Low-Fouling Magnetic Nanoparticles and Evaluation of their Potential

Letter Cite This: ACS Appl. Nano Mater. XXXX, XXX, XXX−XXX

www.acsanm.org

Low-Fouling Magnetic Nanoparticles and Evaluation of Their Potential Application as Disease Markers Assay in Whole Serum Lihua Chen,*,†,‡,§ Shuli Lv,†,§ Mingchao Liu,† Chuangfu Chen,‡ Jinliang Sheng,‡ and Xiliang Luo*,† †

Key Laboratory of Sensor Analysis of Tumor Marker and Key Laboratory of Biochemical Analysis, Shandong Province, Ministry of Education, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, China ‡ Key Laboratory of Prevention and Control of Animal Disease of Xinjiang Corps, College of Animal Science and Technology, Shihezi University, Shihezi 832000, Xinjiang, China S Supporting Information *

ABSTRACT: A novel chondroitin sulfate (CSA) coated magnetic nanoparticle, with almost perfect antifouling properties in a variety of external environments, especially in complex biological systems, was successfully prepared. This is the first report on the utilization of CSA for the construction of an antifouling surface of magnetic nanoparticles. More encouragingly, probes based on these nanoparticles have successfully shown great applied potency in the rapid and direct diagnosis of disease markers in the whole blood.

KEYWORDS: Fe3O4@Au NPs, chondroitin sulfate, antifouling, poly(ethylene glycol), fluorescence is the first report on the utilization of CSA for the construction of an antifouling surface of magnetic NPs. In fact, many antifouling materials, including poly(ethylene glycol) (PEG)type materials,4 dextran derivatives,5 polypeptides,6 and zwitterionic polymers,7 have been widely used in biosensors and biotechnology as well as biomedicine. However, only a very few antifouling materials have been reported that have been successfully applied to complex biological systems. In addition, different from these technologies, incorporating materials into the magnetic NPs have to fabricate an effective functional polymer layer to prevent not only the nonspecific binding of protein but also agglomeration and sedimentation of NPs. During the surface-modification process of NPs, two main mechanisms, charge and steric stabilization, are considered to stabilize NPs.8 Therefore, the material with the rich isotropic charge and a large number of hydrophilic groups becomes our ideal candidate, which is also consistent with the characteristics of antifouling materials. The amazing properties of PEG have triggered our interest at the initial stage of magnetic NP modification. As is well-known, surface hydration is generally thought to be crucial for the capacity of resisting protein adsorption.9 Many scientific researches10 demonstrated that rich C−O−C functional groups from PEG provide hydrogen-bonding donor/acceptors, thus

T

he core−shell magnetic nanoparticles (NPs) have drawn considerable attention as promising materials for clinical diagnostic and therapeutic applications because of their particular physical properties.1−3 All the time, biofouling caused by nonspecific protein adsorption is undesirable for magnetic NPs when they come in contact with complex biological media. However, the cruel reality is that the ingredients of the actual samples, including plasma, serum, crushing cell fluid, and urine, are very complex, containing a large number of organic and inorganic molecules and biological disturbance. Those contaminants may cause a significant change in the properties of magnetic NPs, such as serious cell adhesion as well as interface passivation, and therefore result in its rapid degradation as a drug adjuvant and carrier or its poor selectivity and accuracy as a diagnosis probe and purified material of protein and cell. Even worse is that it may directly lose all of its functionality because of serious agglomeration and sedimentation. All of these facts are the reasons for serious restriction of the extensive application of magnetic NPs; therefore, the preparation of magnetic NPs with desirable dispersibility and stabilization under physiological conditions, biocompatible, especially nonfouling surfaces, is essential. Here, a novel chondroitin sulfate (CSA) coated magnetic NP, with almost perfect antifouling properties in a variety of external environments, especially in complex biological systems, was successfully prepared, and, more importantly, its successful application in the rapid and direct diagnosis of disease markers in 100% serum was demonstrated, as shown in Scheme 1. This © XXXX American Chemical Society

