Applied Materials Today
Targeted self-activating Au-Fe3O4 composite nanocatalyst for enhanced precise hepatocellular carcinoma therapy via dual nanozyme-catalyzed cascade reactions
Graphical abstract
The sequential catalytic−therapeutic mechanism of CD44MMSN/AuNPs on the generation of hydroxyl radicals for cancer therapy.
Introduction
Largely attributed to lack of tumor-targeted specificity, chemotherapy as one of commonly used procedures in tumor treatments, usually leads to severe side effects [1,2]. Therapeutic approaches including radiation, ultrasound, and photothermal treatments generally enable positioning the therapeutic sites, but may be harmful to surrounding tissues, or even arouse unwanted tumor invasion and metastasis [3], [4], [5], [6], [7]. To achieve efficient and tumor site-specific treatments, tumor microenvironment (TME) has been extensively investigated recently, in which the tumor cell metabolism, physical environment and vascular formation are significantly different from those in normal tissues [8,9]. TME-responsive drug releasing and diagnostic imaging have been widely developed, however, the introduced toxic antitumor agents would induce undesired cytotoxicity and damage to normal tissues subsequently [10].
Recently, chemodynamic therapy (CDT) has gained increasing research interest due to its special mechanism of producing reactive oxygen species (ROS) [11,12]. During the CDT process, hydroxyl radicals (•OH), a stronger ROS than H2O2, can be generated by endogenous H2O2 through a metal ion mediated Fenton reaction, and cause a more oxidative damage to tumor cells [13]. Therefore, converting endogenous H2O2 to more toxic •OH by catalysts is promising for tumor therapy. Furthermore, this process can avoid disavantages such as nonspecific side effects and low efficiency existing in traditional cancer therapy methods. However, the in vivo level of H2O2 is low and the efficiency of catalysts is also not sufficient, both of which have limited the CDT application in cancer therapy. Therefore, it is now urgent and important to develop a nanocatalytic system with prominent catalytic activity for specific and efficient tumor treatments.
Nanozymes integrating functions of natural nanomaterials and enzymes have inspired great research interest because of their tunable catalytic activities, low cost, and high stability and comparable to natural enzymes [14], [15], [16], which allow their wide applications in biomolecular detection [17,18], biosensing [19], disease diagnosis [20,21], antibacterial treatment [22], etc. The potential capability of nanozymes in various tumor treatments has drawn more and more attention recently. These nanocatalytic tumor treatment strategies based non-toxic but can be catalytically activated nano-sized catalysts to produce high-toxic ROS in tumors [23], [24], [25]. Tumor cells need more energy and nutrients than normal cells for growth because of the disorder in their metabolism [26,27]. Most cellular energy in tumor cells is produced via the glycolytic pathway, leading to a higher glucose consumption in tumor cells than in normal cells [28]. Once shutting down of glucose supply happens, tumor growth will be dramatically suppressed, therefore, cancer-starving via consumption of glucose is a promising strategy in cancer therapy [29,30]. Some glucose consumption strategies have been put forward in cancer therapy [31]. Glucose oxidase (GOD) can catalyze glucose to yield gluconic acid and H2O2 with O2, which has been shown promosing in tumor treatment [32]. Nevertheless, delivery of GOD strategies currently are mainly through electrostatic or covalent conjugation GOD with nanocarriers [33], the natural GOD has shortcomings like low operational stability and high cost, which limit its applications in physiological environments. Therefore, developing novel natural GOD alternatives with lower cost and higher stability is urgently desired.
Herein, we endeavored to formulate a novel upgraded stradegy for tumor precision treatment, which is in practice of great use to improve therapeutic efficiency in clinical tumor treatments. In this stradegy, as illustrated in Scheme 1, the acidic TME can specifically initiate the sequentially catalyzed cascade reactions in tumor cells and/or tissues including: (i) the hyaluronic acid (HA)-conjugated nanocatalysts effectively recognize the CD44 receptor-expressing HepG2 cells, making the nanocatalysts more easily to enter tumor cells; (ii) glucose oxidation is catalyzed by the GOD-mimic ultrasmall AuNPs in the silicon pores to produce abundant of H2O2 and gluconic acid in tumor cells; (iii) self-accelerated glucose oxidation in the acidic condition generates in situ elevation of the H2O2 level; (iv) the elevated H2O2 is then catalyzed through the synergistic peroxidase (POD)-like activity between ultrasmall AuNPs and Fe3O4 NPs component to release highly toxic •OH, leading to apoptosis of tumor cells. The well-defined CD44MMSN/AuNPs can trigger a ROS-mediated apoptosis mechanism in cells, and thus remarkably and specifically suppress tumor growth. Therefore, the fabricated nanocatalysts with dual enzymatic activities represent an insightful paradigm for selective and effective tumor therapy.
Section snippets
Materials
(3-aminopropyl) triethoxysilane (APTES), gold chloride solution (HAuCl4), tetraethyl orthosilicate (TEOS), and decane were obtained from Aladdin Industrial Co., Ltd. (Shanghai, China). GOD (10KU), glucose, POD (≥250 U/mg) were obtained from Solarbio Technology Co., Ltd (Beijing, China). 2–(N-morpholino) ethanesulfonic acid (MES) was obtained from Shanghai Sangon Biological Engineering Technology Co., Ltd (Shanghai, China). Fetal bovine serum (FBS) and cell culture medium were obtained from
Synthesis and characterization of CD44MMSN/AuNPs
Herein, we report a TME-responsive cascade reaction triggered by biomimetic dual inorganic nanozyme, which bears both GOD and POD mimicking catalytic activity of the nanoparticle complexes assembled with the ultrasmall AuNPs and Fe3O4 NPs for targeted nanocatalytic tumor therapy nanosystem, without employing any toxic chemical drug. The synthetic procedures of the targeted nanocatalysts are shown in Scheme 1, which include: (i) synthesis of Fe3O4 NPs magnetic core utilized partial reduction
Conclusion
This work reports on the nanocatalytic tumor-specific precision therapy with targeting TME-responsive catalytic cascade reactions based on inorganic biomimetic CD44MMSN/AuNPs nanozymes. The in situ growing AuNPs within the large mesopores of MMSN as a GOD-like nanozyme especially catalyze glucose oxidation to generate a large amount of gluconic acid and H2O2, and the generated H2O2 can be catalyzed by the POD-like activity of Fe3O4 NPs and AuNPs to generate •OH that induces tumor-cell apoptosis
Author statement
Xueqin Wang is responsible for proposing ideas, research aims, and supervising the whole research.
Tiandi Xiong, Miao Cui, and Xinglei Guan are responsible for conducting the experiment.
Jiacheng Yuan is responsible for constructing tumor animal models.
Zichao Wang is responsible for data analysis and manuscript writing.
Shaofeng Duan and Fang Wei are responsible for supervising the whole research and editing manuscript.
Declaration of Competing Interest
The work described has not been submitted elsewhere for publication, in whole or in part; and it has been read and approved by all the named authors. There are no known conflicts of interest associated with this publication.
Acknowledgements
This work is kindly supported by the Postdoctoral Science Foundation of China (No. 2019M652541), National Natural Science Foundation of China (No. 314 008 55), the Young Core Instructor Program in Higher Education Institution of Henan province (No.2018 GGJS 067), the Young Core Instructor Program from Henan University of Technology (No.214 200 55), and the Scientific and Technological Project of Henan Province (No. 182 102 210 394).
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