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Synthesis of Multi-Au Nanoparticles-embedded Mesoporous Silica Microspheres as Self-filtering and Reusable Substrates for SERS Detection Miao Chen, Wen Luo, Zhimin Zhang, Ranhao Wang, Yuqiu Zhu, Hua Yang, and Xiaoqing Chen ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b16618 • Publication Date (Web): 15 Nov 2017 Downloaded from http://pubs.acs.org on November 16, 2017

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ACS Applied Materials & Interfaces

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Synthesis of Multi-Au Nanoparticles-embedded Mesoporous Silica Microspheres as Self-filtering

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and Reusable Substrates for SERS Detection

4 5 6

Miao Chen,a Wen Luo,a Zhimin Zhang,a Ranhao Wang,a Yuqiu Zhu,a Hua Yang,*a and Xiaoqing

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Chen*a,b

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a College of Chemistry and Chemical Engineering, Central South University, Changsha 410083,

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China

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b Hunan Provincial Key Laboratory of Efficient and Clean Utilization of Manganese Resources,

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Central South University, Changsha 410083, Hunan, China

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*Corresponding author: Tel:/fax: +86-731-88830833.

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E-mail address: [email protected]; [email protected]

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Keywords: surface-enhanced Raman scattering (SERS), self-filtering, reusable substrates,

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mesoporous silica microspheres, methotrexate, human serum

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ACS Paragon Plus Environment


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Abstract

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Surface-enhanced Raman scattering (SERS) based biosensing in biological fluids is constrained

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by nonspecific macromolecules adsorptions and disposable property of the SERS substrate. Here,

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novel multi-Au nanoparticles-embedded mesoporous silica microspheres (AuNPs/mSiO2) was

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prepared using a one-pot method, which served as reliable substrates for SERS enhancement

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associated with salient features of self-filtering ability and reusability. The fabrication and physical

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characterization of AuNPs/mSiO2 microspheres were discussed, and SERS activity of this novel

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substrates was investigated by using 4-mercaptobenzoic acid (4-MBA) as Raman probe. The

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responses of our substrates to Raman intensities exhibited a SERS enhancement factor of 2.01 ×

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107 and high reproducibility (relative standard deviation of 6.13%). Proof-of-concept experiments

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were designed to evaluate the self-filtering ability of the substrates in bovine serum albumin (BSA)

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and human serum solution, respectively. The results clearly demonstrate that mesoporous SiO2 can

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serve as a molecular sieve via size exclusion and avoid Raman signal interference of

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biomacromolecules in biological fluids. Subsequently, feasibility of practical application of

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AuNPs/mSiO2 microspheres was assessed by quantitative detection of methotrexate (MTA) in

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serum. The method exhibited good linearity between 1 and 110 nM with the correlation

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coefficients of 0.996, which proved that the obtained AuNPs/mSiO2 microspheres were good

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SERS substrates for determination of small biomolecules directly in biological fluids without need

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of manipulating samples. In addition, the substrate maintained its SERS response during multiple

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cycles, which was evaluated by recording Raman signals for 4-MBA before and after thermally

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annealing, thereby demonstrating the high thermostability and satisfactory reusability. These

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results offered the AuNPs/mSiO2 microspheres attractive advantages in their SERS biosensing.

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1. Introduction

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Biosensing based on surface-enhanced Raman spectroscopy (SERS) platform has

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recently acquired considerable attention because of its molecular fingerprint specificity,

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high sensitivity, and non-destructive data acquisition1-3. Ultrasensitive analysis can be

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achieved by virtue of SERS owing to the chemical and electromagnetic enhancement

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mechanism of precious metal nanostructures4-5. Besides, the detection specificity can be

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realized according to the vibrational modes of the target molecule directly adsorbed on

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SERS-active substrate surfaces or via Raman reporters and probes6. Nevertheless, reliable

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SERS-based biosensing in complex biological media is still challenging due to the random

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and

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nanostructures7. This retention process might impede the adsorptions of the target analytes

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and give rise to the difficulty of vibrational assignment8. Consequently, intensive efforts

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have been made to address this issue. One commonly used strategy is to form a mixed

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self-assembled monolayers (SAMs) on SERS-active substrates9-10, in which SAMs bearing

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thiol moieties with long-alkyl chains served as nonfouling materials to physically or

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chemically prevent the nonspecific protein adsorption and the thiolated compound worked

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as Raman probe to recognize and bind analytes. However, it is always problematic in the

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modification of SERS-active substrates by using conventional nonfouling materials

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without introducing extra interference as SERS is sensitive to the first layer of molecules

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on the SERS-active substrate surfaces11. Recently, Yu reported a stealth surface

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modification strategy in the determination of fructose in protein solutions by modifying

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SERS substrate with a mixed SAM of 4-mercaptophenylboronic acid (4-MPBA) and

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N,N-dimethyl-cysteamine-carboxybetaine (CBT)12. It is worth mentioning that utilization

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of CBT suffers from the limitation of availability though it would not cause any

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interference with target molecules in Raman analysis.

nonspecific

adsorptions

of

an

array

of

biomacromolecules

onto

metallic

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On the other side, it is well known that biofluids are generally made of

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biomacromolecules such as lipids, nucleic acids, proteins, and thus. Given the fact that they

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could be specifically excluded from smaller analytes through appropriate sieving, coating

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protective filtering material on the surface of metal nanostructures could provide more



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effective and selective SERS probes. In this way, only the target analytes were allowed to

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ultimately reach the nanoparticles and the selectivity would thus be significantly enhanced.

