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International Journal of Nanomedicine Volume 14, 2019 - Issue
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Original Research

Folic acid-modified ginsenoside Rg5-loaded bovine serum albumin nanoparticles for targeted cancer therapy in vitro and in vivo

Yanan Dong1 Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China;2 Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China;3 Biotech & Biomed Research Institute, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China
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Rongzhan Fu1 Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China;2 Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China;3 Biotech & Biomed Research Institute, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China
,
Jing Yang1 Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China;2 Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China;3 Biotech & Biomed Research Institute, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China
,
Pei Ma1 Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China;2 Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China;3 Biotech & Biomed Research Institute, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China
,
Lihua Liang2 Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China
,
Yu Mi1 Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China;2 Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China;3 Biotech & Biomed Research Institute, Northwest University, Xi’an, Shaanxi710069, People’s Republic of ChinaCorrespondence[email protected] [email protected]
&
Daidi Fan1 Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China;2 Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China;3 Biotech & Biomed Research Institute, Northwest University, Xi’an, Shaanxi710069, People’s Republic of China
 show all
Pages 6971-6988 | Published online: 29 Aug 2019

Figures & data

Figure 1 Schematic illustration of preparation of FA-Rg5-BSA NPs.

Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles.

Figure 1 Schematic illustration of preparation of FA-Rg5-BSA NPs.Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles.

Figure 2 (A) Hydrodynamic size distributions, (B) Zeta potentials, (C) SEM and (D) TEM images of Rg5-BSA NPs (top) and FA-Rg5-BSA NPs (bottom), and (E) UV-vis absorption spectra determining the amount of FA in Rg5-BSA NPs.

Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles; SEM, scanning electron microscopy; TEM, transmission electron microscopy.

Figure 2 (A) Hydrodynamic size distributions, (B) Zeta potentials, (C) SEM and (D) TEM images of Rg5-BSA NPs (top) and FA-Rg5-BSA NPs (bottom), and (E) UV-vis absorption spectra determining the amount of FA in Rg5-BSA NPs.Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles; SEM, scanning electron microscopy; TEM, transmission electron microscopy.

Table 1 Key parameters of Rg5-BSA NPs and FA-Rg5-BSA NPs

Figure 3 Characterization of folic acid modification.

Notes: (A) The FT-IR and (B) 1H NMR spectra of BSA, Rg5, FA, Rg5-BSA NPs and FA-Rg5-BSA NPs.

Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles; FT-IR, fourier transform infrared spectroscopy; 1H NMR, nuclear magnetic resonance.

Figure 3 Characterization of folic acid modification.Notes: (A) The FT-IR and (B) 1H NMR spectra of BSA, Rg5, FA, Rg5-BSA NPs and FA-Rg5-BSA NPs.Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles; FT-IR, fourier transform infrared spectroscopy; 1H NMR, nuclear magnetic resonance.

Figure 4 The stability of Rg5-BSA NPs and FA-Rg5-BSA NPs over time.

Notes: The stability of Rg5-BSA NPs (A) and FA-Rg5-BSA NPs (B) in water at 4 °C for 8 weeks. Data are represented as mean ± SD, n=3.

Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles; PDI, polydispersity index.

Figure 4 The stability of Rg5-BSA NPs and FA-Rg5-BSA NPs over time.Notes: The stability of Rg5-BSA NPs (A) and FA-Rg5-BSA NPs (B) in water at 4 °C for 8 weeks. Data are represented as mean ± SD, n=3.Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles; PDI, polydispersity index.

Figure 5 The release curve of Rg5 from Rg5-BSA NPs and FA-Rg5-BSA NPs.

Notes: The in vitro cumulative release percentage of Rg5 from Rg5-BSA NPs and FA-Rg5-BSA NPs over 140 hrs at different pH values (pH 5 and 7.4).Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles.

Figure 5 The release curve of Rg5 from Rg5-BSA NPs and FA-Rg5-BSA NPs.Notes: The in vitro cumulative release percentage of Rg5 from Rg5-BSA NPs and FA-Rg5-BSA NPs over 140 hrs at different pH values (pH 5 and 7.4).Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles.

