Pharmaceutical nanotechnology
Core–shell structured Fe3O4@TiO2-doxorubicin nanoparticles for targeted chemo-sonodynamic therapy of cancer

https://doi.org/10.1016/j.ijpharm.2015.03.070Get rights and content

Abstract

To facilitate targeting drug delivery and combined therapy, we develop titanium dioxide-encapsulated Fe3O4 nanoparticles (Fe3O4@TiO2 NPs). Titanium dioxide (TiO2), which is employed as a sonosensitizer for sonodynamic therapy (SDT), can also be used for the loading of doxorubicin (DOX). The fabricated Fe3O4@TiO2 NPs exhibit pH-dependent loading and release of doxorubicin (DOX) in vitro. After incubation with cancer cells, reactive oxygen species (ROS) are generated efficiently upon the irradiation of ultrasound. In the biodistribution experiments, extremely high in vivo tumor accumulation of Fe3O4@TiO2 NPs and long-time retention effect are observed. Compared with chemotherapy or sonodynamic treatment alone, the combined therapy demonstrated a synergistic effect, resulting in stronger cytotoxicity and higher therapeutic efficacy. Thus, the constructed NPs are endowed with multifunctions which allow them to selectively deliver combinatorial therapeutic payload to tumor with enhanced therapeutic effectiveness and minimal side effects.

Introduction

Chemotherapy is commonly used in the clinical treatment of many cancers. However, the treatment based on single chemotherapy is unsatisfied due to the emergency of multidrug resistance (MDR) (MacDiarmid et al., 2009, Nagasubramanian et al., 2003). To improve therapeutic efficiency and minimize side effect, various combined treatments have been explored (e.g., thermo-chemotherapy, chemo-photodynamic therapy, chemo-sonodynamic therapy) (Gong et al., 2013, Lin et al., 2014, Park et al., 2009, Shi et al., 2014, Yang et al., 2013). The combination of chemotherapy with other therapeutic approaches has been demonstrated to generate synergistic antitumor effect, resulting in lower doses of therapeutic agent and side effects (Park et al., 2009, You et al., 2010). Recently, sonodynamic therapy (SDT) by using ultrasound (US) activating sonosensitizers, to generate reactive oxygen species (ROS), has been expected to be an effective therapeutic tool for the tumors developed in deep tissue due to the good penetration ability of US. The US-induced SDT can not only be applied to directly damage tumors by ROS, but is also able to augment the cytotoxicity of chemotherapeutic agents by enhancing the drug uptake (Siu et al., 2007). Several kinds of sonosensitizers such as phthalocyanine (Kolarova et al., 2009), porphyrin and its derivatives (Wang et al., 2010, Yumita et al., 2012), 5-aminolevulinic acid (Ohmura et al., 2011, Song et al., 2011) and TiO2 (Ninomiya et al., 2012, Yamaguchi et al., 2011), have been explored for SDT treatment of cancers. As a widely used photosensitizer, TiO2 which can generate oxidative radicals under irradiation of ultraviolet (UV) light has been applied as sonosensitizer for cancer cells recently (Ashikaga et al., 2000). Besides, TiO2 nanoparticles have been demonstrated to be nontoxic, easy to prepare and highly stable in biological systems (Rozhkova et al., 2009, Song et al., 2009, Yamaguchi et al., 2011). Therefore, it is supposed that sonocatalytic TiO2 nanoparticles may have great potential in cancer sonodynamic therapy.

However, to achieve synergistic therapeutic effect, it is especially essential that sonosensitizer and anti-cancer drug could be simultaneously delivered to the targeted tumor site after intravenous administration. Numerous platforms for targeting delivery of drugs have been studied. Among these, magnetic nanoparticles have attracted extensive interest for the multifunctions of magnetic resonance imaging (MRI) (Zeng et al., 2014), photothermal therapy (Shen et al., 2013), targeted drug delivery (El-Dakdouki et al., 2014), magnetic enrichment and purification (Ma et al., 2012). Furthermore, magnetic nanoparticles can be used as core to construct core–shell structure, which allow the single nanocomposite to exert multifunctions including drug delivery, therapy and imaging (Chen et al., 2008, Hao et al., 2010, Zhao et al., 2014). Therefore, a rational design to coat magnetic nanoparticles with TiO2 for doxorubicin (DOX) loading is developed, with the aim of achieving the targeting co-delivery of sonosensitizer and anti-cancer drug for the combined caner treatment.

