Afterglow Resonance Energy Transfer Inhibition for Fibroblast

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Afterglow Resonance Energy Transfer Inhibition for Fibroblast Activation Protein-alpha Assay Fan Feng, Xi Chen, Guojie Li, Song Liang, Zhangyong Hong, and He-Fang Wang ACS Sens., Just Accepted Manuscript • DOI: 10.1021/acssensors.8b00680 • Publication Date (Web): 06 Sep 2018 Downloaded from http://pubs.acs.org on September 17, 2018

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ACS Sensors

Afterglow Resonance Energy Transfer Inhibition for Fibroblast Activation Protein-alpha Assay †

†

†

†

†

†‡

Fan Feng, Xi Chen, Guojie Li, Song Liang, Zhangyong Hong and He-Fang Wang * †

Research Center for Analytical Sciences, College of Chemistry, Nankai University, Tianjin Key Laboratory of Biosensing and Molecular Recognition, State Key Laboratory of Medicinal Chemical Biology, Tianjin 300071, China

‡

Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China

*E-mail: [email protected]

1

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ABSTRACT The traditional photoluminescence resonance energy transfer (PRET)-based sensors are widely applied, but still suffer from the severe background interference from in-situ excitation. The afterglow nature of the persistent luminescence nanoparticles (PLNPs) allows the optosensing after the stoppage of in-situ illumination, and thus subtly overcomes that interference. We proposed a simple strategy for functionalizing PLNPs for bioanalytical applications and the new afterglow resonance energy transfer (ARET)-based assay for quantitative determination and imaging of fibroblast activation protein-alpha (FAPα) in live cells using Au-decorated Cr3+0.004:ZnGa2O4 as donors and Cy5.5-KGPNQC-SH as acceptor. The ARET between the donor and acceptor quenches the afterglow of the donor, and the cleavage of peptide KGPNQC by FAPα inhibits the ARET and restores the afterglow of the donor. The ARET-based assay of FAPα, with the linear range of 0.1–2.0 mg·L-1 (1.2–22.9 nM), LOD of 11 µg·L-1 (115 pM), and RSD of 3.9% (for 0.5 mg·L-1 FAPα, n=5), displays higher sensitivity, lower limit of detection (LOD) and better anti-interference capability than the corresponding PRET-based assay. Besides, the ARET-based sensors are lighted up by the FAPα-positive U87MG and MDA-MB-435 cells, but kept in dark when incubated in the FAPα-negative AD293 cells. The proposed ARET-based sensor can detect FAPα of U87MG and MDA-MB-435 living cells in human serum with the spiked recoveries of 95.6–103%. Our data demonstrated a simple and effective strategy for bridging PLNPs to bioanalytical applications, and an attractive ARET assay of FAPα. KEYWORDS: afterglow resonance energy transfer, persistent luminescence nanoparticles, Au nanoparticles, fibroblast activation protein-alpha, Cr3+-doped zinc gallate

2


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Photoluminescence resonance energy transfer (PRET) was widely used for the design of optical sensors.1-2 The traditional PRET-based sensors usually need in-situ excitation, which lead to the severe interference of autofluorescence and scattering light from real samples.3 The afterglow nature of the persistent luminescence nanoparticles (PLNPs)4-7 allows the optosensing after the stoppage of in-situ illumination, and thus subtly overcomes that interference.8-12 For instance, Yan group reported the first Eu2+,Dy3+-doped Ca1.86Mg0.14ZnSi2O7-based fluorescence resonance energy transfer (FRET) inhibition assay for background-free detection and imaging of α-fetoprotein (AFP)3 and prostate specific antigen (PSA);8 Tang group reported the Sr2MgSi2O7:1% Eu, 2% Dy-based FRET nanoprobe for determination and imaging of ascorbic acid.12 To date, the PLNPs-based optical sensors are still limited, and most of them focus on the avoidance of background of real samples.3, 8-9, 12 Herein, we proposed an afterglow resonance energy transfer (ARET)-based assay considering the elimination of coexisted interference and a new simple strategy for functionalizing PLNPs as ARET donors. The functionalization is essential for engineering the PLNPs for biological applications. The reported functionalizing strategy of PLNPs mainly began with the coating of siloxanes, including tetraethoxysilane

