Cancer Letters

Cancer Letters

Volume 418, 1 April 2018, Pages 27-40
Cancer Letters

Original Articles
FePt-Cys nanoparticles induce ROS-dependent cell toxicity, and enhance chemo-radiation sensitivity of NSCLC cells in vivo and in vitro

https://doi.org/10.1016/j.canlet.2018.01.024Get rights and content

Highlights

  • FePt-Cys NPs are a novel nanoparticle system with good water-solubility, dispersity and biocompatibility.

  • FePt-Cys NPs have a synergistic effect with radiotherapy by impairing DNA damage repair.

  • FePt-Cys NPs promote chemotherapy effect by activating caspase-dependent apoptosis.

  • FePt-Cys NPs inhibit NSCLC cell invasion and migration by downregulating metalloproteases and enhancing cell adhesion.

Abstract

FePt-Cys nanoparticles (FePt-Cys NPs) have been well used in many fields, despite their poor solubility and stability. We synthetized a cysteine surface modified FePt NPs, which exhibited good solubility, stability and biocompatibility. We explored the insight mechanisms of the antitumor effects of this new nanoparticle system in lung cancer cells. In the in vitro study, FePt-Cys NPs induced a reactive oxygen species (ROS) burst, which suppressed the antioxidant protein expression and induced cell apoptosis. Furthermore, FePt-Cys NPs prevented the migration and invasion of H1975 and A549 cells. These changes were correlated with a dramatic decrease in MMP-2/9 expression and enhanced the cellular attachment. We demonstrated that FePt-Cys NPs promoted the effects of chemo-radiation through activation of the caspase system and impairment of DNA damage repair. In the in vivo study, no severe allergies or drug-related deaths were observed and FePt-Cys NPs showed a synergistic effect with cisplatin and radiation. In conclusion, with good safety and efficacy, FePt-Cys NPs could therefore be potential sensitizers for chemoradiotherapy.

Graphical abstract

FePt-Cys Nanoparticles induce ROS-dependent cell toxicity, and enhance chemo-radiation sensitivity of NSCLC cells in vivo and in vitro.

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Introduction

Non-small cell lung cancer (NSCLC), with the highest mortality rate over the past 30 years, is one of the most common human malignancies [1]. Sixty percent of cases are diagnosed at an advanced stage. Chemotherapy and radiotherapy are the standard treatments for advanced NSCLC in multiple guidelines [2]. Recently, chemoradiotherapy emerged as a well-established treatment paradigm for tumors. Compared to single radiotherapy and chemotherapy or sequential treatment, the combination strategy offers better potential for consistent control of local tumors and improvement of cure rates [3]. However, the additional toxicity of chemoradiotherapy has impeded its clinical application, the 5 years survival rate for NSCLC is still 16.1% and most treatment failure results from chemotherapy and radiotherapy resistance [4]. Although the golden standard treatments of chemotherapy and radiotherapy have advantages, they also lead to many unfavorable outcomes, including bone marrow arrest, vomiting, and nausea, which severely limit their clinical applications [2,3]. Therefore, there is an urgent to find a safer and more effective method for treatment.

The development of nanomaterials has substantially improved tumor diagnosis and treatment [5]. Traditional antitumor molecules frequently encountered several obstacles, such as the lack of a specific drug target, the need for a higher dose to achieve a high local concentration and other adverse effects [6]. Nanoparticles (NPs) are anticipated to provide a viable strategy to overcome these disadvantages and potential therapeutic effects [7]. Owing to the enhanced permeability and retention effect, NPs with a size of 20–200 nm can circumvent rapid renal filtration and passively accumulate in tumors [[8], [9], [10]]. This diversity of distribution between tumor and normal tissue enabled the use of NPs for magnetic resonance image (MRI), radiation sensitization and anticancer drugs design [[11], [12], [13]]. Thus, NPs are ideal carrier for molecular drugs to reduce the prescribed dose and the incidence of complications [14].

