Elsevier

Biomaterials

Volume 44, March 2015, Pages 82-90
Biomaterials

Inorganic photosensitizer coupled Gd-based upconversion luminescent nanocomposites for in vivo magnetic resonance imaging and near-infrared-responsive photodynamic therapy in cancers

https://doi.org/10.1016/j.biomaterials.2014.12.040Get rights and content

Abstract

Inorganic photosensitizer coupled Gd-based upconversion luminescent (UCL) nanocomposites have potential application for both magnetic resonance imaging (MRI) and photodynamic therapy (PDT) of cancers using the light stability and biocompatibility of TiO2 inorganic photosensitizer. However, TiO2 inorganic photosensitizer could only be excited by ultraviolet (UV) light, which was harmful and weakly penetrable in tissues. In this work, folic acid (FA)-targeted NaGdF4:Yb/Tm@SiO2@TiO2 nanocomposites (FA-Gd-Si-Ti NPs) were constructed and synthesized for both in vivo MRI and near infrared (NIR)-responsive inorganic PDT, in which TiO2 component could be excited by NIR light due to the UCL performance of NaGdF4:Yb/Tm component converting NIR to UV light. The results showed the as-prepared FA-Gd-Si-Ti NPs had good biocompatibility in vitro and in vivo. Moreover, MR study indicated that FA-Gd-Si-Ti NPs were good T1-weighted MRI contrast agents with high longitudinal relaxivity (r1) of 4.53 mm−1 s−1, also in vivo MRI of nude mice showed “bright” signal in MCF-7 tumor. Under the irradiation of 980 nm laser at the power density of 0.6 W/cm2 for 20 min, the viability of HeLa and MCF-7 cells incubated with FA-Gd-Si-Ti NPs could decrease from about 90 % to 35 % and 31%, respectively. Furthermore, in vivo PDT of MCF-7 tumor-bearing nude mice model showed that the inhibition ratio of tumors injected with FA-Gd-Si-Ti NPs reached up to 88.6% after 2-week treatment, compared with that of nude mice in control group. Based on the deep penetration of NIR light and the good biocompatibility of TiO2 inorganic photosensitizer, the as-prepared FA-Gd-Si-Ti NPs could have potential applications in both MRI and NIR-responsive PDT of cancers in deep tissues.

Introduction

Magnetic resonance imaging (MRI) and photodynamic therapy (PDT) had potential application in early diagnoses and therapy, also prognosis assessment of cancers. Especially, PDT was considered to be very promising in noninvasive treatment for malignant tumors due to high sensitivity and selectivity [1], [2], [3], [4]. Under an external light source, photosensitizers could be excited to induce cytotoxic reactive oxygen species which would aggressively destroy cancer cells. However, single photosensitizers always had bad ability to locate tumors and could not remain in body for a long time, so the therapeutic exactitude and efficiency were limited to some extent [5], [6]. In recent years, photosensitizers combined with nanomaterials as multifunctional PDT agents have attracted great attention for simultaneous imaging and therapy, such as Au nanorods@mSiO2-porphyrin for two-photon imaging and PDT [7], NaYF4:Yb/Er-ZnPc for fluorescence imaging and PDT [8], NaYF4:Yb,Er/NaGdF4-Ce6 for dual-modal imaging and PDT [9], and so on [10], [11], [12]. Because of the enhanced permeability and retention (EPR) effect, and with the guidance of imaging, the accuracy and efficiency of PDT were greatly promoted.

However, organic molecules usually used as photosensitizers in PDT [1], [9], [10], [11], [12], [13], [14], which have some drawbacks, for example easy light bleaching, quick circulation, poor stability even in the absence of light, and so on. TiO2 nanoparticles were well known as inorganic photosensitizers widely used for photocatalytic degradation in environment [15], [16], [17], [18], [19], but they also could be applied in PDT [20], [21], [22], [23]. Under the excitation of ultraviolet (UV) light, TiO2 nanoparticles could produce reactive oxygen species, such as hydroxyl radicals (OH·), superoxide anion (O2), hydrogen peroxide (H2O2) and singlet oxygen (1O2), which would oxidize protein and lipid in the cell membrane and cellular components, and finally caused cell death resulting from both apoptosis and necrosis [23], [24]. Specially, inorganic TiO2 nanoparticles could have good light stability, good biocompatibility and long retention time in body, a favorable occurrence for the applications in biomedicine. Previously, our research group synthesized Janus Fe3O4–TiO2 nanocomposites used for T2-weighted MRI and inorganic PDT under UV light [25]. However, TiO2 inorganic photosensitizer could only be excited by UV light for PDT, which had weak penetration ability and could cause additional lesions on normal tissues. Therefore, it is a crucial challenge exploring a noninvasive light source to trigger TiO2 inorganic photosensitizer for PDT of cancers in deep tissues.

