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

Doxorubicin and indocyanine green loaded superparamagnetic iron oxide nanoparticles with PEGylated phospholipid coating for magnetic resonance with fluorescence imaging and chemotherapy of glioma

Chen Shen1 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China, [email protected];2 Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, Heilongjiang, China, [email protected]
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Xiaoxiong Wang1 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China, [email protected];2 Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, Heilongjiang, China, [email protected]
,
Zhixing Zheng1 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China, [email protected];2 Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, Heilongjiang, China, [email protected]
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Chuang Gao3 Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China, [email protected]
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Xin Chen1 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China, [email protected];2 Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, Heilongjiang, China, [email protected]
,
Shiguang Zhao1 Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China, [email protected];2 Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin, Heilongjiang, China, [email protected]Correspondence[email protected]
&
Zhifei Dai3 Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, China, [email protected]Correspondence[email protected]
 show all
Pages 101-117 | Published online: 20 Dec 2018

Figures & data

Figure 1 Schematic illustration. SPIO@DSPE-PEG/DOX/ICG NPs preparation procedure and MR/NIR fluorescence dual-modal imaging and chemotherapy of glioma through intravenous injection.

Abbreviations: BBB, blood–brain barrier; DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; MR, magnetic resonance; SPIO NPs, superparamagnetic iron oxide nanoparticles; NIR, near-infrared.

Figure 1 Schematic illustration. SPIO@DSPE-PEG/DOX/ICG NPs preparation procedure and MR/NIR fluorescence dual-modal imaging and chemotherapy of glioma through intravenous injection.Abbreviations: BBB, blood–brain barrier; DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; MR, magnetic resonance; SPIO NPs, superparamagnetic iron oxide nanoparticles; NIR, near-infrared.

Table 1 Physicochemical properties of nanoparticles

Figure 2 Characterization of nanoparticles.

Notes: TEM images of hydrophobic SPIO NPs (A) and SPIO@DSPE-PEG/DOX/ICG NPs (C). The bar represents 40 nm. Particle size distribution of hydrophobic SPIO NPs (B) and SPIO@DSPE-PEG/DOX/ICG NPs (D) by DLS measurements. Fluorescence spectra of nanoparticles with an excitation wavelength of 480 nm (E) and 740 nm (F). In vitro release profiles of DOX in PBS at 37°C (G). Data are presented as mean ± SD, n=3.

Abbreviations: DLS, dynamic light scattering; DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles; TEM, transmission electron microscopy.

Figure 2 Characterization of nanoparticles.Notes: TEM images of hydrophobic SPIO NPs (A) and SPIO@DSPE-PEG/DOX/ICG NPs (C). The bar represents 40 nm. Particle size distribution of hydrophobic SPIO NPs (B) and SPIO@DSPE-PEG/DOX/ICG NPs (D) by DLS measurements. Fluorescence spectra of nanoparticles with an excitation wavelength of 480 nm (E) and 740 nm (F). In vitro release profiles of DOX in PBS at 37°C (G). Data are presented as mean ± SD, n=3.Abbreviations: DLS, dynamic light scattering; DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles; TEM, transmission electron microscopy.

Figure 3 Cellular uptake of nanoparticles.

Note: CLSM images of U251 cells incubated with free DOX and SPIO@DSPE-PEG/DOX/ICG NPs at a DOX concentration of 6 µg/mL for 1 hour.

Abbreviations: CLSM, confocal laser scan microscopy; DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure 3 Cellular uptake of nanoparticles.Note: CLSM images of U251 cells incubated with free DOX and SPIO@DSPE-PEG/DOX/ICG NPs at a DOX concentration of 6 µg/mL for 1 hour.Abbreviations: CLSM, confocal laser scan microscopy; DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure 4 Biocompatibility and cytotoxicity of nanoparticles in vitro.

Notes: Viability of HUVEC cells after incubation with blank SPIO@DSPE-PEG NPs at varying concentrations (equivalent to Fe concentrations) for 24, 48, and 72 hours (A). In vitro antitumor efficiency of SPIO@DSPE-PEG/DOX/ICG NPs or free DOX (control) against U251 cells at different concentrations for 24 hours (B), 48 hours (C), and 72 hours (D). Data are mean ± SD, n=3, *P<0.05 vs free DOX group.

Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; HUVEC, human umbilical vein endothelial cells; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure 4 Biocompatibility and cytotoxicity of nanoparticles in vitro.Notes: Viability of HUVEC cells after incubation with blank SPIO@DSPE-PEG NPs at varying concentrations (equivalent to Fe concentrations) for 24, 48, and 72 hours (A). In vitro antitumor efficiency of SPIO@DSPE-PEG/DOX/ICG NPs or free DOX (control) against U251 cells at different concentrations for 24 hours (B), 48 hours (C), and 72 hours (D). Data are mean ± SD, n=3, *P<0.05 vs free DOX group.Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; HUVEC, human umbilical vein endothelial cells; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure 5 In vivo fluorescence imaging efficacy.

