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International Journal of Nanomedicine Volume 11, 2016 - Issue
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Original Research

Daunorubicin and gambogic acid coloaded cysteamine-CdTe quantum dots minimizing the multidrug resistance of lymphoma in vitro and in vivo

Yi Zhou1 Department of Hematology, Drum Tower Hospital, School of Medicine;2 Institute of Materials Engineering and Collaborative Innovation Center of Chemistry for Life Sciences, College of Engineering and Applied Sciences, Nanjing University, Nanjing People’s Republic of China
,
Ruju Wang1 Department of Hematology, Drum Tower Hospital, School of Medicine
,
Bing Chen1 Department of Hematology, Drum Tower Hospital, School of Medicine
,
Dan Sun3 School of Mechanical Engineering, Queen’s University Belfast, Belfast, UK
,
Yong Hu2 Institute of Materials Engineering and Collaborative Innovation Center of Chemistry for Life Sciences, College of Engineering and Applied Sciences, Nanjing University, Nanjing People’s Republic of ChinaCorrespondence[email protected]
&
Peipei Xu1 Department of Hematology, Drum Tower Hospital, School of MedicineCorrespondence[email protected]
Pages 5429-5442 | Published online: 18 Oct 2016

Figures & data

Figure 1 Schematic illustration of the structure of DNR-GA-Cys-CdTe NPs.

Notes: These DNR-GA-Cys-CdTe NPs can enter the cancer cells by endocytosis. Drugs can be released from DNR-GA-Cys-CdTe NPs in the acidic environment of endosomes/lysosomes to exert the synergistic antitumor effect.

Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; EPR, enhanced permeability and retention; GA, gambogic acid; NPs, nanoparticles.

Figure 1 Schematic illustration of the structure of DNR-GA-Cys-CdTe NPs.Notes: These DNR-GA-Cys-CdTe NPs can enter the cancer cells by endocytosis. Drugs can be released from DNR-GA-Cys-CdTe NPs in the acidic environment of endosomes/lysosomes to exert the synergistic antitumor effect.Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; EPR, enhanced permeability and retention; GA, gambogic acid; NPs, nanoparticles.

Figure 2 Characterization of DNR-GA-Cys-CdTe NPs.

Notes: (A) Ultraviolet-vis spectra of DNR, GA, Cys-CdTe QDs, and DNR-GA-Cys-CdTe NPs; (B) Fourier transform infrared spectra of DNR-GA-Cys-CdTe NPs, GA, DNR-Cys-CdTe NPs, DNR, and Cys-CdTe QDs; (C) TEM images of DNR-GA-Cys-CdTe NPs; (D) DLS analysis of DNR-GA-Cys-CdTe NPs.

Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DLS, dynamic light scattering; DNR, daunorubicin; EPR, enhanced permeability and retention; GA, gambogic acid; NPs, nanoparticles; QDs, quantum dots; TEM, transmission electron microscopy.

Figure 2 Characterization of DNR-GA-Cys-CdTe NPs.Notes: (A) Ultraviolet-vis spectra of DNR, GA, Cys-CdTe QDs, and DNR-GA-Cys-CdTe NPs; (B) Fourier transform infrared spectra of DNR-GA-Cys-CdTe NPs, GA, DNR-Cys-CdTe NPs, DNR, and Cys-CdTe QDs; (C) TEM images of DNR-GA-Cys-CdTe NPs; (D) DLS analysis of DNR-GA-Cys-CdTe NPs.Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DLS, dynamic light scattering; DNR, daunorubicin; EPR, enhanced permeability and retention; GA, gambogic acid; NPs, nanoparticles; QDs, quantum dots; TEM, transmission electron microscopy.

Table 1 Encapsulation efficiency and loading efficiency of DNR and GA on DNR-Cys-CdTe NPs or DNR-GA-Cys-CdTe NPs

Figure 3 DNR release behavior from DNR-GA-Cys-CdTe NPs at pH 7.4 and pH 6.0.

Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; NPs, nanoparticles.

Figure 3 DNR release behavior from DNR-GA-Cys-CdTe NPs at pH 7.4 and pH 6.0.Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; NPs, nanoparticles.

Figure 4 The cytotoxicity of GA (A) or Cys-CdTe QDs (B) for HELF and Raji/DNR cells with different concentration in 24 hours (P>0.05).

Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; HELF, human embryonic lung fibroblast; QDs, quantum dots.

Figure 4 The cytotoxicity of GA (A) or Cys-CdTe QDs (B) for HELF and Raji/DNR cells with different concentration in 24 hours (P>0.05).Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; HELF, human embryonic lung fibroblast; QDs, quantum dots.

Figure 5 Intracellular accumulation of DNR with different treatment evaluated by FCM (P<0.05).

Notes: (A) Control; (B) DNR; (C) DNR+GA; (D) DNR-Cys-CdTe NPs; (E) DNR-GA-Cys-CdTe NPs; (F) relative fluorescence intensity (RFI) of DNR in Raji/DNR cells; sol: DNR or DNR+GA alone.

Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; FCM, flow cytometry; GA, gambogic acid; NPs, nanoparticles.

