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. 2017 Apr 10:12:2733-2748.
doi: 10.2147/IJN.S127528. eCollection 2017.

Magnetic and pH dual-responsive mesoporous silica nanocomposites for effective and low-toxic photodynamic therapy

Jieqiong Zhan  1   2 , Zhiqiang Ma  2 , Dan Wang  3 , Xinfang Li  2 , Xiangui Li  2 , Lijing Le  2 , Anfeng Kang  2 , Pengwei Hu  1 , Lan She  2 , Feng Yang  1   2
Affiliations

Magnetic and pH dual-responsive mesoporous silica nanocomposites for effective and low-toxic photodynamic therapy

Jieqiong Zhan et al. Int J Nanomedicine. .

Abstract

Nonspecific targeting, large doses and phototoxicity severely hamper the clinical effect of photodynamic therapy (PDT). In this work, superparamagnetic Fe3O4 mesoporous silica nanoparticles grafted by pH-responsive block polymer polyethylene glycol-b-poly(aspartic acid) (PEG-b-PAsp) were fabricated to load the model photosensitizer rose bengal (RB) in the aim of enhancing the efficiency of PDT. Compared to free RB, the nanocomposites (polyethylene glycol-b-polyaspartate-modified rose bengal-loaded magnetic mesoporous silica [RB-MMSNs]) could greatly enhance the cellular uptake due to their effective endocytosis by mouse melanoma B16 cell and exhibited higher induced apoptosis although with little dark toxicity. RB-MMSNs had little dark toxicity and even much could be facilitated by magnetic field in vitro. RB-MMSNs demonstrated 10 times induced apoptosis efficiency than that of free RB at the same RB concentration, both by cell counting kit-8 (CCK-8) result and apoptosis detection. Furthermore, RB-MMSNs-mediated PDT in vivo on tumor-bearing mice showed steady physical targeting of RB-MMSNs to the tumor site; tumor volumes were significantly reduced in the magnetic field with green light irradiation. More importantly, the survival time of tumor-bearing mice treated with RB-MMSNs was much prolonged. Henceforth, polyethylene glycol-b-polyaspartate-modified magnetic mesoporous silica (MMSNs) probably have great potential in clinical cancer photodynamic treatment because of their effective and low-toxic performance as photosensitizers' vesicles.