Owing to their optimal magnetic [15], optical properties [16] and controllable morphology, FePt NPs offer substantial advantages in biomedical applications. Magnetic NPs can be collected and manipulated by an external magnetic field, which promotes the accumulation the NPs to the targeted lesions, Teruaki et al. [5] established the fabrication of porous FePt network magnetic capsules and developed a magnet guided drug delivery system [9]. Shang-Wei Chou et al. [11,15] demonstrated that the alloy FePt nanoparticles served as a dual modality contrast agent for computer tomography and MRI molecular imaging. Moreover, Zheng et al. [11,12] revealed the potential of NPs as chemotherapy agents and sensitizers for chemoradiotherapy. Radiation sensitizers can induce more DNA damages and ROS in tumor cells [[17], [18], [19]], which results from the extremely high X-rays mass absorption coefficient of Pt. Although FePt NPs act as a kind of multifunctional nanomedicine, the mechanisms of their cytotoxic and pharmacological actions are unclear thus far. The synergistic effect of FePt NPs as a chemoradiotherapy sensitizer is yet to be investigated.

In this work, we explored the tumoricidal effect of FePt-Cys NPs in human NSCLC cells in vitro and in vivo. FePt-Cys NPs enhanced the effects of radiation though the dramatic impairment of DNA repair. Moreover, FePt-Cys NPs triggered apoptosis pathway which was lethal to cultured NSCLC cells in combination with cisplatin. Though the augmentation of intracellular ROS accumulation, the inhibition of ROS production reversed FePt-Cys NP-induced apoptosis. Furthermore, FePt-Cys NPs prevented cell migration and invasion through the decrease of MMP-2/9 expression and the enhancement of the cellular attachment. Therefore, we described a novel and promising nanoparticle system for the treatment of NSCLC, which might improve the clinical outcomes and decrease toxic side reactions.

Section snippets

Synthesis of FePt NPs

A chemical reduction method was applied to synthesize the NPs. Briefly, 0.386 mmol Iron acetylacetonate (Fe(acac)3, 98%, Aladdin®, USA), 1.5 ml oleic acid (C18H34O2, OA, Aladdin®, USA) and 1.5 ml oleylamine (C18H37N, OL, 95%, Aladdin®, USA) were sequentially added into a flask with 100 ml anhydrous ethanol. After stirring for 30 min using a magnetic stirrer, Chloroplatinic acid (H2PtCl6·6H2O, Reagent No.1 Factory Of Shanghai Chemical Reagent Co., Ltd., China) ethanol solution (19.3 mmol/l,

Characterization of FePt and FePt-Cys NPs

During the chemical synthesis of FePt NPs, the OA and OL were used as surfactants to stabilize the course of reaction, and to prevent the aggregation of NPs. The TEM micrographs of FePt NPs were shown in Fig. 1A. The average size of FePt NPs was approximately 3.3 nm in diameter. FePt NPs were remodified with Cys to improve the solubility and stability of water solutions. The TEM microgragh of FePt-Cys NPs showed in Fig. 1B. After 6 h of ultrasonic disposal, the FePt NPs sequentially grew to a

Discussion

FePt NPs with suitable surface functionalization have been widely utilized in cancer diagnosis and treatment, inducing in MRI contrast, drug delivery, chemotherapeutic agents, radiation sensitizing agents, thermal therapy and photothermic therapy owing to their excellent physicochemical characteristics [11,19].

However, the mechanism of the effects of FePt-Cys NPs on cancer cells remains largely undetermined. FePt-Cys NPs were reported to be transported into cells by endocytosis and processed at

Author contributions

Yingming Sun, Hongtao Miao, Hong Quan and Conghua Xie conceived and designed the experiments, Hongtao Miao, Lei Zhang and Cui Yang contributed to synthesis the FePt-Cys NPs. Yingming Sun, Hongtao Miao, Fang Tang, Shijing Ma, Yuan Luo, Feng Wang, Hongnv Yu performed the experiments in vitro. Yingming Sun, Hongtao Miao, Hui Wang, Xiangjie Lin and Xiaoli Tian performed the experiments in vivo. Yingming Sun, Hongtao Miao, Chengcheng You, Zhijun Li analysed the results. Yingming Sun, Hongtao Miao,

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

This study was supported in part by grants from the Chinese National Natural Science Foundation (grant No. 81572967, No. 10875092 and No. 31271511), Hubei Natural Science Foundation (grant No. 2013CFA006) and Zhongnan Hospital of Wuhan University Science, Technology and Innovation Seed Fund (grant No. znpy2016050, No. 2012KB04449), National key clinical speciality construction program of China (No. [2013]544), Wuhan City Huanghe Talents Plan and Medical Physics Teaching and Research Fund of

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