(TEOS),13-18

3-aminopropyl)-triethoxysilane

(APTES),3,

14,

16-27

and

(3-iodopropyl)-trimthoxysilane (IPTMS).28 For instance, Maldiney T. et al24 reported the synthesis of polyethylene glycol (PEG)-PLNPs via the amino-PLNPs acquired from coating of APTES. The polyethyleneimine, PEG and transactivator of transcription penetration peptide-co-functional PLNPs fabricated via a three-step procedure started from the coating of IPTMS.28 Liu et al synthesized the gold nanoshell capped GdAlO3:Mn4+, Ge4+ beginning with the coating of TEOS by the Stöber method.13 For broadening the strategy of bridging PLNPs to bioanalytical applications, other simple and biocompatible protocols are still extremely needed. Fibroblast activation protein-alpha (FAPα) is a cell surface glycoprotein, expressed in stromal fibroblasts in more than 90% of human epithelial cancers including breast, ovarian, bladder, colorectal and lung cancers, but not expressed in normal fibroblasts and other normal tissues.29-31 As a biomarker of the cancer-associated fibroblasts, FAPα plays an important role in affecting the proliferation, invasion and metastasis of cancer cells, early diagnosis, real time monitoring of treatment and prognosis.30-31 Therefore, development of sensitive and robust methods for 3


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quantitative analysis of FAPα is of great significance. However, the reported methods for FAPα assay were very limited.31-32 We report a simple strategy of decorating PLNPs with Au nanoparticles for functionalizing PLNPs as the reliable ARET donors for quantitative determination and imaging of FAPα in live cells and human serum. The widely-reported Cr3+0.004:ZnGa2O4 with 695 nm emission was used as the example of PLNPs. The raw Cr3+0.004:ZnGa2O4 was stirred with 3-mercaptopropionic acid (MPA), and then the harvested Cr3+0.004:ZnGa2O4@MPA was stirred with aqueous solutions of HAuCl4 and ascorbic acid (Scheme 1), finally the Cr3+0.004:ZnGa2O4@MPA@Au with fine aqueous-dispersity was ready for bioanalysis. Except for the good biocompatibility, the gold nanoparticles are liable to bind with mercapto groups,33-36 thus Cr3+0.004:ZnGa2O4@MPA@Au was the fine ARET donor for convenient design of various desired optical sensors. The Cy5.5-KGPNQC-SH with absorbance of 550-750 nm, which overlapped to the emission of Cr3+0.004:ZnGa2O4,

was

used

as

the

acceptor

to

quench

the

afterglow

of

Cr3+0.004:ZnGa2O4@MPA@Au donor. In the presence of FAPα, the peptide KGPNQC would be cleaved at Pro-X (X stands for other amino acids) site32,

37-38

and the afterglow of

Cr3+0.004:ZnGa2O4@MPA@Au would be restored (Scheme 1). In this way, the simple ARET sensor for FAPα assay was established. We systematically examined the PRET (with constant illumination) and ARET inhibition assays. Our data demonstrated the higher sensitivity, lower limit of detection (LOD) and better anti-interference capability of the ARET over PRET for FAPα assay. Besides, we also demonstrated the simple and effective strategy of decorating PLNPs with Au nanoparticles for bridging PLNPs to bioanalytical applications.

