Biocompatible Eu doped mesoporous calcium silicate nanospheres for pH-responsive drug release

https://doi.org/10.1016/j.inoche.2021.108872Get rights and content

Highlights

  • Eu-doped MCS nanoparticles were prepared via a facile hydrothermal synthesis method.

  • Eu-MCS has high drug loading capacity and can realize pH-responsive drug release.

  • DOX@Eu-MCS exhibits an effect lethality on Hela cancer cells.

  • Red emissive and biocompatible Eu-MCS may be used for imaging guided cancer therapy.

Abstract

Calcium silicate is a kind of inorganic biomaterial containing Si, Ca, O elements, they have been widely investigated and applied in a variety of medical applications in the past four decades. Herein, Europium (Eu) doped mesoporous calcium silicate nanoparticles (Eu-MCS) with sizes ranging from 60 nm to 110 nm were prepared via a simple hydrothermal synthesis method. The morphology, structure, texture and optical property were characterized by SEM, TEM, XRD, N2 adsorption/desorption and PL spectra, respectively. The prepared material emits strong red luminescence at 613 nm upon UV irradiation and is cytocompatible at a wide range of concentrations, exibiting promising application in bioimaging. The Eu-MCS has a high loading capacity of 356.67 μg/mg for the anticancer drug DOX, and the drug loaded material DOX@Eu-MCS showed pH-controlled drug release behaviour. Moreover, both of the biocompatibility tests on normal human cells HEK293 and human colon cancer cells HT29 indicate a low cytotoxicity of Eu-MCS. The cell cytotoxity assays of the DOX loaded nanomaterial (DOX@Eu-MCS) on Hela cancer cells prove a high cancer cell mortality. Therefore, the as-prepared red emissive nanocarrier Eu-MCS has great potential to be used as an integrated platform for cancer diagnosis and therapy.

Graphical abstract

Introduction

Cancer is increasingly becoming a serious threat to human life and health. In recent years, the number of new diagnosed cancer cases exceeds 10 million every year, and about 9.6 million patients died of cancer in 2018. This number is predicted to increase by 70% in the next two decades [1], [2], [3], [4]. Hence, in-depth research on the cause, diagnosis, treatment and prevention of cancer is of great significance to human’s life.

Cancer diagnosis, especially the early diagnosis, plays a vital role in cancer treatment. At present, the commonly used diagnostic methods for cancer include endoscopic checking, imaging checking, pathological checking. In imaging checking, fluorescent biological probes are powerful analysis tools for biological and optical imaging benefiting from their easy design, preparation and functionalization [5]. Among the cancer therapies, chemotherapy is the most common clinical treatment for malignant tumors. However, clinical diagnosis and therapy are two relatively independent processes in currently. Diagnostic medication and therapeutic medication will increase the burden of patient’s metabolism, and frequent administration and over-dosage of drugs usually causes drug resistance and serious toxic side effects [6], which reduce the quality of patients’ life. Therefore, it is of crucial significance to construct an integrated platform for cancer diagnosis and therapy [7]. So far, an increasing number of nanomaterials are applied as integrated platforms for cancer diagnosis and treatment because of their advantages: (a) increase the drug delivery system’s water solubility and protect drugs dissolved in the bloodstream, improving the pharmacological and pharmacokinetic characteristics of the drugs; (b) target the delivery of drugs in the tumor through active targeting strategies involve utilizing affiliative ligands on the surface of nanocarriers for specific homing or through passive targeting which is well known as Enhanced Permeability and Retention effect that allows nanocarriers (~200 nm) accumulating preferentially in the tumor due to the leaky tumor endothelial vessels and defect in tumor lymphatic drainage [8], consequently limiting drug accumulation in the liver, spleen, kidneys, and other non-targeted organs, reducing toxic side effects and enhancing therapeutic efficacy; (c) easily functionalized, especially stimuli-responsive nanocarriers are widely investigated and designed [9], [10] because they have the ability to controllably and reversibly change their microstructures or physical or chemical properties in response to slight variations in specific triggers such as pH [11], photo/light [12], magnetism [13] etc; (d) deliver a combination of imaging and therapeutic agents for monitoring the therapeutic efficacy in real time [14], [15], [16]. However, fluorescent molecules, as a pivotal factor in fluorescence imaging, generally are coated in nanomaterials or conjugated to nanomaterials covalently. The preparation procedure is complex, and the fluorescence functionalized nanocarriers usually show a low signal-to-noise ratio due to their limited loading capacities (generally less than 10.0 wt%) and their uncontrolled leakage in advance [17].