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In this respect, mesoporous silica (mSiO2) presents a great potential as it contains ordered

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and monodisperse pores in different size (2-50 nm), thus the size exclusion efficiency can

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be facilely tuned 13. Prominently, owning such advantages as thermal stability, relatively

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low cost, easy preparation and biocompatibility, mSiO2 is optically transparent, allowing

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light to penetrate and excite internal analytes molecules without introducing Raman signal

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interference14-15, and the SERS activity of the metal nanostructures embedded in the inner

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of mSiO2 shell would not be obviously affected and restricted. In 2015, Luis fabricated a

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SERS substrate containing a submonolayer of AuNPs on glass covered with a mSiO2 film,

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which acted as molecular sieves for size exclusion in biological media16. However, it is a

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challenging task to achieve the dense and uniform AuNPs distribution on the glass. We

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envisaged that utilizing an appropriate template instead of glass for in situ synthesis of

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AuNPs and in situ coating mSiO2 shell should afford a reliable solution to this problem.

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Meanwhile, embedding multiple dispersive AuNPs in one single porous unit could

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facilitate molecule-metal interactions and accordingly improve SERS activity17 .

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Consider that SERS substrates are mostly made of precious metal nanostructures

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generally including Au18-19, Ag20, and Cu21，the disposable and costly preparation property

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of metallic substrates severely block the generalizability of SERS analysis. Accordingly,

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reusability has become an important evaluation index for the usefulness of SERS detection

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systems and is likely to promote the development of SERS technique as a routine

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analytical tool in many applications. Many techniques have been developed in recent years

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to fabricate recyclable SERS sensors, and the most common approach is to regenerate

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SERS substrates through ultraviolet irradiation22, magnet separation23, plasma treatment or

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thermal annealing24. In particular, thermal annealing is a convenient and quick approach to

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detach molecules from the adsorbed surface, and accordingly is effective to clean and

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regenerate SERS substrates. One important prerequisite for this thermal cleaning means is

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the reliable thermal robustness of SERS substrates. Colloidal precious metals were

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extensively used as SERS substrates owning to their plasmonic enhancement. However,

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the colloidal precious metals are easily aggregated after thermal annealing duo to the


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detachment of surface stabilizing groups. The aggregation colloids is intrinsically unstable

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and easily precipitate from solution, leading to decrease of SERS effect25. Recently, Ma

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fabricated a SERS substrate by depositing of Ag NRs on Si film covered with a HfO2 shell,

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which maximizes the high melting point of the HfO2 shell and thus ensures the thermal

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stability and SERS sensitivity of the substrates24. Therefore, it can be expected that protect

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AuNPs within thermal stability SiO2 matrix could improve the thermal stability of the

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AuNPs meanwhile could avoid aggregation.

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Literature search discloses that previous works on AuNPs-embedded mSiO2 microspheres were

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mostly focused on the improvement of stability and catalytic activity of AuNPs. Wang synthesized

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AuNPs-embedded silica (Au/M-SiO2) for cyclohexane oxidation19. Ren reported the fabrication of

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porous silica microspheres embedded with magnetic γ-Fe2O3 and AuNPs as magnetic recoverable

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catalysts20. Guo reported the fabrication of AuNPs embedded in silica hollow nanospheres induced

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by compressed CO2 as an efficient catalyst for selective oxidation26. Besides, there is only a single

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example for the application of multi-AuNPs@mesoSiO2 in SERS detection of DTNB molecule27.

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However, the above-mentioned reports for preparing AuNPs embedded mSiO2 microspheres

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commonly suffer from low homogeneity for embedding AuNPs in mSiO2 and wide variation in

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particle size, which would adversely affect the performance of these prepared materials in either

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catalysis or SERS detection. Furthermore, the AuNPs-embedded mSiO2 microspheres prepared in

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some cases are too small (< 8 nm) to serve as effective SERS substrates28. Obviously, the

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challenge for synthesizing AuNPs-embedded mSiO2 microspheres with uniform particle size and

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structure is still unmet, which would be an intimidating hurdle for their application in SERS

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detection. Undoubtedly, novel protocol for addressing this issue is highly demanding at this stage.