Scheme 1. Illustration for synthesis and design of Cr3+0.004:ZnGa2O4@MPA@Au as ARET sensor of FAPα. 4


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EXPERIMENTAL SECTION Synthesis of Cr3+0.004:ZnGa2O4@MPA and Cr3+0.004:ZnGa2O4@MPA@Au nanoparticles. The prepared Cr3+0.004:ZnGa2O4 (Supporting Information (SI) shows the details, 0.10 g) was ultrasonically dispersed in 20 mL ultrapure water. MPA (80 µL) was added under vigorous stirring at room temperature for 24 h. The resultant dispersion was centrifuged at 8000 rpm for 10 min and washed with ultrapure water for three times. Afterwards, the collected Cr3+0.004:ZnGa2O4@MPA was dried in vacuum for 12 h. 50 mg of Cr3+0.004:ZnGa2O4@MPA nanoparticles were ultrasonically dispersed in 20 mL of ultrapure water, and then 1.0, 1.5 or 2.0 mL of HAuCl4 (1% wt) was dropwise added into the dispersion of Cr3+0.004:ZnGa2O4@MPA under magnetic stirring, followed by addition of 6 mL NH4OH (10% wt) solution and 16 mL aqueous solution of ascorbic acid (10 mM). After being stirred for 4.5 h at room temperature, the resultant Cr3+0.004:ZnGa2O4@MPA@Au were collected by centrifugation, washed sequentially with ethanol-water (60% wt) and ultrapure water and then dried in vacuum for 24 h.

Photoluminescence (PL) and Afterglow Spectra Measurements. All measurements were at 37 oC. The PL spectra were recorded under the constant excitation of 254 nm (both slits of 4 nm), and the afterglow spectra were recorded immediately after the stoppage of 5 min irradiation of 254 nm (slit 40 nm) by Xe light (75 W) of the fluorometer (with EM slit of 20 nm, the samples were always in the sample holder, and the measurements began as soon as the optical shutter between the light and excitation monochromator was closed. The reliability was ascertained by 11 measurements of afterglow spectra).

PRET and ARET between Cr3+0.004:ZnGa2O4@MPA@Au and Cy5.5-KGPNQC-SH. The 5


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interaction time was first examined. In a standard quartz cell, 2 mL PBS (0.01 M, pH=7.4) solution of Cr3+0.004:ZnGa2O4@MPA@Au (15 mg·L-1) and Cy5.5-KGPNQC-SH (5 µM) was stirred and the PL spectra were recorded every 10 min, until the records of two contiguous measurements were nearly the same. We found that the spectra were invariable after 1 h incubation. Second, the quenching effect of Cy5.5-KGPNQC-SH was tested. Two milliliter PBS solutions

of

Cr3+0.004:ZnGa2O4@MPA@Au

(15

mg·L-1)

and

various

amounts

of

Cy5.5-KGPNQC-SH (1, 2, 3, 4 and 5 µM) were incubated at 37 oC for 1 h respectively, and then the PL (or afterglow) spectra were recorded. The PL or afterglow intensity of Cr3+0.004:ZnGa2O4@MPA@Au was gradually quenched with the increased amount of Cy5.5-KGPNQC-SH.

FAPα Determination. Into the one-hour-stirred 2 mL PBS (0.01 M, pH=7.4) solution of Cr3+0.004:ZnGa2O4@MPA@Au (15 mg·L-1) and Cy5.5-KGPNQC-SH (5 µM), 100 µL of FAPα (40.5 mg·L-1) was added under stirring and the PL spectra were recorded in 20 min intervals (the sample was in dark except measurements). One hour later, the intensity at 695 nm reached the maximal value. To test how the concentration of FAPα affect the PL or afterglow recovery, different volume of FAPα (40.5 mg·L-1) was gradually added into the one-hour-stirred 2 mL PBS solutions of Cr3+0.004:ZnGa2O4@MPA@Au (15 mg·L-1) and Cy5.5-KGPNQC-SH (5 µM). The resultant mixture was stirred at 37 oC for one hour, and then the spectra were recorded. The intensity at 695 nm was gradually restored with the increase of FAPα concentration (0.1, 0.5, 1.0, 1.5 and 2.0 mg·L-1).