It was well known that near-infrared (NIR) light could have deep penetration in body, and was noninvasive for tissues and organs [26], [27]. NaGdF4 nanoparticles doped with lanthanide, such as Yb/Er or Yb/Tm, could convert NIR light into visible or UV light [28], [29], [30]. Moreover, NaGdF4 nanoparticles have been widely developed as T1-weighted MRI contrast agents owing to their excellent biocompatibility, compared with Gd-based chelates [31], [32], [33], [34], [35]. Therefore, TiO2 inorganic photosensitizer coupled with Gd-based upconversion luminescent (UCL) nanoparticles could be used for T1-weighted MRI and NIR-responsive PDT of cancers, which was interesting for early diagnoses and therapy, also prognosis assessment of cancers.

Herein, folic acid (FA) targeted NaGdF4:Yb/Tm@SiO2@TiO2 nanocomposites were designed and synthesized for both T1-weighted MRI and inorganic PDT under the excitation of NIR light. In this structure, the NaGdF4:Yb/Tm component served as T1-weighted MRI contrast agent and the TiO2 component served as PDT agent. Due to the UCL performance of NaGdF4:Yb/Tm converting NIR light into UV light, TiO2 could be excited by NIR light for PDT in deep tissues. The detailed schematic illustration of FA targeted NaGdF4:Yb/Tm@SiO2@TiO2 nanocomposites for MRI and near-infrared-responsive PDT was shown in Fig. 1(a).

Section snippets

Materials

Rare-earth oxides including gadolinium oxide (Gd2O3, 99.9%), ytterbium oxide (Yb2O3, 99.9%), thulium oxide (Tm2O3, 99.99%), polyvinylpyrrolidone (PVP, K29-32), ammonium fluoridenitric (NH4F, 98%), ammonium hydroxide (NH3·H2O, 25–28%), Tetraethyl orthosilicate (TEOS, 99.9%), titanium butoxide (TBOT, ≥99.0%), (3-aminopropyl)triethoxysilane (APTES, 99%), and dimethyl sulfoxide (DMSO, analytical grade) were purchased from Aladdin Industrial Inc. (Shanghai, China). Sodium chloride (NaCl, analytical

Synthesis and characterization of FA-Gd-Si-Ti NPs

Fig. 1(b)-(d) showed TEM images of the as-prepared NaGdF4:Yb/Tm, Gd-Si and Gd-Si-Ti NPs, respectively. As shown in Fig. 1(b), the morphology of NaGdF4:Yb/Tm NPs was nearly spherical or rodlike, and the size was about 50–80 nm. In the inset of Fig. 1(b), the HRTEM image of NaGdF4:Yb/Tm NPs indicated that the distance between lattice fringes was 0.302 nm, which corresponded to the d spacing of the (110) lattice plane in the hexagonal NaGdF4 structure. By stöber method, a layer of silica about

Conclusions

TiO2 inorganic photosensitizer coupled Gd-based UCL (NaGdF4:Yb/Tm@SiO2@TiO2) nanocomposites were successfully constructed and synthesized for in vivo MRI and NIR-responsive PDT of cancers, in which TiO2 could be excited by 980 nm laser due to UCL of NaGdF4:Yb/Tm converting NIR to UV light. The cytotoxicity, MRI and PDT of FA-Gd-Si-Ti NPs in vitro and in vivo were systematically investigated. The results showed the as-prepared FA-Gd-Si-Ti NPs had good biocompatibility, and the MR relaxivity

Acknowledgments

This work was supported by the National Natural Science Foundation of China (U1332117, U1432114), the National Key Basic Re-search Program of China (2014CB744504), the Postdoctoral science foundation of China and Jiangsu Province, and the Hundred Talents Program of Chinese Academy of Sciences.

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