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Herein, novel multi-Au nanoparticles-embedded mesoporous silica microspheres

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(AuNPs/mSiO2) with uniform particle size, mesoporous structures and high surface areas

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were first prepared via a templating approach. The synthetic route of AuNPs/mSiO2 is

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outlined in Scheme 1, in which poly(4-vinylpyridine) (P4VP) microspheres act as the

141

templates. Initially, AuNPs were seeded within the P4VP microspheres (AuNPs/P4VP)

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through the coordination of Au ion with P4VP chains followed by a reduction with

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aqueous sodium citrate solution. Subsequently, silica precursor (tetraethylorthosilicate,

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TEOS) and mesostructure template (cetyltrimethyl ammonium bromide, CTAB) were



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added to the AuNPs/P4VP microspheres solution. As the pyridyl moieties of P4VP were

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able to catalyze the hydrolysis of TEOS29, silica nanoparticles were directly deposited onto

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the P4VP chains through sol-gel reactions in neutral aqueous solution, resulting in uniform

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AuNPs/P4VP/silica composite microspheres. At this stage, the composite microspheres

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were successfully prepared through this one-pot protocol. At the end, the resultant

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microspheres were calcined, where P4VP and CTAB templates and organic agents were

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thoroughly removed to afford the expected AuNPs/mSiO2 microspheres. The prepared

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AuNPs/mSiO2 microspheres showed salient SERS enhancement as multiple large AuNPs

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were embedded in one mSiO2 matrix. More importantly, by taking advantage of the

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mesoporous structure of mSiO2, mSiO2 shell took the full responsibility for the

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self-filtering to exclusively allow the small molecules of interest detected by Raman

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spectroscopy. In addition, reusability of the substrate was readily realized through thermal

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annealing. All these properties offer the AuNPs/mSiO2 microspheres attractive advantages

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in their SERS biosensing.

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Scheme 1. Schematic synthesis of multi-AuNPs-embedded mesoporous silica

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(AuNPs/mSiO2) microspheres using a one-pot protocol and calcinations method.

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2. Experimental section

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Chemicals. The monomer of 4-vinylpyridine (4VP, >96%) was purchased from Alfa Aesar

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(Heysham, Lancs, UK) and distilled under vacuum before being used. Tetraethylorthosilicate

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(TEOS, >99%), cetyltrimethylammonium bromide (CTAB, >99%), K2S2O8 (>99.5%), hydrogen

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tetrachloroaurate

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(Na3C6H5O7•3H2O, >99%) were obtained from Sinopharm Chemical Reagent Co., Ltd (Shanghai,

trihydrate

(HAuCl4•3H2O,

>99.9%),


and

tri-sodium

citrate

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China).

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poly(vinylpyrrolidone) (PVP, Mw = 58000, K29-32) were purchased from TCI Co. Ltd. (Shanghai,

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China). Bovine serum albumin (BSA) was obtained from sigma-Aldrich. (Shanghai, China). Fresh

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human serum was supplied by a local hospital. Aqueous solutions were prepared with DI water

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(18.4 MΩ•cm-1).

4-mercaptobenzoic

acid

(4-MBA,

>99%),

methotrexate

(MTA,

>98%)

and

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Synthesis of the AuNPs/P4VP/silica Microspheres Through the One-pot Protocol. P4VP

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microspheres was synthesized according to the reported method30. For the one-pot reaction, 0.1

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mL of HAuCl4 (w/v 1%) was added to 20 mL of P4VP microspheres solution (0.008 g/mL) and

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stirred for 30 min. Then the mixture was heated to boiling under magnetic stirring. 1 mL of

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sodium citrate solution (w/v 1 %) was fast injected, and get the obtained mixture boiling for 20

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min. Then turn off the heat and let the mixture cool down to room temperature. With no need of

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further treatment, 0.137 g of CTAB was directly added to the resultant mixture solution and stirred

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for another 30 min. After 0.175 mL of TEOS was added, the reaction continued to react for 48 h at

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ambient temperature. The sediment was collected by centrifugal method and washing with water

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and was then stored in water.

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Synthesis of AuNPs/mSiO2 Microspheres. The AuNPs/P4VP/silica microspheres were

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collected by centrifugal method and then dried under vacuum at 40℃ for 12 h. Then calcination

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of the dried AuNPs/P4VP/silica microspheres at 650℃ (heating rate: 2 °C/min) in air for 4 h was

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carried out to remove the template (P4VP and CTAB) and therefore to fabricate the AuNPs/mSiO2

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microspheres.

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SERS Detection Using the AuNPs/mSiO2 Microspheres. Generally, 6 µL of analyte solution

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was incubated with 4 µL of AuNPs/mSiO2 microspheres solution (0.005 g/mL) and were then

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deposited on a silica plates for SERS measurements. The exposure time for every measurement

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was 2 s with 3 accumulations.

193 194

4-MBA were first dissolved in ethanol (0.01M) and then diluted to different concentrations. BSA was dissolved in PBS (pH=7.4). Human serum was diluted to one percent (in water).