Received: March 30, 2018 Accepted: May 11, 2018 Published: May 11, 2018 A

DOI: 10.1021/acsanm.8b00525 ACS Appl. Nano Mater. XXXX, XXX, XXX−XXX

Letter

ACS Applied Nano Materials

Scheme 1. Illustration of the Fabrication and Stabilization of Fe3O4@Au@PEG@CSA NPs and Procedure for Detection of Its Antifouling Performance (A) and the Application of Magnetic NPs in Disease Marker Detection (B)

that long PEG chains are coiled rather than stretched on spherical surfaces, resulting in a packing density below the theoretical maximum.12 In addition, the curvature of the NP surface13 also has an effect on the PEG density of the surface. Therefore, PEG-coated NPs are difficult to obtain a complete rejection of protein, which is also consistent with this fact that only densely grafted planar PEGylated surfaces are likely to obtain “zero” nonspecific protein adsoption.14 Interestingly, our results indeed demonstrated that only PEG is not able to endow the magnetic NPs with favorable antifouling properties, and the change rate of the differential pulse voltammetry (DPV) responses of Fe3O4@Au@PEG NP-modified electrodes before and after incubation with 100% serum is as high as 25.9% (the details were presented in the blue three-dimensional

enhancing the hydration strength and creating a repulsive force on external proteins or steric stabilization on magnetic NPs. In our cases, PEG tailed with an amino group contains a lot of positive charges. The coating of a rich charge polymer on magnetic NPs can directly result in the occurrence of strong electrostatic repulsion between NPs, thus reinforcing the excellent dispersion and stability of NPs again. In this respect, previous researches11 had reported that a PEGylated platform modified on magnetic NPs demonstrated an effective proteinresistant surface based on the hydration layer formed around Fe3O4 NPs. However, according to those previous reports, PEG-coated Fe3O4@Au NPs only show decreased adsorption against a nonspecific protein to a certain extent. The detailed reasons are B


Letter


Figure 1. HR-TEM image of the Fe3O4 (A and B) and Fe3O4@Au (C and D) NPs. TEM image of the Fe3O4@Au NPs (E). SEM images of the Fe3O4@Au@PEG (F) and Fe3O4@Au@PEG@CSA (G) NPs.

dispersion in biological systems and a variety of external environments, which lays the foundation for their application to the subsequent complex biological system. Sure enough, specific probes for disease based on these materials show very excellent specific recognition in a buffer, even in whole serum. At the beginning of this experiment, based on this idea that an excellent magnetic NP should be used in a variety of complex external environments besides its excellent physical and chemical properties, the core−shell magnetic NPs, which were composed of a core of magnetic materials (iron oxide NPs) and a shell of a precious metal (Au), were chosen as the basis of modifications not only to circumvent the selfdegradation of the magnetic NPs (Fe3O4 NPs) caused by the invasion of a strong corrosive solution but also to provide robust chemistry for modification.26 To confirm the successful synthesis of the core−shell structure of Fe3O4@Au NPs, both Fe3O4 and Fe3O4@Au NPs were characterized by highresolution transmission electron microscopy (HR-TEM) and X-ray diffraction (XRD). According to the typical HR-TEM image of Fe3O4 and Fe3O4@Au NPs (Figure 1A−D), the Fe3O4@Au NPs appear darker, while the Fe3O4 NPs are lightcolored.27 Also, the interfringe distance was measured to be 0.14 nm for Fe3O4 and 0.24 nm for Au (core−shell Fe3O4@ Au), corresponding to the (440) plane of an inverse spinel structured magnetite and the (111) plane of face-centeredcubic-structured Au, respectively. Figure 1E shows a panorama of TEM images from Fe3O4@Au NPs, and excellent dispersity

histogram). Additionally, PEG is susceptible to thermal oxidation.15,16 All of them make us have to consider the incorporation of the second components. The charged polypeptide or zwitterionic polymers are a good choice, but the expensive price or relatively complex modification process blocks their further utilization. Glycosaminoglycans containing a large number of hydroxyl groups have been extensively used in biosensors and marine antifouling coating surfaces,17−22 because of their long-term stability, excellent compatibility to biomolecules, rich source, and ease of functionalization. CSA, one of the natural glycosaminoglycans, is commonly applied in various biomedical fields,23,24 such as tissue engineering, drug delivery, and gene delivery, but few studies have been involved in the antifouling field. This compound is composed of repeating disaccharide units, including (1−3)-β-D-glucuronic acid and the sulfated Nacetylgalactosamine. Previous works have proven that the massive amide (CO-NH) and hydroxyl (OH) groups are also the important functional groups for increasing the strength of hydration because of their strong proton-accepting ability.25 In addition, SO3− and COO− groups of CSA obviously benefit from a stable state between NPs. So, we are eager to achieve the goal of improvement of the magnetic nanoparticle properties that were not observed in the individual PEG components by grafting CSA with Fe3O4@Au@PEG NPs. Fortunately, the magnetic NPs coated with CSA not only have excellent antifouling properties but also retain their good stability and C


