Central
Figure 8 In vitro cytotoxicity of MSNs for biocompatibility evaluations on brain cancer cells (SW1088 and A172) and normal brain cells (HCN2) after 48 and 72 hrs of incubation with cells. Notes: Biocompatibility of MSN on SW1088 cancer cells with different concentrations from 12.3 to 1,000 µg/mL (A). Biocompatibility of MSN on A172 cancer cells with different concentrations from 12.3 to 1,000 µg/mL (B). Biocompatibility of MSN on HCN2 normal cells with different concentrations from 12.3 to 1,000 µg/mL (C); all data are expressed as mean ± SD. The differences are labeled with * (between the groups/samples) at p<0.05 based on the least significant difference (LSD values). Non-significant differences are marked as NS, it indicated by line linked the NS groups (for two samples). Abbreviations: MSN, mesoporous silica nanoparticles; SW1088, human astrocytoma brain cancer cells; A172, human glioma cells; HCN2, human cortical neuronal cells-2 normal cells; SD, standard deviation.
Figure 8 In vitro cytotoxicity of MSNs for biocompatibility evaluations on brain cancer cells (SW1088 and A172) and normal brain cells (HCN2) after 48 and 72 hrs of incubation with cells. Notes: Biocompatibility of MSN on SW1088 cancer cells with different concentrations from 12.3 to 1,000 µg/mL (A). Biocompatibility of MSN on A172 cancer cells with different concentrations from 12.3 to 1,000 µg/mL (B). Biocompatibility of MSN on HCN2 normal cells with different concentrations from 12.3 to 1,000 µg/mL (C); all data are expressed as mean ± SD. The differences are labeled with * (between the groups/samples) at p<0.05 based on the least significant difference (LSD values). Non-significant differences are marked as NS, it indicated by line linked the NS groups (for two samples). Abbreviations: MSN, mesoporous silica nanoparticles; SW1088, human astrocytoma brain cancer cells; A172, human glioma cells; HCN2, human cortical neuronal cells-2 normal cells; SD, standard deviation.CC BY-NC · PubMed Central
Figure 9 In vitro cytotoxicity of core nanoformulation (MSNTQ) and core-shell nanoformulations (MSNTQ-CS and MSNTQ-WA), and TQ in free form on brain cancer cells (SW1088 and A172), and normal brain cells (HCN2) after 48 and 72 hrs of incubation with cells. Notes: Cytotoxicity on SW1088 cancer cells with different concentrations from 1.2 to 100 µg/mL (A). Cytotoxicity on A172 cancer cells with different concentrations from 1.2 to 100 µg/mL (B). Cytotoxicity on HCN2 normal cells with different concentrations from 1.2 to 100 µg/mL (C). All data are expressed as mean ± SD. The differences are labeled with * (between the samples) at p<0.05 based on the least significant difference (LSD values). The orange line indicated the significant differences between incubation times. Non-significant differences are marked as NS, it indicated by line linked the NS (for two samples). For nanoformulations, the concentration was calculated as an equivalent amount of TQ in MSNTQ, MSNTQ-CS, and MSNTQ-WA. Abbreviations: MSNTQ, MSNs loaded with thymoquinone; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; TQ, thymoquinone; SW1088, human astrocytoma brain cancer cells; A172, human glioma cells; HCN2, human cortical neuronal cells-2 employed as normal cells; SD, standard deviation.
Figure 9 In vitro cytotoxicity of core nanoformulation (MSNTQ) and core-shell nanoformulations (MSNTQ-CS and MSNTQ-WA), and TQ in free form on brain cancer cells (SW1088 and A172), and normal brain cells (HCN2) after 48 and 72 hrs of incubation with cells. Notes: Cytotoxicity on SW1088 cancer cells with different concentrations from 1.2 to 100 µg/mL (A). Cytotoxicity on A172 cancer cells with different concentrations from 1.2 to 100 µg/mL (B). Cytotoxicity on HCN2 normal cells with different concentrations from 1.2 to 100 µg/mL (C). All data are expressed as mean ± SD. The differences are labeled with * (between the samples) at p<0.05 based on the least significant difference (LSD values). The orange line indicated the significant differences between incubation times. Non-significant differences are marked as NS, it indicated by line linked the NS (for two samples). For nanoformulations, the concentration was calculated as an equivalent amount of TQ in MSNTQ, MSNTQ-CS, and MSNTQ-WA. Abbreviations: MSNTQ, MSNs loaded with thymoquinone; MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; TQ, thymoquinone; SW1088, human astrocytoma brain cancer cells; A172, human glioma cells; HCN2, human cortical neuronal cells-2 employed as normal cells; SD, standard deviation.CC BY-NC · PubMed Central