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Recyclable SERS Detection in Liquids. 0.5 mL of 4-MBA solution (10-4 M) was mixed with 5

196

mg of AuNPs/mSiO2 microspheres and incubation for 10 min. Then the AuNPs/mSiO2

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microspheres were collected by centrifugal method, and then redispersed in 0.5 mL water. The

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mixture was directly used for SERS analysis. After SERS detection, thermal annealing was



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realised by heating the mixture on a hot plate at 300 °C for 5 min. Then the microspheres were

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redispersed in 0.5 mL water and the mixture was directly used for SERS analysis. After SERS

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detection, the microspheres were collected by centrifugation. Thus, a “detection-heating” cycle

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was completed. The collected microspheres were used for the next cycle and this

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“detection-heating” cycle was repeated 20 times. For SERS detection, the exposure time for every

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measurement was 2 s with 3 accumulations.

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Measurements and characterization. Scanning electron microscope (SEM) images were

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investigated on Tescan MIRA 3 XMU. Transmission electron microscopy (TEM) was taken by

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using Hitachi model H-7650 transmission electron microscope (Hitachi, Tokyo, Japan). The

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thermogravimetric analysis (TGA) curve was registed by using a thermal gravimetric analyzer

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(TG-209, Netzscha, Germany) from ambient temperature to 800 °C in air at a heating rate of

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10 °C/min. X-ray diffractometry (XRD) curve was recorded using D-MAX 2200 VPC (RIGAKU,

211

Japan). Nitrogen adsorption-desorption isotherms were measured at 77 K using a Micromeritics

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ASAP 2020 M+C system (Norcross, GA, USA). The total pore volume was calculated from the

213

amount adsorbed at a maximum relative pressure (P/P0) of 0.99. The Barrett-Joyner-Halenda (BJH)

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method was conducted to calculate the sample pore size from the desorption branches of the

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isotherms. The Brunauer-Emmett-Teller (BET) method was used to calculate the specific surface

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area. Fourier transform infrared (FTIR) spectra were investigated on a TENSOR

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spectrophotometer (Bruker, Ettlingen, Germany) with a spectral width of 4000-400 cm-1. All

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SERS and Raman spectra were collected by a portable Raman instrument (i-Raman, B&W Tek

219

Inc., USA) attached with a microscope (20 objective). The laser excitation wavelength was 785

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nm.

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3. Results and discussions

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Preparation and Characterization of the AuNPs/mSiO2 Microspheres. Due to the

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presence of pyridyl moieties, P4VP microspheres have been effectively used as platforms

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for immobilizing the dispersed AuNPs. Commonly, two pathways including the

225

corporation of pre-synthesized AuNPs or in situ synthesis of AuNPs in P4VP microspheres

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were frequently employed31-32. However, the obtained AuNPs (3-5 nm) through in-situ

227

synthesis were usually too small to serve as effective SERS substrates28. Herein, for the


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first time, large AuNPs were in-situ synthesized and incorporated into the P4VP

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microspheres (AuNPs/P4VP) by using sodium citrate as reductant. The SEM image of the

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AuNPs/P4VP microspheres shows a uniform spherical shape with an average size of 270

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nm and the surface profile of P4VP is essentially kept intact after being embedded with

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AuNPs (Fig. 1A). The TEM image (Fig. 1B) reveals that the AuNPs with a mean diameter

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of 15 nm are densely immobilized in the P4VP microspheres (the dispersed black dots),

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owing to the unique function of P4VP chain as linker and locator for AuNPs.

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Fig. 1. SEM (A) and TEM (B) images of AuNPs/P4VP microspheres. The dispersed black

237

dots in B are AuNPs.

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Through the sol-gel process of TEOS within the AuNPs/P4VP microspheres, the

240

corresponding AuNPs/P4VP/silica composite microspheres were generated (prepared from

241

molar ratio of TEOS/P4VP as 1.7/1), which was confirmed by the increase in the average

242

size of AuNPs/P4VP microspheres from 270 to 293 nm (Fig. S1A, see the Supporting

243

Information, SI). Furthermore, the AuNPs are still uniformly distributed inside the

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microspheres (Fig. S1B). However, shrinkage of the AuNPs/P4VP/silica microspheres

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during the template removal was observed (as shown in Fig. S1C,D, SI). Presumably, the

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porous volume of P4VP was significantly diminished after being seeded with AuNPs,

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which would result in a relatively lower SiO2/P4VP weight ratio and structure collapse of

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the microshperes after the removal of P4VP. To address this issue, we sought to utilize

249

P4VP chain and CTAB as dual templates to form mesostructure. The TEM images of the

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AuNPs/P4VP/silica microspheres (prepared from molar ratio of CTAB/TEOS/P4VP as



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0.85/1.7/1) are illustrated in Fig. S2 A,B (SI). The average size of the microspheres is 337

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nm, which is much larger than that of the prepared microspheres (293 nm) without adding

253

CTAB. This expansion of the microspheres might be ascribed to that CTAB surfactant

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could prompt the release of P4VP chains from the AuNPs/P4VP microspheres into the

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aqueous solution to give high SiO2/P4VP weight ratio. As a result, after removing the

256

templates through calcination, the sizes of the microspheres remained unchanged (340 nm,

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Fig. S2 C, SI). However, the AuNPs were distributed both in the inner and on the surface