Immunostaining and Flow Cytometry Analysis of FAPα α. Typically, in a humidified atmosphere of 5% CO2 at 37 oC, U87MG and MDA-MB-435 cells were cultured in DMEM 6


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(Gibco) medium with 10% fetal bovine serum (Biological Industries, U.S.A.) and 1% penicillin-streptomycin (HyClone), while AD293 cells were cultured in RPMI 1640 (Gibco) complete medium. 5×105 cells of U87MG, MDA-MB-435 and AD293 were cultured in complete medium in a 12-well plate for 24 h at 37 oC under 5% CO2. The cultured cells were harvested using trypsin/EDTA solution (Gibco), and washed with PBS once. Then 400 µL PBS solution of anti-FAPα antibody (1 g·L-1, Abcam, ab28244) (1:500) was added, and the cells were incubated at 4 oC for 2 h. After wash with PBS, the cells were incubated with 400 µL PBS solution of phycoerythrin (PE) goat anti-rabbit lgG (H+L) (secondary antibody, 0.2 g·L-1) (1:500) at 4 °C for 1 h. Then, the cells suspension was centrifuged at 1000 rpm for 3 min and washed with PBS once. Finally, the cells were resuspended in 500 µL PBS and analyzed using a FACS Calibur flow cytometer (BD, U.S.A.).

In

Vitro

Cell

Imaging.

The

PBS

(0.01

M,

pH=7.4)

solution

containing

Cr3+0.004:ZnGa2O4@MPA@Au (1 g·L-1) and Cy5.5-KGPNQC-SH (333.3 µM) were freshly made for use (marked as the CZMA-based probe). U87MG, MDA-MB-435 and AD293 cells were involved for cell imaging (the cell cytotoxicity and live/dead cells staining were also tested, SI showed the details). For cell imaging, 5×104 cells of U87MG, MDA-MB-435 or AD293 seeded on one coverslip (Costar, U.S.A.) were cultured in complete medium in a 24-well plate for 24 h respectively, and then the cells were incubated with 10 mg·L-1 of CZMA-based probe (calculated as Cr3+0.004:ZnGa2O4@MPA@Au) for 4 h. Afterwards, the cells were washed with PBS for three times to remove the excess CZMA-based probe. Paraformaldehyde (4%) was added to fix cells morphology (300 µL per well) for 15 min in the dark, followed by the treatment of 300 µL of 4,6-diamidino-2-phenylindole dihydrochloride (DAPI, 0.5 mg·L-1) for 5 min, and then three-time 7


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washes with PBS. The cells were finally covered by a cover slide and subjected to microscopic studies using an A1/Ti-E/PFS confocal laser scanning microscope.

Quantitative Analysis of FAPα α in Living Cells. The quantitative analysis of FAPα was done on PTI fluorometer. Two milliliter of complete medium containing CZMA-based probe (15 mg·L-1 Cr3+0.004:ZnGa2O4@MPA@Au and 5 µM Cy5.5-KGPNQC-SH) was stirred at 37oC for 1 h, then 5-25 µL of U87MG cell dispersion (1×103/mL) (the preparation of cell suspension was given in SI) was added under stirring. The afterglow spectra were recorded immediately after the stoppage of 5 min irradiation of 254 nm (slit 40 nm) by Xe light (75 W) of the fluorometer (with EM slit of 20 nm). We found the afterglow intensity at 695 nm of CZMA-based probe was gradually recovered with the increased number of U87MG cells.