Keywords: magnetic mesoporous silica; magnetic targeting; pH responsive; photodynamic therapy; polymer polyethylene glycol-b-poly(aspartic acid); rose bengal.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Illustration of MMSN-mediated treatment in a magnetic field. Note: RB was loaded into the mesoporous silica pores and surrounded by PEG-b-PAsp in blood vessels, when they were released in tumor sites. Abbreviations: MMSN, magnetic mesoporous silica nanoparticle; RB, rose bengal; PEG-b-PAsp, polyethylene glycol-b-poly(aspartic acid); RB−MMSNs, polyethylene glycol-b-polyaspartate-modified rose bengal-loaded magnetic mesoporous silica.
Figure 2
Figure 2
Schematic illustration for the synthesis of core–shell RB−MMSNs. Abbreviations: RB−MMSNs, polyethylene glycol-b-polyaspartate-modified rose bengal-loaded magnetic mesoporous silica; MMSN, magnetic mesoporous silica nanoparticle; RB, rose bengal; PEG-b-PAsp, polyethylene glycol-b-poly(aspartic acid).
Figure 3
Figure 3
The structural characterization of samples. Notes: (A) The TEM images of Fe3O4, Fe3O4@nSiO2 and MMSN. (B) BET nitrogen absorption/desorption isotherms for MMSN. Inset shows BJH pore size distributions of MMSN. (C) Wide-angel XRD patterns of Fe3O4, Fe3O4@nSiO2 and MMSN. Abbreviations: TEM, transmission electron microscope; MMSN, magnetic mesoporous silica nanoparticle; BET, Brunauer–Emmett–Teller; BJH, Barrett–Joyner–Halenda; XRD, X-ray diffraction; au, atomic unit.
Figure 4
Figure 4
Characterization on the magnetic properties of nanoparticles. Notes: (A) FTIR spectra of MMSNs and PEG-b-PAsp. (B) Hysteresis loop of Fe3O4, MMSNs and RB−MMSNs normalized to per gram of the dry powder by the means of VSM. Inset: digital photos of RB−MMSNs aqueous solution without (left) and with (right) an external magnetic field. (C and D) T2-weighted MRI (left) and T2 relaxation rates (right) of Fe3O4 or RB−MMSNs gel solutions at different Fe concentrations. Abbreviations: FTIR, Fourier transform infrared spectroscopy; MMSNs, polyethylene glycol-b-polyaspartate-modified magnetic mesoporous silica; PEG-b-PAsp, polyethylene glycol-b-poly(aspartic acid); RB−MMSNs, polyethylene glycol-b-polyaspartate-modified rose bengal-loaded magnetic mesoporous silica; VSM, vibrating sample magnetometer; MRI, magnetic resonance image.
Figure 5
Figure 5
RB loading and release performance of nanoparticles. Notes: (A) The columnar contrast diagram of Fe3O4@nSiO2, MMSN and MMSNs in terms of RB loading rate. (B) pH responsiveness release curve of drugs in vitro. (C) Decay curves of the UA absorption band at 292 nm as a function of the irradiation time in the presence of MMSNs, RB−MMSNs and free RB. Abbreviations: MMSN, magnetic mesoporous silica nanoparticle; MMSNs, polyethylene glycol-b-polyaspartate-modified magnetic mesoporous silica; RB, rose bengal; UA, uric acid; RB−MMSNs, polyethylene glycol-b-polyaspartate-modified rose bengal-loaded magnetic mesoporous silica.
Figure 6
Figure 6
Cellular uptake and magnetic targeting of RB-MMSNs in vitro. Notes: (A) Fluorescence images of B16 cells after co-incubation with 10 μg/mL RB and RB−MMSNs for 2 h. Scale bar =50 μm. (B) Low magnification (left) and high magnification (right) biological TEM images of B16 cells treated with MMSNs using the concentration of 50 μg/mL for 2 h. Arrows and circles point out the intercellular locations for nanoparticles. (C) Flow cytometry showing the fluorescence intensity of B16 cells under different culture conditions for 2 h (left) and photos of B16 cells culture dish (right). Abbreviations: RB, rose bengal; RB−MMSNs, polyethylene glycol-b-polyaspartate-modified rose bengal-loaded magnetic mesoporous silica; TEM, transmission electron microscope; MMSNs, polyethylene glycol-b-polyaspartate-modified magnetic mesoporous silica; DAPI, 4′,6-diamidinio-2-phenylindole.
Figure 7
Figure 7
The therapeutical effect of the RB-MMSNs in vitro. Notes: (A) Relative viabilities (left) and half inhibition curve (right) of B16 cells treated with various concentrations of MMSNs, RB−MMSNs and RB with or without green light irradiation. The wavelength was 535 nm, and the optical dose was 25 mW/cm2 for 3 min (mean ± SD, n=3; **P<0.01, ***P<0.001.) (B) Flow cytometry showing the apoptosis of B16 cells treated with different concentrations of free RB and RB−MMSNs without (up) or with (down) 535 nm green light irradiation for 3 min (25 mW/cm2). (C) ROS generation of B16 cells incubated with MMSNs, RB−MMSNs and free RB with green light irradiation (mean ± SD, n=3; *P<0.05, **P<0.01). The wavelength was 535 nm, and the optical dose was 25 mW/cm2 for 3 min. Abbreviations: FITC, fluorescein isothiocyanate; MMSNs, polyethylene glycol-b-polyaspartate-modified magnetic mesoporous silica; PI, propidium iodide; RB−MMSNs, polyethylene glycol-b-polyaspartate-modified rose bengal-loaded magnetic mesoporous silica; RB, rose bengal; ROS, reactive oxygen species.
Figure 8
Figure 8
Magnetic targeting of RB-MMSNs in vivo. Notes: (A) T2-weighted MRI of mice: preinjection, injection and 2 h postinjection with RB−MMSNs. Circles point out the locations of nanocomposites in tumor site. (B) Prussian blue-stained images of major organs and tumor tissues (black arrows indicate RB−MMSNs deposition). Scale bar =50 μm. Abbreviations: MRI, magnetic resonance image; RB−MMSNs, polyethylene glycol-b-polyaspartate-modified rose bengal-loaded magnetic mesoporous silica.
Figure 9
Figure 9
Antitumor experiments in vivo. Notes: (A and B) The survival, tumor growth and body weight change curves of different treatment groups (control, RB+, RB−MMSNs+ and M+RB−MMSNs+). (C) TUNEL analysis of tumor sections from the C57BL/6J xenografts mice treated with different therapeutics (control, RB+, RB−MMSNs+ and M+RB−MMSNs+). *Indicates P<0.05, ***P<0.001, they are all the statistically significant differences between the control group and the treatment group of M+RB-MMSNs+. &Indicates the treatment group of M+RB-MMSNs+ shows significant differences with the other three groups (control, RB+ and RB-MMSNs+) at day 14. Abbreviations: RB, rose bengal; RB−MMSNs, polyethylene glycol-b-polyaspartate-modified rose bengal-loaded magnetic mesoporous silica; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling.
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