258

of the microspheres (Fig. S2 D, SI), which could undermine the effect of filtering for SERS

259

detection. When the molar ratio of CTAB/TEOS/P4VP was modified to 1.7/3.5/1, the

260

average size of the obtained microspheres was enlarged to 370 nm (Fig. 2 A). As observed

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in Fig. 2 B,C, the sol-gel process promoted by pyridine moieties took place both in the

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inner and on the surface of the AuNPs/P4VP microspheres, yielding a 20 nm thick silica

263

coating. Ultimately, the polymeric template and CTAB were completely removed through

264

calcination at 650 ℃, and the morphology and size (366 nm) of the obtained microspheres

265

were kept unchanged (Fig. 2 D). Furthermore, the mesoporous structure of the silica shell

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is clearly observed in the HRTEM image (Fig. S3, SI). The TEM images (Fig. 2 E,F)

267

verifies the distribution of AuNPs over the inner of the microspheres.

268


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Fig. 2. SEM images of AuNPs/P4VP/silica composite microspheres (A) prepared from molar ratio

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of CTAB/TEOS/P4VP as 1.7/3.5/1 and after calcinations (D). TEM images of the composite

271

microspheres (B,C) and after calcinations (E,F), the dispersed black dots are AuNPs.

272 273

TGA was carried out to evaluate the efficacy of template removal by calcination. As

274

demonstrated in Fig. 3A, P4VP microspheres can be fully decomposed when the

275

temperature is higher than 600℃. Considering that the decomposition temperature of

276

CTAB is about 320℃30, AuNPs/mSiO2 microspheres can be obtained after calcination at

277

650 ℃. TGA of the prepared AuNPs/mSiO2 microspheres (Fig. 3A, red line) show that

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only one weight-loss occurs around 200℃, which corresponds to the evaporation of

279

physically adsorbed water33. These results confirm the complete removal of P4VP and

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CTAB template at 650℃. FTIR (Fig. 3B) of the reference microspheres also proves the

281

deposition of silica nanoparticles (1087 cm-1) and the removal of templates (1415 cm-1 for

282

P4VP, 2923 cm-1 for CTAB)34. Energy dispersive X-ray (EDX) analysis of the

283

AuNPs/mSiO2 microspheres in Fig. S4 (SI) clearly showed the presence of Au (AuNPs)

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and Si (mSiO2). An XRD pattern of the AuNPs/mSiO2 microspheres is shown in Fig. 3C,

285

the characteristic diffraction peaks of Au and SiO2, in which a peak with 2θ centered at 23°

286

belong to SiO2 and other peaks belong to Au14, can be identified, which is consistent with

287

EDX results and confirms the existence of AuNPs in the mSiO2 microspheres. A surface

288

plasmon resonance band at 530 nm in the UV-visible absorption spectra (Fig. 3D) further

289

confirms the dispersed AuNPs embedded in the microspheres18, 35. The surface area of the

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AuNPs/mSiO2 is determined to be 926 m2/g based on BET analysis (Fig. 3E). The pore

291

size distribution curve (Fig. 3F) shows that the pore diameters are centered at 3.5 nm and

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13.3 nm respectively. Smaller pores are mostly distributed in the shell, while larger pore

293

are located in the inner of the microsphere.



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294 295

Fig. 3. TGA (A), FTIR (B), XRD (C), UV-vis (D) curves of the synthesized microspheres. N2

296

adsorption-desorption isotherms (E) and the pore size distributions (F) of AuNPs/mSiO2

297

microspheres.

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SERS Activity of the AuNPs/mSiO2 Microspheres. The SERS performance of the

299

AuNPs/mSiO2 substrate was assessed by using 4-MBA as Raman probe, which can

300

directly interact with the Au surface. Fig.4A shows the SERS spectra of different

301

concentration of 4-MBA on AuNPs/mSiO2 microspheres. All spectra with distinct

302

intensities clearly reveal the specific Raman bands of 4-MBA25, 36. Since SERS intensity of

303

the peak located at 1071 cm-1 was strongest, the peak was selected as the Raman label of

304

4-MBA to achieve a more sensitive detection. As shown in Fig. 4B, a correlation

305

coefficient of 0.9904 within the range of 10-9 M to 10-5 M for 4-MBA was achieved for the

306

fabricated AuNPs/mSiO2 microspheres. In order to assess the SERS effect of the


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307

AuNPs/mSiO2 microspheres, the SERS enhancement factor (EF) was calculated using the

308

following equation30:

309

EF = ISERS/NSERS × NRaman/IRaman

310

where ISERS and IRaman are the SERS intensity and Raman intensity of 4-MBA at 1071 cm-1, and

311

NSERS and NRaman mean the number of 4-MBA molecules detected in the focused incident laser

312

spot. The calculated SERS EF was 2.01 × 107 (for the detail calculating process, please see SI),

313

which was likely to be sufficient to detect low concentrations of biomolecules33 and was

314

comparable to the prominent results acquired from the substrates prepared by advanced

315

nanoengineering processes37-41. As well known, the higher the concentration of 4-MBA is used,

316

the stronger SERS intensity of 4-MBA could be obtained. In order to more accurately demonstrate

317

the reproducibility of the AuNPs/mSiO2 substrate, higher concentration of 4-MBA (10-4 M) was

318

used to facilitate the comparison of the obtained SERS data with higher intensity. Thus, high

319

reproducibility (RSD = 6.13%) of the AuNPs/mSiO2 microspheres was demonstrated through

320

conducting Raman analysis of a 10-4 M 4-MBA solution with 14 different batches of

321

AuNPs/mSiO2 microspheres (Fig. 5).