In this article, core@shell nanocomposites of Fe3O4@TiO2 loading DOX were fabricated via the Stober method. Such nanocomposites exhibited high loading capacity and pH-sensitive release of DOX. Under the irradiation of ultrasound, Fe3O4@TiO2 could generate ROS efficiently. With an external magnetic field, the nanocomposites showed an excellent tumor targeting effect after intravenous injection. The comparison of combined treatment of DOX and SDT with chemo- or sonodynamic treatment alone was also carried out. The chemo-sonodynamic therapy demonstrated a clear synergistic effect.

Section snippets

Materials

Iron(III) chloride hexahydrate (FeCl3·6H2O), sodium acetate trihydrate (NaAc·3H2O), trisodium citrate, ethylene glycol (EG), anhydrous ethanol, tetrabutyl titanate (TBOT) and aqueous ammonia solution (28 wt%) were purchased from Sinopharm Chemical Reagents Company (Shanghai, PR China). 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and Hoechst 33342 were purchased from Sigma–Aldrich (Shanghai, PR China). 2′-7′-Dichlorofluorescin diacetate (DCFH-DA) was purchased from Aladdin

Preparation and characterization of Fe3O4@TiO2 nanoparticles

Fe3O4 nanoparticles were synthesized by a reduction reaction between FeCl3 and ethylene glycol (EG) using trisodium citrate (Na3Cit) as an electrostatic stabilizer. As revealed by transmission electron microscopy (TEM) images, uniform Fe3O4 nanospheres with a diameter of ~200 nm were synthesized (Fig. 2a).

The core–shell structured Fe3O4@TiO2 nanocomposites was fabricated using a sol–gel method (Li et al., 2012, Ma et al., 2012, Shen et al., 2014). Briefly, the obtained Fe3O4 NPs were dispersed

Conclusion

In summary, we successfully fabricated the core–shell structured Fe3O4@TiO2 nanoparticles, which could targetedly deliver DOX to tumor regions for combined chemo-sonodynamic therapy. Our results demonstrated that Fe3O4@TiO2 nanoparticles could generate ROS efficiently under the irradiation of ultrasound. The treatment of tumor cells with Fe3O4@TiO2-DOX followed by ultrasound irradiation showed significantly greater toxicity activity than the treatment with DOX or Fe3O4@TiO2-DOX alone. The

Acknowledgements

The work was supported by the National Natural Science Foundation of China (Nos. 81172999, 81373347), Senior Talent Foundation of Jiangsu University (No. 14JDG181) and Jiangsu Planned Projects for Postdoctoral Research Funds (No. 1402075B).

References (29)

  • W. Li et al.

    A versatile kinetics-controlled coating method to construct uniform porous TiO2 shells for multifunctional core–shell structures

    J. Am. Chem. Soc.

    (2012)
  • L.S. Lin et al.

    Graphitic-phase C3N4 nanosheets as efficient photosensitizers and pH-responsive drug nanocarriers for cancer imaging and therapy

    J. Mater. Chem. B

    (2014)
  • J. Liu et al.

    Highly water-dispersible biocompatible magnetite particles with low cytotoxicity stabilized by citrate groups

    Angew. Chem. Int. Ed.

    (2009)
  • W.F. Ma et al.

    Tailor-made magnetic Fe3O4@mTiO2 microspheres with a tunable mesoporous anatase shell for highly selective and effective enrichment of phosphopeptides

    ACS Nano

    (2012)
  • Cited by (142)

    View all citing articles on Scopus
    1

    The authors contributed equally to this paper.

    View full text