Letter


Figure 2. (A) FTIR spectral of Fe3O4@Au@PEG NPs (curve a) and Fe3O4@ Au@PEG@CSA NPs (curve b). (B) EDS spectrum of Fe3O4@Au@ PEG@CSA NPs. (C) Hystersis loops of Fe3O4 NPs (a), Fe3O4@Au NPs (b), Fe3O4@Au@PEG NPs (c), and Fe3O4@Au@PEG@CSA NPs (d). Fe3O4 NPs (a) and Fe3O4@Au@PEG@CSA NPs (d) dispersed or magnetically attracted in a solution are presented in the inset image of part C.

intensity at the 1590−1650 cm−1 (CO and −NH bond stretching) and at the 3000−3500 cm−1 region (O−H and −NH stretching). C−O−S stretches from the skeleton of CSA at 800 cm−1 proved the effective introduction of CSA onto the surface. Moreover, energy-dispersive spectroscopy (EDS) analysis for Fe3O4@Au@PEG@CSA NPs (Figure 2B) shows that C, O, N and S elements are detected. Among these four elements, the S peak just might be from CSA. The morphology of the Fe3O4@Au@PEG@CSA NPs (Figure 1G) is similar to that of the Fe3O4@Au@PEG NPs (Figure 1F), and its average diameter is about 135 nm (Figure S3). During the whole process of modification of the CSA-coated magnetic NPs, the saturation magnetization for every sample was monitored using vibrating-sample magnetometry under temperature-dependent zero-field-cooled conditions. As shown in Figure 2C, the magnetization curves of the parent Fe3O4 NPs, Fe3O4@Au NPs, Fe3O4@Au@PEG NPs, and Fe3O4@ Au@PEG@CSA NPs show no remanence or coercivity at room temperature, indicating their superparamagnetic character. Saturation magnetization of the Fe3O4 sample at 300 K is 64.34 emu g−1, significantly decreasing to 44.08 emu g−1 upon coating with Au. Once PEG is conjugated with the Fe3O4@Au NPs, the saturation magnetization of the NPs then decreases to 35.75 emu g−1. After encapsulation of the CSA, a saturation magnetization of 13.57 emu g−1 is obtained. Obviously, with the layer-by-layer modification, the saturation magnetization of different layers gradually reduces, which once again confirms the successful modification of the Fe3O4@Au NPs with PEG and CSA. In this work, electrochemical methods were employed to measure or monitor the nonspecific protein adsorption of CSA-

of the NPs was demonstrated. In addition, the typical XRD pattern of the Fe3O4 NPs is shown in Figure S2 (curve a). All of the diffraction peaks observed can be indexed as the pattern for Fe3O4 (JCPDS 19-0629). The diffractogram of the Fe3O4@Au NP sample (curve b in Figure S2) shows the characteristic Bragg reflections of the (111), (200), (220), (311), and (222) planes of Au with a cubic structure, indicating the successful fabrication of core−shell Fe3O4@Au NPs. Interestingly, the peaks of the Bragg reflections related with magnetite disappeared, which means that the Fe3O4 NPs were completely encapsulated with Au.28 Then, the four-arm PEG tailed with amino groups as both antifouling materials and dispersants was first self-assembled onto Fe3O4@Au NP surfaces through Au−N bonds.29 In the SEM images (Figure 1F), Fe3O4@Au@PEG NPs show a uniform spherical morphology with no signs of aggregation. Moreover, its relevant Fourier transform infrared (FTIR) spectroscopy (Figure 2A, curve a) reveals that the PEG-coated Fe3O4@Au NPs afforded several characteristic peaks, including asymmetric and symmetric −CH2 stretches (2923 and 2853 cm−1), −NH2 deformation (1590−1650 cm−1), −NH stretching (3000−3500 cm−1), and C−N and C−O stretching (1261 cm−1). Finally, CSA was introduced to conjugate with Fe3O4@Au@ PEG NPs. The carboxyl groups from the disaccharide unit in CSA molecules react with carbodiimide hydrochloride/ nhydroxysuccinimide to produce an active ester (O-acylisourea)-leaving group, which can more effectively covalently bond to the primary amine on the surface of Fe3O4@Au@PEG NPs.30 FTIR data of CSA-coated Fe3O4@Au@PEG NPs (Figure 2A, curve b) reveal a significant increase of the peak D