322

323 324

Fig. 4. SERS spectra of different concentrations of 4-MBA in water (A): blank (a), 10-9-10-5 M

325

(b-f); and variation in Raman intensity at 1071 cm-1 with different 4-MBA concentrations (B). The

326

regression equation is y = 4007.28 + 385.14x (where x is the logarithm of 4-MBA concentration in

327

water and y is the Raman intensity) with a squared correlation coefficient of 0.9904.

328



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

329 330

Fig. 5. SERS spectra of 10-4 M 4-MBA acquired from 14 batches AuNPs/mSiO2 microspheres (A)

331

and the SERS intensity distribution at 1071 cm-1 (B). The relative standard deviation was 6.13%.

332 333

Sieving Effect of the AuNPs/mSiO2 microspheres. To investigate the size exclusion

334

function of the AuNPs/mSiO2 microspheres-based SERS measurement, 4-MBA and bovine

335

serum albumin (BSA) were chosen as model analytes, which can be strongly adsorbed onto

336

the surface of AuNPs via their thiol moieties. The regular AuNPs colloid (20 nm) were

337

added to their solutions respectively, the specific Raman bands of 4-MBA and BSA were

338

registered (Fig. 6A a,c). Since, incubation of 10-4 M of 4-MBA with regular AuNPs colloid

339

(20 nm) could afford stronger Raman signals for 4-MBA, same concentration of 4-MBA

340

(10 -4 M) was used in the incubation of AuNPs/mSiO2 microspheres for better comparison

341

for the obtained results. Interestingly, after being incubated with AuNPs/mSiO2

342

microspheres, strong SERS signals were readily identified for 4-MBA while Raman

343

response was almost undetectable for BSA (Fig. 6A b,d). It can be rationalized that BSA

344

hardly diffuses through the mesoporous shell to attach to the surface of embedded AuNPs

345

and thus cannot be effectively detected through SERS effect. Furthermore, time-dependent

346

SERS signals for 4-MBA reached a platform within about 5 min, which might be

347

correlated with the diffusion process (Fig. 6B). Accordingly, it can be postulated that the

348

sieving effect of mSiO2 is crucial to the size-dependent Raman response as the mesoporous

349

structure discriminates guest molecules on the basis of their sizes by functioning as

350

self-filtering. As a result, the selectivity for small molecules can be thus improved by

351

effectively excluding those macromolecules larger than the pore size of mSiO2.


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352 353

Fig. 6. (A) SERS spectra from different microspheres incubation with different size molecules

354

showing the size exclusion proof-of-concept: (a) Spectrum of 4-MBA (10-4 M) on AuNPs colloid

355

(20 nm); (b) Spectrum of 4-MBA (10-4 M) on AuNPs/mSiO2 microspheres; (c) Spectrum of BSA

356

(1 mg/mL) on AuNPs colloid (20 nm); (d) Spectrum of BSA (1mg/mL) on AuNPs/mSiO2

357

microspheres. Green indicates the specific Raman bands of 4-MBA and BSA. (B) Raman intensity

358

plotted against time at 1030 and 1071 cm-1 for BSA (1 mg/mL) and 4-MBA (10-4 M) incubation

359

with AuNPs/mSiO2 microspheres, respectively.

360 361

Ultimately, BSA solutions containing different concentration of 4-MBA were mixed

362

with AuNPs/mSiO2 microspheres and the SERS spectra are illustrated in Fig. 7A. As

363

4-MBA was dissolved in water (Fig. 4A), the SERS intensity of 4-MBA was proportional

364

to the concentration of 4-MBA in BSA. Besides, similar pattern and intensity of SERS

365

spectrum for 4-MBA in BSA (Fig. 8a) and in water (Fig. 8d) were observed respectively.

366

The linear response of SERS can be observed from 10-9 to 10-5 M (Fig. 7B) and lowest

367

detected concentration of 4-MBA in BSA is found to be 1 nM as shown in Fig. 7A b. The



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

368

concentration gradient experiments of 4-MBA in BSA prove that AuNPs/mSiO2

369

microspheres could be good SERS substrates for quantitative detection in complex

370

biological media.

371

372 373

Fig. 7. SERS spectra of different concentrations of 4-MBA in BSA solution incubation with

374

AuNPs/mSiO2 microspheres (A): blank (a), 10-9-10-5 M (b-f); and variation in Raman intensity at

375

1071 cm-1 with different 4-MBA concentrations (B). The regression equation is y = 3888.77 +

376

366.29x (where x is the logarithm of 4-MBA concentration in BSA and y is the Raman intensity)

377

with a squared correlation coefficient of 0.9880.