Figure 10 Molecular mechanism of targets of core nanoformulation (MSNTQ), and core-shell nanoformulations (MSNTQ-CS and MSNTQ-WA), and TQ in free form on brain cancer cells (SW1088 and A172), and normal brain cells (HCN2) after 48 and 72 hrs of incubation with cells. Notes: caspase-3 activation in fold change measured by ELISA for all samples after 48 and 72 hrs of incubation with SW1088, A172, and HCN2 at IC50 concentration for each sample (A). Cytochrome c intracellular release in fold change measured by RT-PCR for all samples after 48and 72 hrs of incubation with SW1088, A172, and HCN2 at IC50 concentration for each sample (B). All data are expressed as mean ± standard deviation. The differences are labeled with * (between the samples or time effect) at p<0.05 based on the least significant difference (LSD values). Non-significant differences marked as NS (between the samples or time effect). In case of caspase-3: solid-gray line indicates the significance between cell lines; the dashed-orange line indicates differences between incubation times. In case of cytochrome c: solid-orange line indicates NS between some linked samples together, the solid-olive line indicates significant differences between some linked samples together, and the dashed-orange line indicates the differences between some samples. The cells treated with IC50 concentrations of TQ, MSNTQ, MSNTQ-CS, and MSNTQ-WA. A significant difference was obtained between cell lines (SW1088 and A172, with LSD of 0.655 regarding the obtained mean values of the two groups). Abbreviations: MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; TQ, thymoquinone; SW1088, human astrocytoma brain cancer cells; A172, human glioma cells; HCN2, human cortical neuronal cells-2 employed as normal cells; ELISA, enzyme-linked immunosorbent assays; IC50, the half maximal inhibitory concentration; SD, standard deviation.
Figure 10 Molecular mechanism of targets of core nanoformulation (MSNTQ), and core-shell nanoformulations (MSNTQ-CS and MSNTQ-WA), and TQ in free form on brain cancer cells (SW1088 and A172), and normal brain cells (HCN2) after 48 and 72 hrs of incubation with cells. Notes: caspase-3 activation in fold change measured by ELISA for all samples after 48 and 72 hrs of incubation with SW1088, A172, and HCN2 at IC50 concentration for each sample (A). Cytochrome c intracellular release in fold change measured by RT-PCR for all samples after 48and 72 hrs of incubation with SW1088, A172, and HCN2 at IC50 concentration for each sample (B). All data are expressed as mean ± standard deviation. The differences are labeled with * (between the samples or time effect) at p<0.05 based on the least significant difference (LSD values). Non-significant differences marked as NS (between the samples or time effect). In case of caspase-3: solid-gray line indicates the significance between cell lines; the dashed-orange line indicates differences between incubation times. In case of cytochrome c: solid-orange line indicates NS between some linked samples together, the solid-olive line indicates significant differences between some linked samples together, and the dashed-orange line indicates the differences between some samples. The cells treated with IC50 concentrations of TQ, MSNTQ, MSNTQ-CS, and MSNTQ-WA. A significant difference was obtained between cell lines (SW1088 and A172, with LSD of 0.655 regarding the obtained mean values of the two groups). Abbreviations: MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; TQ, thymoquinone; SW1088, human astrocytoma brain cancer cells; A172, human glioma cells; HCN2, human cortical neuronal cells-2 employed as normal cells; ELISA, enzyme-linked immunosorbent assays; IC50, the half maximal inhibitory concentration; SD, standard deviation.CC BY-NC · PubMed Central
Figure 11 The cell cycle and apoptosis analysis by flow cytometry measurements after treating SW1088 cancer cells with core-shell nanoformulations and free TQ for 72 hrs compared without any treatments (control, only SW1088 cells). Notes: Cell cycle arrest evaluations in SW1088 investigated by means of by propidium iodide staining (A–D). Apoptosis evaluation in SW1088 cells was done through Annexin-V/FITC staining (E–H). The cells treated with IC50 concentrations. Abbreviations: MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; TQ, thymoquinone; SW1088, human astrocytoma brain cancer cells; A172, human glioma cells; HCN2, human cortical neuronal cells-2 employed as normal cells; IC50, the half maximal inhibitory concentration; EAPO, early apoptosis; LAPO, late apoptosis; NC, necrosis; SD, standard deviation.
Figure 11 The cell cycle and apoptosis analysis by flow cytometry measurements after treating SW1088 cancer cells with core-shell nanoformulations and free TQ for 72 hrs compared without any treatments (control, only SW1088 cells). Notes: Cell cycle arrest evaluations in SW1088 investigated by means of by propidium iodide staining (A–D). Apoptosis evaluation in SW1088 cells was done through Annexin-V/FITC staining (E–H). The cells treated with IC50 concentrations. Abbreviations: MSNTQ, MSNs loaded with TQ as core; MSNTQ-CS, MSNTQ coated with the shell consists of chitosan and stearic acid; MSNTQ-WA, MSNTQ coated with the shell consists of whey protein and gum Arabic; TQ, thymoquinone; SW1088, human astrocytoma brain cancer cells; A172, human glioma cells; HCN2, human cortical neuronal cells-2 employed as normal cells; IC50, the half maximal inhibitory concentration; EAPO, early apoptosis; LAPO, late apoptosis; NC, necrosis; SD, standard deviation.CC BY-NC · PubMed Central

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Metadata

Authors
Shahein, S. A., Aboul-Enein, A. M., Higazy, I. M., Abou-Elella, F., Lojkowski, W., Ahmed, E. R., Mousa, S. A., & AbouAitah, K.
ORCID
Venue
International Journal of Nanomedicine
Publisher
Informa UK Limited
Published
2019-07
Volume
Volume 14
Pages
5503-5526
ISSN
1178-2013
DOI
10.2147/ijn.s206899
PMC
PMC6650459
Cited by
52
References
1
Language
en
Licence
creativecommons.org/licenses/by-nc/3.0/ (unspecified)

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