Letter


Figure 3. (A) DPV response changes of Fe3O4@Au@PEG NPs (PEG) and Fe3O4@Au@PEG@CSA NPs (CSA) to different concentrations of serum [1%, 5%, 10%, 20%, 50%, and 100% (v/v) serum]. (B) DPV response changes of the Fe3O4@Au @PEG@CSA NPs to different media (1 μM DNA, 10 mg mL−1 BSA, 100% cow milk, 1.0 × 10 8 pfu mL−1 M13KO7, and 100% serum). Error bars represent the standard deviations of three repeated determinations (n = 3).

Figure 4. (A) Fluorescence emission spectra of a series of mixtures after incubation in a Tris-HCl buffer (A) or 100% serum (B): Hoechst 33258 + Fe3O4@Au@PEG@CSA NPs/probe in Tris-HCl (a) and in serum (a′); Hoechst 33258 + Fe3O4@Au@ PEG@CSA NPs/probe/ noncomplementary DNA (M) in Tris-HCl (b) and in serum (b′); Hoechst 33258 + Fe3O4@ Au@PEG@CSA NPs/probe/target DNA (T) in buffer (c) and in serum (c′).

carried out with more samples, including DNA (1 uM), single protein (BSA, 10 mg mL−1), helper phage (M13KO7, 1 × 108 pfu mL−1), and 100% cow milk (∼30 mg mL−1 protein). Figure 3B shows that the changes of DPV caused by nonspecific adsorption from DNA, BSA, helper phage, and cow milk were 0.01%, 3.05%, 4.55%, and 3.1%, respectively, which only have slight differences from those before incubation with these samples. This fact means that the interface of Fe3O4@Au@ PEG@CSA NPs has excellent antifouling properties in a variety of contaminants, especially in complex biological systems. More excitingly, CSA-coated Fe3O4@Au NPs can stably exist at a wide range of temperatures (4−95 °C), salt ion concentrations (0−50 mM), and pH values (5.5, 7.4, 8.0, and 12.0) and in cow milk or serum (Figure S8) as well as for a long time (at least 6 months; Figure S9), which is the basis for the wide application of the magnetic bead. However, the efficacy of this material applied to biological complex systems is still not known. Cervical cancer, as is wellknown, remains one of the leading causes of death from cancer in women worldwide, and HPV infection (a fragment of DNA virus from the papillomavirus family) is considered to be a high risk factor for cervical cancer.31,32According to the statistics, HPV DNA was present in 95% of cervical cancer subjects. So, diagnosis of HPV infections relies on detection of the viral DNA. Here, DNA probes with the specific sequences based on