Table 2 The IC50 of Rg5, Rg5-BSA NPs and FA-Rg5-BSA NPs in MCF-7 and L929 cells

Figure 6 In vitro cell viability assay.

Notes: Cell viability of blank BSA NPs, FA-BSA NPs against MCF-7 cells (A) and L929 cells (B) after incubating for 72 hrs; cell toxicity of Rg5, Rg5-BSA NPs and FA-Rg5-BSA NPs against MCF-7 cells (C, E) and L929 cells (D, F) for 24 hrs and 48 hrs. Values are represented as mean ± SD. (n=3, *P<0.05, **P<0.01).

Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles.

Figure 6 In vitro cell viability assay.Notes: Cell viability of blank BSA NPs, FA-BSA NPs against MCF-7 cells (A) and L929 cells (B) after incubating for 72 hrs; cell toxicity of Rg5, Rg5-BSA NPs and FA-Rg5-BSA NPs against MCF-7 cells (C, E) and L929 cells (D, F) for 24 hrs and 48 hrs. Values are represented as mean ± SD. (n=3, *P<0.05, **P<0.01).Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles.

Figure 7 Cell apoptosis assay of MCF-7 cells treated with Rg5, Rg5-BSA NPs and FA-Rg5-BSA NPs by (A) Hoechst 33,342, AO/EB, and (B) Annexin V-FITC/PI staining.

Note: Magnification 20× and scale bar is 100 µm.

Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles; AO/EB, Acridine orange/ethidium bromide.

Figure 7 Cell apoptosis assay of MCF-7 cells treated with Rg5, Rg5-BSA NPs and FA-Rg5-BSA NPs by (A) Hoechst 33,342, AO/EB, and (B) Annexin V-FITC/PI staining.Note: Magnification 20× and scale bar is 100 µm.Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles; AO/EB, Acridine orange/ethidium bromide.

Figure 8 The cellular uptake of FITC-labeled NPs treated with MCF-7 cells for 3 hrs was observed by CLSM (A) and flow cytometry (B).

Note: Magnification 40× and scale bar is 50 µm.

Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles; FITC, fluorescein isothiocyanate; CLSM, confocal laser scanning microscopy.

Figure 8 The cellular uptake of FITC-labeled NPs treated with MCF-7 cells for 3 hrs was observed by CLSM (A) and flow cytometry (B).Note: Magnification 40× and scale bar is 50 µm.Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles; FITC, fluorescein isothiocyanate; CLSM, confocal laser scanning microscopy.

Figure 9 Rg5, Rg5-BSA NPs and FA-Rg5-BSA NPs significantly inhibited the growth of MCF-7 xenograft in vivo.

Notes: (A) The image of MCF-7 xenograft tumors with different treatments at 21 days. (B) Tumor volume and (C) body weight were measured every 3 days. (D) Tumor weight after 21 days treatment. p<0.05 was considered to have a significant difference. Different letters indicate significant differences between each group.

Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles.

Figure 9 Rg5, Rg5-BSA NPs and FA-Rg5-BSA NPs significantly inhibited the growth of MCF-7 xenograft in vivo.Notes: (A) The image of MCF-7 xenograft tumors with different treatments at 21 days. (B) Tumor volume and (C) body weight were measured every 3 days. (D) Tumor weight after 21 days treatment. p<0.05 was considered to have a significant difference. Different letters indicate significant differences between each group.Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles.

Figure 10 The in vivo real-time biodistribution imaging.

Notes: MCF-7 tumor-bearing mice treated with free DiR, Rg5-BSA NPs/DiR, and FA-Rg5-BSA NPs/DiR at 2 h, 8 h and 24 h.

Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles; DiR, dioctadecyl-tetramethyl indotricarbocyanine iodide.

Figure 10 The in vivo real-time biodistribution imaging.Notes: MCF-7 tumor-bearing mice treated with free DiR, Rg5-BSA NPs/DiR, and FA-Rg5-BSA NPs/DiR at 2 h, 8 h and 24 h.Abbreviations: BSA, bovine serum albumin; Rg5, ginsenoside Rg5; FA, folic acid; NPs, nanoparticles; DiR, dioctadecyl-tetramethyl indotricarbocyanine iodide.

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