378 379

SERS Detection of Methotrexate in Human Serum. Methotrexate (MTA) is an

380

important anti cancer drug, which is widely used in acute leukemia and other neoplastic

381

diseases42. In clinical therapy, intake of MTA by patients require on site monitoring of the

382

drug in serum to cut down poison and side effects. Therefore, it is of great significance to

383

monitor MTA levels of patients in clinics and pharmaceutics. From the view of practical

384

application, we applied the novel AuNPs/mSiO2 microspheres SERS substrate for the rapid

385

determination of MTA in serum combined with a portable Raman spectrometer. Firstly,

386

proof-of-concept experiments were proceeded to demonstrate the self-filtering efficacy of

387

the AuNPs/mSiO2 microspheres in analyzing complex biological matrix - human serum

388

(HS). After the incubation of regular AuNPs colloid (20 nm) with HS solution, main

389

characteristic vibrational bands (450 cm-1) were registered due to the interaction of the

390

proteins present in HS with AuNPs (Fig. 8c)7,

391

characteristic signals for MTA (10-4 M) upon incubation of AuNPs colloid with MTA

43

. SERS spectrum (Fig. 8d) shows the


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392

solution, which were confirmed according to the reported work44. As predicted, when

393

AuNPs colloid was incubated with a mixture sample containing MTA (10 -4 M) and HS,

394

characteristic vibrational bands for HS were registered while MTA Raman signal was

395

unable to be recorded (Fig. 8b). Clearly, the complex matrix of HS adversely blocked the

396

adsorption of MTA on AuNPs (as shown in schematic in Fig. 8). Pleasingly, when the

397

mixture sample SERS detection was performed by using the prepared AuNPs/mSiO2

398

microspheres instead of regular AuNPs, MTA Raman signals were distinctly recorded and

399

main characteristic Raman signals for HS became undetectable (Fig. 8a). Besides, similar

400

pattern and intensity of SERS spectrum for MTA in serum (Fig. 8a) and in water (Fig. 8d)

401

were observed respectively. It is worth mentioning that a few additional peaks in the SERS

402

spectrum attributed to the components in serum would not disturb the identification of

403

MTA in serum. Based on the above results, it can be concluded that the pores and necks

404

between pores in the mSiO2 shell inherently posed self-filtering effect to perfectly stumble

405

the diffusion of large molecules including proteins, nucleic acids, or lipids in HS to AuNPs

406

surface, meanwhile the thickness of mSiO2 shell is about 20 nm, which could prevent the

407

entry of large molecules into the electromagnetic field of the embedded AuNPs44.

408

Therefore, the large molecules in serum that may attach to the surface of AuNPs/mSiO2

409

would not restrict the SERS activity of the AuNPs. On the other hand, small MTA

410

molecules can diffuse through the mesoporous shell to be adsorbed on the embedded

411

AuNPs surface would be exposed to the electromagnetic field produced by laser irradiation

412

and detected through this technology (as shown in schematic in Fig. 8).

413



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

414

Fig. 8. SERS spectra from different samples: (a) a mixture sample containing MTA (10-4 M) and

415

HS on AuNPs/mSiO2 microspheres; (b) a mixture sample containing MTA (10-4 M) and HS on

416

AuNPs colloid (20 nm); (c) HS on AuNPs colloid (20 nm); (d) MTA (10-4 M) on AuNPs colloid

417

(20 nm).

418 419

To investigate the feasibility of the quantitative determination of MTA in serum,

420

different amounts of MTA was added to the diluted HS to the final concentration in the

421

range of 1-110 nM. Then the serum containing MTA was incubated with AuNPs/mSiO2

422

microspheres solution. Additional procedure to pretreat serum was unnecessary. Fig. 9A

423

show the SERS spectra of different concentrations of MTA in diluted human serum. We

424

can see that the SERS intensity of MTA increased with the rise concentrations of MTA,

425

indicating that the intensity was proportional to the amount of MTA molecules diffuse

426

through the mesoporous shell to be adsorbed on the embedded AuNPs surface. As shown

427

in the SERS spectra of MTA, SERS intensity of the peak located at 681 cm-1 was strongest,

428

so the peak was selected as the Raman label of MTA to achieve a more sensitive detection.

429

Fig. 9B show the relationship between the SERS intensity of the peak located at 681 cm-1

430

and the concentration of MTA, and a linear SERS response from 1 to 110 nM of MTA (R2

431

= 0.996) was achieved. The quantitative analysis of MTA demonstrated that the obtained

432

AuNPs/mSiO2 microspheres were good SERS substrates for the determination of MTA in

433

serum, and the self-filtering efficacy of the AuNPs/mSiO2 microspheres indicated a

434

potential application to detect small biomolecules directly in other practical biological

435

fluids.