coated NPs with a DPV module of CHI660E. First of all, DPV was used to monitor the total modified process of magnetic glassy carbon electrodes (MGCEs) for Fe3O4@Au@PEG NPs and Fe3O4@Au@PEG@CSA NPs. As shown in Figure S4, DPV of the bare MGCEs demonstrates its representative curve in the presence of a redox mediator. After the successful modification of Fe3O4@Au@PEG NPs or Fe3O4@Au@PEG@ CSA NPs, a significant increase of the DPV signal occurred as a result of the good conductive properties of Fe3O4@Au NPs. Here, 30 min was chosen as the incubation time (Figure S5). In our original design, Fe3O4@Au@PEG NPs were expected to have an excellent antifouling performance; the percent change of DPV [(Ip0 − Ip)/Ip0] of Fe3O4@Au@PEG NPs, however, ranges from 1.5% to 25.9% after incubation in different serum samples including 1%, 5%, 10%, 20%, 50%, and 100% (v/v) (Figure 3A and S6A). In contrast, for Fe3O4@Au@ PEG@CSA NPs, the largest current response change [(Ip0 − Ip)/Ip0] to 100% serum was only 1.61% (Figures 3A and S6B), which indicated that synergism between PEG and CSA can form a more excellent antifouling layer. Its contact angle result is consistent with this conclusion. Fe3O4@Au@PEG @CSA NPs (11.34°) are more hydrophilic than Fe3O4@Au@PEG NPs (58.0°) (Figure S7). Subsequently, further experiments for evaluation of the antifouling properties of Fe3O4@Au@PEG @CSA NPs were E


Letter

ACS Applied Nano Materials ORCID

this material for the detection of HPV were constructed as models. Complete matching with the target is defined as a positive result, and the opposite is negative. The detailed detection procedure and principle are schematically illustrated in Scheme 1B. Complementary DNA (T) targets containing rich adenine and thymine were captured onto the probe-modified Fe3O4@Au@PEG@CSA NP in a buffer or 100% serum. After the introduction of dye (Hoechst 33258), the samples issue a strong fluorescence peak at 465 nm at optimal conditions [pH 8.0 (Figure S11A) and 5.0 min (Figure S11B)] because the Hoechst 33258 strongly inserts into the minor groove of double-stranded DNA sequences,33 which can notably be distinguished from the others [noncomplementary (M) and single-stranded DNA; Figure 4]. In all of experiments, the probe-modified Fe3O4@Au@ PEG@CSA NPs with Hoechst in a buffer were considered to control samples based on the fact that Fe3O4@Au@PEG@CSA NPs with Hoechst or pure Hoechst 33258 can not bring the obvious fluorescence background signals under the same conditions (Figure S11C). Notably, although Figure S11D shows that 1% serum with Hoechst also generated fluorescence at near 460 nm, the change of the fluorescence intensity of Fe3O4@Au@PEG@CSA NPs/probe before and after incubation in 100% serum for 1 h can be still unobvious (Figure 4), which powerfully verifies that the magnetic beads soaked in serum have a weak adsorption of the interference. This is consistent with the previous antifouling test results. As shown in Figure 4A, the value of (F − F0)/F0 in response to complementary DNA is 1.52 in the buffer, which is much higher than that in response to noncomplementary DNA, with a value of 0.25. Interestingly, in 100% serum, the value of (F − F0)/F0 in response to complementary DNA is 1.44 (Figure 4B), which still remains a great difference from noncomplementary DNA [F0 = Fe3O4@Au@PEG@CSA NPs/ probe + Hoechst 33258; F = Fe3O4@Au@PEG@CSA NPs/ probe/(T or M) + Hoechst 33258]. In addition, this method exhibits a wide linear range and low detection limit (Figure S12). These facts indicate that this novel magnetic bead has great application potential in the disease detection of complex biological systema. By the way, in order to prove that the material has a wide range of applications, we have also applied the material to construct a HPV electrochemical sensor, and good results have also been obtained in 100% serum (Figure S13). On the basis of our experimental data, it was demonstrated that CSA-coated Fe3O4@Au NPs possess a superhydrophility, desirable stability, and excellent antifouling ability. In addition, this novel nanomaterial can be used in a wide range of detection areas and shows very excellent specific recognition in buffer, even in whole serum.

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Lihua Chen: 0000-0001-6469-5559 Xiliang Luo: 0000-0001-6075-7089 Author Contributions §

These authors contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by National Science and Technology Major Project (Grant 2017YFD0500304), Joint Funds of the National Science Foundation of China (Grant U1303283), National High Technology Research and Development Program of China (Grant 2015AA034602), The Science and Technology Project and Achievement Transformation Plan of Modern Agricultural of Xinjiang Corps (Grant 2016AC010), and Key Laboratory of Prevention and Control of Animal Disease of Xinjiang Corps (Grant BTDJ05).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsanm.8b00525.

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REFERENCES

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Low-Fouling Magnetic Nanoparticles and Evaluation of their Potential

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