In this work, we utlized a new method that is the simple hydrothermal synthesis method to prepare a kind of red emissive nanomaterial, Eu doped mesoporous calcium silicate nanospheres (Eu-MCS). The prepared nanomaterial not only has luminescence feature without leakage trouble but also can act as pH-responsive nanocarrier, which makes it a promising nano integrated platform for cancer diagnosis and therapy.Scheme 1.. Europium (Eu) is a bioactive rare earth element with low toxicity, and usually exists in trivalent form (Eu3+) with fantastic chemical properties [18], [19]. Rare earth ions’ luminescence features include high quantum yield (QY), narrow bandwidth, long-lived emission, large Stokes shifts etc, which have made rare earth materials satisfy the strict requirements of solar cells, telecommunication, electroluminescent devices and bioimaging set-ups etc in the market [20], [21], [22]. Mesoporous calcium silicate (MCS) is gaining increasing interest in drug delivery and bone regeneration [23], [24] due to their outstanding characteristics, including mesopores arrangements, extensive surface areas, excellent bioactivity and biocompatibility, biodegradability [25] and abundant Si-OH groups on the surface, which plays a principal role in facilitating drug adsorption and release mechanisms [26], [27]. Eu3+ could be successfully doped into MCS because its ionic radius (0.95 Ǻ) is close to that of Ca2+ (0.99 Ǻ), which enabled an efficient replacement of Ca2+ in MCS [28], [29]. The obtained nanomaterial emits red fluorescence under UV radiation and is proved to be an efficient drug carrier for pH-responsive drug delivery by using doxorubicin hydrocloride (DOX) as a model drug. Both of the biocompatibility tests on normal human cells HEK293 and human colon cancer cells HT29 indicate a low cytotoxicity of Eu-MCS. The cell cytotoxity assays of the DOX loaded nanomaterial (DOX@Eu-MCS) on Hela cancer cells prove an inhibitory effect on cancer cells in vitro. From above, the prepared Eu-MCS has great potential application in integrated nanoplatforms for cancer diagnosis and therapy and bioactive coating of metallic implants in tissue engineering [30], [31], [32].

Section snippets

Preparation of Eu-MCS nanoparticles

Europium-doped mesoporous calcium silicate nanoparticles (Eu-MCS) were synthesized according to the literature with a little modification [33]. We incorporated 1, 2 and 5% mol Eu into MCS respectively using CTAB and PVP K30 as co-templates. In a typical process of preparing MCS nanoparticles containing 5% mol Eu, 0.25 g PVP K30, 0.115 g NaOH and 0.35 g CTAB were firstly dissolved in 30 mL H2O and stirred for 1 h. Then, 836 μL TEOS, 0.1771 g Ca(NO3)2·4H2O, 0.1115 g Eu(NO3)3·6H2O and 42.6 μL TEP

Mesostructure, morphology and composition of 5% Eu-MCS

Fig. 1(a) shows wide-angle XRD of 1 % mol, 2 % mol and 5 % mol Eu containing MCS, one wide peak can be observed from 15 degree to 40 degree in the three spectra, suggesting the amorphous state of the materials. The small-angle XRD pattern in Fig. 1(b) shows one characteristic peak in low angle range, indicating that as-prepared materials have disordered but uniform-sized mesopores. The XRD pattern of pure MCS without doping Eu was also recorded, which is shown in Fig. S2†. An obvious wide peak

Conclusion

In conclusion, we successfully prepared a luminescent Eu-doped MCS nanoparticles via a facile hydrothermal synthesis method. Experimental results indicated that the obtained Eu-MCS nanoparticles emit strong red luminescence and have good biocompatibility, which makes the nanomaterial be a promising fluorescent probe candidate for intracellular labelling and bioimaging without fluorescent dyes’ leakage trouble. In addition, the nanocarrier Eu-MCS has a mesoporous structure with high drug loading

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work is supported by the “Young Talents” Project of Northeast Agricultural University(Grant No:18QC62) and Heilongjiang Provincial Postdoctoral Science Foundation(Grant No:LBH-Z19116).

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