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. 2016 Feb 15:6:21225.
doi: 10.1038/srep21225.

Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer

Yumin Zhang  1 , Cuihong Yang  1 , Weiwei Wang  2 , Jinjian Liu  1 , Qiang Liu  1 , Fan Huang  1 , Liping Chu  1 , Honglin Gao  1 , Chen Li  2 , Deling Kong  2 , Qian Liu  3 , Jianfeng Liu  1
Affiliations

Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer

Yumin Zhang et al. Sci Rep. .

Abstract

Ample attention has focused on cancer drug delivery via prodrug nanoparticles due to their high drug loading property and comparatively lower side effects. In this study, we designed a PEG-DOX-Cur prodrug nanoparticle for simultaneous delivery of doxorubicin (DOX) and curcumin (Cur) as a combination therapy to treat cancer. DOX was conjugated to PEG by Schiff's base reaction. The obtained prodrug conjugate could self-assemble in water at pH 7.4 into nanoparticles (PEG-DOX NPs) and encapsulate Cur into the core through hydrophobic interaction (PEG-DOX-Cur NPs). When the PEG-DOX-Cur NPs are internalized by tumor cells, the Schiff's base linker between PEG and DOX would break in the acidic environment that is often observed in tumors, causing disassembling of the PEG-DOX-Cur NPs and releasing both DOX and Cur into the nuclei and cytoplasma of the tumor cells, respectively. Compared with free DOX, free Cur, free DOX-Cur combination, or PEG-DOX NPs, PEG-DOX-Cur NPs exhibited higher anti-tumor activity in vitro. In addition, the PEG-DOX-Cur NPs also showed prolonged blood circulation time, elevated local drug accumulation and increased tumor penetration. Enhanced anti-tumor activity was also observed from the PEG-DOX-Cur-treated animals, demonstrating better tumor inhibitory property of the NPs. Thus, the PEG-DOX-Cur prodrug nanoparticle system provides a simple yet efficient approach of drug delivery for chemotherapy.

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Figures

Figure 1
Figure 1. Schematic illustration of the synthesis and working principle of PEG-DOX-Cur NPs.
(A) Synthesis of PEG-DOX NPs via Schiff’s base. (B) Preparation of PEG-DOX-Cur NPs by nanopreciptated technique. (C) Passive tumor targeting was achieved by EPR effect. (D) The PEG-DOX-Cur NPs could be internalized by cancer cells through endocytosis. (E) DOX and Cur were released with the cleavage of the Schiff’s base in tumor cells and diffused into nucleus.
Figure 2
Figure 2
The synthetic route to PEG-DOX (A) and 1H NMR spectra of mPEG-CHO (B) and PEG-DOX (C).
Figure 3
Figure 3
Hydrodynamic size distributions (A) and TEM images of PEG-DOX (B) and PEG-DOX-Cur NPs (C).
Figure 4
Figure 4
Drug release profiles of PEG-DOX-Cur NPs, (A) DOX of PEG-DOX-Cur NPs and (B) Cur of PEG-DOX-Cur NPs) under different pH values. Data were expressed as mean ± SDs (n = 3). (C) The morphology of PEG-DOX-Cur NPs after incubation at pH 5.0 for 48 h.
Figure 5
Figure 5. Cellular uptake and localization of PEG-DOX-Cur NPs in HepG 2 cancer cells observed by fluorescence microscopy after incubation for 2, 4, and 8 h, respectively.
Scale bar = 40 μm (A). Colocalization studies of PEG-DOX-Cur NPs carried out using lysosome tracker in HepG 2 cells after incubation for 0.5 h. Scale bar = 25 μm (B).
Figure 6
Figure 6. Quantitative analysis of mean fluorescence intensity after incubated with PEG-DOX-Cur NPs and free drugs for 2, 4, and 8 h through flow cytometry.
(Blank cells as the control, **P < 0.01 in comparison with DOX and Cur, respectively).
Figure 7
Figure 7
Cytotoxicity of free drugs, PEG-DOX NPs, PEG-DOX-Cur NPs and free drug mixtures against HepG 2 (A) and HeLa (B) cancer cells. Data were expressed as mean ± SDs (n = 6).
Figure 8
Figure 8. Representative ex vivo images and mean fluorescence intensity of tumor and main organs (heart, liver, spleen, lung and kidney).
Tissues were excised at 1 (A,D), 8 (B,E) and 24 h (C,F) after administration of DOX and PEG-DOX-Cur NPs and subjected to the imaging equipment. Quantitative analysis the concentration of Cur in tumor tissues after administration of Cur and PEG-DOX-Cur NPs (G). (*P < 0.05 in comparison with DOX or Cur).
Figure 9
Figure 9
Rough measurement of tumor penetrating efficiency of PEG-DOX-Cur NPs and DOX (A) and the statistical data (B) of red signals in tumor sections. Tumors were removed at 24 h after different formulations administration. (*p < 0.05 in comparison with DOX).
Figure 10
Figure 10. In vivo anti-tumor effects of DOX/Cur mixture, PEG-DOX NPs and PEG-DOX-Cur NPs on BALB/c nude mice (male, 6–8 weeks) bearing HepG2 xenografts.
(A) Relative tumor volume of different treatment groups (n = 10); (*p < 0.05, **p < 0.01). (B) Relative body weight change after treatment. Data expressed as mean ± standard deviation values. (C) H&E assays of tumors from HepG2 tumor xenograft-bearing BALB/c nude mice after being received different treatments for 18 days. Scale bar = 50 μm.
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