Figure 5 Intracellular accumulation of DNR with different treatment evaluated by FCM (P<0.05).Notes: (A) Control; (B) DNR; (C) DNR+GA; (D) DNR-Cys-CdTe NPs; (E) DNR-GA-Cys-CdTe NPs; (F) relative fluorescence intensity (RFI) of DNR in Raji/DNR cells; sol: DNR or DNR+GA alone.Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; FCM, flow cytometry; GA, gambogic acid; NPs, nanoparticles.

Figure 6 Inhibition profiles of DNR, DNR-Cys-CdTe NPs, DNR+GA, and DNR-GA-Cys-CdTe NPs for (A) Raji and (B) Raji/DNR cells.

Notes: IC50 of DNR, DNR-Cys-CdTe NPs, DNR+GA, and DNR-GA-Cys-CdTe NPs for (A) Raji (P>0.05) and (B) Raji/DNR cells (P<0.05).

Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; NPs, nanoparticles.

Figure 6 Inhibition profiles of DNR, DNR-Cys-CdTe NPs, DNR+GA, and DNR-GA-Cys-CdTe NPs for (A) Raji and (B) Raji/DNR cells.Notes: IC50 of DNR, DNR-Cys-CdTe NPs, DNR+GA, and DNR-GA-Cys-CdTe NPs for (A) Raji (P>0.05) and (B) Raji/DNR cells (P<0.05).Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; NPs, nanoparticles.

Figure 7 Confocal fluorescence microscopy images of Raji/DNR cells QDs.

Notes: (A) Control; (B) DNR; (C) Cys-CdTe QDs; (D) DNR-GA-Cys-CdTe NPs. Scale bar =10 μm.

Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; NPs, nanoparticles; QDs, quantum dots.

Figure 7 Confocal fluorescence microscopy images of Raji/DNR cells QDs.Notes: (A) Control; (B) DNR; (C) Cys-CdTe QDs; (D) DNR-GA-Cys-CdTe NPs. Scale bar =10 μm.Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; NPs, nanoparticles; QDs, quantum dots.

Figure 8 The apoptosis of Raji/DNR cells with different treatment evaluated by FCM.

Notes: (A) Control; (B) DNR; (C) DNR+GA; (D) DNR-Cys-CdTe NPs; (E) DNR-GA-Cys-CdTe NPs.

Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; FCM, flow cytometry; FITC, fluorescein isothiocyanate; GA, gambogic acid; NPs, nanoparticles.

Figure 8 The apoptosis of Raji/DNR cells with different treatment evaluated by FCM.Notes: (A) Control; (B) DNR; (C) DNR+GA; (D) DNR-Cys-CdTe NPs; (E) DNR-GA-Cys-CdTe NPs.Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; FCM, flow cytometry; FITC, fluorescein isothiocyanate; GA, gambogic acid; NPs, nanoparticles.

Figure 9 Fluorescence microscope images of (A) control, (B) DNR, (C) DNR+GA, (D) DNR-Cys-CdTe, and (E) DNR-GA-Cys-CdTe NPs. (400×).

Note: The typical phenomena of apoptosis were indicated by red arrows.

Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; NPs, nanoparticles.

Figure 9 Fluorescence microscope images of (A) control, (B) DNR, (C) DNR+GA, (D) DNR-Cys-CdTe, and (E) DNR-GA-Cys-CdTe NPs. (400×).Note: The typical phenomena of apoptosis were indicated by red arrows.Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; NPs, nanoparticles.

Figure 10 Tumor inhibition in a nude mouse model of DNR-resistant Raji xenograft after treatment.

Notes: (A) Isolated tumor bodies. (B) Histopathological examination of tumor tissues in the mouse model at day 12 posttreatment (hematoxylin and eosin staining, ×40). (C) Tumor inhibition rates of different groups; (D) Relative tumor volumes of different treatments: Saline; DNR; DNR+GA; DNR-Cys-CdTe NPs; DNR-GA-Cys-CdTe NPs.

Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; NPs, nanoparticles.

Figure 10 Tumor inhibition in a nude mouse model of DNR-resistant Raji xenograft after treatment.Notes: (A) Isolated tumor bodies. (B) Histopathological examination of tumor tissues in the mouse model at day 12 posttreatment (hematoxylin and eosin staining, ×40). (C) Tumor inhibition rates of different groups; (D) Relative tumor volumes of different treatments: Saline; DNR; DNR+GA; DNR-Cys-CdTe NPs; DNR-GA-Cys-CdTe NPs.Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; NPs, nanoparticles.

Figure 11 The expressions of apoptosis-related proteins (Bax, Bcl-2, and caspase-3) and P-gp after treatment. 1, saline; 2, DNR; 3, DNR+GA; 4, DNR-Cys-CdTe NPs; 5, DNR-GA-Cys-CdTe NPs. The results were normalized by β-actin expression.

Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; NPs, nanoparticles.

Figure 11 The expressions of apoptosis-related proteins (Bax, Bcl-2, and caspase-3) and P-gp after treatment. 1, saline; 2, DNR; 3, DNR+GA; 4, DNR-Cys-CdTe NPs; 5, DNR-GA-Cys-CdTe NPs. The results were normalized by β-actin expression.Abbreviations: Cys, cysteamine; CdTe, cadmium-tellurium; DNR, daunorubicin; GA, gambogic acid; NPs, nanoparticles.

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