Notes: Fluorescence images of glioma-bearing nude mice at different times after tail vein injection of free ICG and SPIO@DSPE-PEG/DOX/ICG NPs (A); arrow indicates direction of the glioma. Ex vivo fluorescence images (B) and quantitative analysis (C) of main organs from glioma-bearing nude mice after 72 hours of tail vein injection. Data are mean ± SD, n=3, *P<0.05, **P<0.01 vs flurensence intensity in tumor.

Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure 5 In vivo fluorescence imaging efficacy.Notes: Fluorescence images of glioma-bearing nude mice at different times after tail vein injection of free ICG and SPIO@DSPE-PEG/DOX/ICG NPs (A); arrow indicates direction of the glioma. Ex vivo fluorescence images (B) and quantitative analysis (C) of main organs from glioma-bearing nude mice after 72 hours of tail vein injection. Data are mean ± SD, n=3, *P<0.05, **P<0.01 vs flurensence intensity in tumor.Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure 6 In vivo MRI efficacy.

Notes: T2-weighted MR images of glioma-bearing Wistar rats at different times after tail vein injection of SPIO@DSPE-PEG/DOX/ICG NPs (A); arrow indicates direction of the glioma. The quantitative analyses of the T2 value in brain (B) and tumor (C). Data are mean ± SD, n=3, *P<0.05 and **P<0.01 vs 0 hours.

Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; MRI, magnetic resonance imaging; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure 6 In vivo MRI efficacy.Notes: T2-weighted MR images of glioma-bearing Wistar rats at different times after tail vein injection of SPIO@DSPE-PEG/DOX/ICG NPs (A); arrow indicates direction of the glioma. The quantitative analyses of the T2 value in brain (B) and tumor (C). Data are mean ± SD, n=3, *P<0.05 and **P<0.01 vs 0 hours.Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; MRI, magnetic resonance imaging; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure 7 Antitumor efficacy in vivo.

Notes: T1-weighted brain MR images of glioma-bearing Wistar rats treated with saline, SPIO@DSPE-PEG NPs, free DOX, and SPIO@DSPE-PEG/DOX/ICG NPs on days 7, 14, 21, and 28 after tumor implantation (A); arrow indicates direction of the glioma. Tumor volumes monitored by MRI (B). Kaplane–Meier survival curves (C) of rats. Data are shown as mean ± SD, n=6. ***P<0.001 vs control group, #P<0.001 vs free DOX group.

Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; MR, magnetic resonance; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure 7 Antitumor efficacy in vivo.Notes: T1-weighted brain MR images of glioma-bearing Wistar rats treated with saline, SPIO@DSPE-PEG NPs, free DOX, and SPIO@DSPE-PEG/DOX/ICG NPs on days 7, 14, 21, and 28 after tumor implantation (A); arrow indicates direction of the glioma. Tumor volumes monitored by MRI (B). Kaplane–Meier survival curves (C) of rats. Data are shown as mean ± SD, n=6. ***P<0.001 vs control group, #P<0.001 vs free DOX group.Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; MR, magnetic resonance; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure 8 Histological sections of brain and tumor stained with H&E.

Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure 8 Histological sections of brain and tumor stained with H&E.Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure S1 Body weights of glioma-bearing Wistar rats treated with saline, SPIO@DSPE-PEG NPs, free DOX, and SPIO@DSPE-PEG/DOX/ICG NPs. Data are shown as mean ± SD, n=6.

Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure S1 Body weights of glioma-bearing Wistar rats treated with saline, SPIO@DSPE-PEG NPs, free DOX, and SPIO@DSPE-PEG/DOX/ICG NPs. Data are shown as mean ± SD, n=6.Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure S2 TUNEL analysis of frozen tumor sections after different treatments.

Note: Green: TUNEL-stained apoptosis cells; blue: DAPI-labeled cell nuclei; G: glioma tissues; B: brain tissues.

Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure S2 TUNEL analysis of frozen tumor sections after different treatments.Note: Green: TUNEL-stained apoptosis cells; blue: DAPI-labeled cell nuclei; G: glioma tissues; B: brain tissues.Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure S3 Histological sections of the heart, liver, spleen, lung, kidney, and muscle stained with H&E.

Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

Figure S3 Histological sections of the heart, liver, spleen, lung, kidney, and muscle stained with H&E.Abbreviations: DOX, doxorubicin; DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)]; ICG, indocyanine green; SPIO NPs, superparamagnetic iron oxide nanoparticles.

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