436

437


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438

Fig. 9. (A) SERS spectra of different concentrations of MTA in serum incubation with

439

AuNPs/mSiO2 microspheres: blank (a), 1 nM (b), 5 nM (c), 10 nM (d), 40 nM (e), 80 nM (f) and

440

110 nM (g). The grey indicate the peaks located at 681 cm-1. (B) SERS dilution series of MTA in

441

serum based on the peak located at 681 cm-1. The linear curve was y = 220.4 + 14.49x with a

442

squared correlation coefficient of 0.996.

443 444

Recyclable SERS Detection in Liquids. Thermal annealing is a convenient and quick

445

approach to detach molecules from the adsorbed surface, leading to clean and regenerate

446

SERS substrates24. One important prerequisite for this thermal cleaning means is reliable

447

thermal robustness of SERS substrates. For AuNPs/mSiO2 microspheres, as AuNPs are

448

evenly embedded in the inner of mesoporous silica microspheres, the silica would

449

effectively isolate the well-organized AuNPs and maximally prevent sintering for AuNPs

450

during thermal annealing, accordingly preventing the growth of Au particles in this process.

451

On the other hand, mesoporous silica was prepared via calcinations at 650℃ to remove

452

template. And previous studies demonstrated that the morphology of mSiO2 shell can be

453

well maintained even through the calcination at 750 ℃ 45. Therefore, to achieve its

454

reusability, thermal annealing (300℃) was adopted to detach the adsorbed molecules from

455

the embedded AuNPs surface. Since 4-MBA can be strongly adsorbed onto the surface of

456

AuNPs via its thiol moieties, regeneration efficiency was confirmed by measuring 4-MBA

457

Raman signals before and after annealing the substrate. All of Raman peaks for 4-MBA are

458

undetectable after heating, confirming the complete removal of the analytes from the

459

AuNPs/mSiO2 microspheres (Fig. 10A). The intensity for the characteristic peak at 1071

460

cm-1 was persistently monitored to test the robustness of substrate in response to 20 cycles.

461

As shown in Fig. 10B, despite with minor fluctuations for 4-MBA signals (RSD=6.67%),

462

SERS performance of AuNPs/mSiO2 microspheres is well maintained within the

463

“sensing-cleaning” cycles. Besides, structures of recycled AuNPs/mSiO2 microspheres

464

were also characterized by means of TEM analysis. As can be seen from the TEM images

465

of the as-prepared AuNPs/mSiO2 (Fig. S5 A,B, SI) and the recycled AuNPs/mSiO2 (Fig.S5

466

C,D, SI), the morphology of AuNPs/mSiO2 can be well maintained after thermal annealing

467

and the mesoporous structure of the silica shell is still clearly observed, demonstrating the



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

468

efficacy of recyclability through high-temperature annealing and satisfactory reusability for

469

this developed substrate.

470

471 472

Fig. 10. (A) Raman spectra of 4-MBA (10-4 M) on the same AuNPs/mSiO2 microspheres

473

measured in multiple cyclic detections. D and H indicates the SERS spectra recorded before and

474

after thermally annealing, respectively. The SERS spectra after five “detection-heating” cycles

475

were randomly selected and shown in the figure. (B) Peak intensity at 1071 cm-1 against thermal

476

annealing of SERS substrates and the relative standard deviation (RSD) of 4-MBA signals was

477

6.67%.

478 479

4. Conclusions

480

In summary, novel multi-Au nanoparticles-embedded mesoporous silica microspheres

481

(AuNPs/mSiO2) with uniform particle size, mesoporous structures and high surface areas

482

were first prepared by developing a one-pot protocol. Furthermore, the integration of SERS

483

enhancement, self-filtering ability and high thermal stability offered the AuNPs/mSiO2

484

microspheres attractive advantages in their SERS biosensing. More broadly, the strategy

485

developed in this work may facilitate wider applications of nanoparticles-functionalized

486

mSiO2 microspheres.

487 488

ASSOCIATED CONTENT

489

Supporting Information

490

Calculation of SERS enhancement factor (EF); TEM images of AuNPs/P4VP/silica

491

composite microspheres and after calcinations (TEOS/P4VP=1.7 and CTAB/TEOS/P4VP=


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492

0.85/1.7/1); HRTEM image of the AuNPs/mSiO2 microspheres and the inner structure of

493

the AuNPs/mSiO2 microspheres; EDX spectrum of AuNPs/mSiO2 microspheres; and TEM

494

images of AuNPs/mSiO2 microspheres before and after recyclable SERS measurement.

495

AUTHOR INFORMATION

496

Corresponding Author

497

E-mail: [email protected]; [email protected]. Tel:/fax: +86-731-88830833.

498

ORCID

499

Hua Yang: 0000-0002-5518-5255

500

Xiao-Qing Chen: 0000-0002-8768-8965

501

Notes

502

The authors declare no competing financial interest.

503 504 505 506

Acknowledgement

We gratefully acknowledge the financial support from National Natural Science Foundation of China (21475152 & 21576296).

507 508

References

509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524

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