Analysis of FAPα α in Human Serum. FAPα analysis of real sample was done in human serum (from healthy men aged 20-35) spiked with low number of U87MG or MDA-MB-435 cells. 2 mL of serum containing CZMA-based probe (15 mg·L-1 Cr3+0.004:ZnGa2O4@MPA@Au and 5 µM Cy5.5-KGPNQC-SH) was stirred at 37oC for 1 h, then 5 µL of cell dispersion (1×103/mL) (the preparation of cell suspension was given in SI) was added. The afterglow spectra were recorded immediately after the stoppage of 5 min irradiation of 254 nm (slit 40 nm) by Xe light (75 W) of the PTI fluorometer (with EM slit of 20 nm). To test the spike recovery, 0.4, 0.8 and 1.2 mg·L-1 of FAPα were added respectively into the mixture of CZMA-based probe and 5 µL cell dispersion, and then the afterglow spectra were recorded and the spike recoveries were calculated according to (Ct-Cc)/Cs× 100%, where Cs was spiked concentration of FAPα, Cc was the concentration of FAPα in 5 µL U87MG or MDA-MB-435 cell dispersion, and Ct was the total concentration of FAPα determined in the spiked human serum. 8


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RESULTS AND DISCUSSION Synthesis of Cr3+0.004:ZnGa2O4@MPA@Au Nanoparticles. Scheme 1 illustrated the synthesis protocol, therein MPA was the linker of Cr3+0.004:ZnGa2O4 and Au nanoparticles. The COOH group of MPA reacted with Cr3+0.004:ZnGa2O4 and SH group of MPA was the site for growing Au nanoparticles, which was proved by the FT-IR (Figure S1) and Raman (Figure S2) spectra of Cr3+0.004:ZnGa2O4, Cr3+0.004:ZnGa2O4@MPA and Cr3+0.004:ZnGa2O4@MPA@Au. Except for the stretching vibration of Zn-O (575 cm-1) and Ga-O (425 cm-1) of Cr3+0.004:ZnGa2O4,39 the Cr3+0.004:ZnGa2O4@MPA showed the MPA-related bands of -CH2 (2925 and 2850 cm-1), S-H (2370 cm-1)40 and COO- (1563 and 1437 cm-1) groups (Figure S1). The presence of COO- group (1563 and 1437 cm-1) instead of COOH group (around 1689 cm-1) suggested that the COOH group of MPA reacted with Cr3+0.004:ZnGa2O4 and then transferred to COO-. In Raman spectra, Cr3+0.004:ZnGa2O4@MPA

displayed

the

S-H

peak

at

2429

cm-1,

while

Cr3+0.004:ZnGa2O4@MPA@Au had no peak at 2429 cm-1, but displayed strong peaks around 200 and 320 cm-1, suggesting the disappearance of S-H group and the presence of Au-S-C bond (Figure S2).41 These data elucidated the Au nanoparticles were bound to Cr3+0.004:ZnGa2O4@MPA via Au-S bond. The necessity of MPA was also supported by the much higher emission of Cr3+0.004:ZnGa2O4@MPA@Au over Cr3+0.004:ZnGa2O4@Au (synthesized without MPA) (Figure S3), which was most probably ascribed to the improvement of the aqueous dispersity of Cr3+0.004:ZnGa2O4 (Figure S4) by MPA. The calcination temperature of Cr3+0.004:ZnGa2O4 also had great

effect

on

the

emission

of Cr3+0.004:ZnGa2O4@MPA@Au

(Figure

S3),

finally

Cr3+0.004:ZnGa2O4 calcined at 750 oC was used for the synthesis of Cr3+0.004:ZnGa2O4@MPA@Au. The feeding amount of HAuCl4 on regulating the absorption, emission and afterglow of 9


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was

evaluated

Page 10 of 25

(Figure

1).

Besides

the

absorption

of

Cr3+0.004:ZnGa2O4@MPA at 200-300 nm, the Cr3+0.004:ZnGa2O4@MPA@Au displayed extra absorption in the range of 500-700 nm (Figure 1a), which was ascribed to the anchored Au nanoparticles on Cr3+0.004:ZnGa2O4@MPA. The absorption of Cr3+0.004:ZnGa2O4@MPA@Au synthesized with 1.0 and 1.5 mL HAuCl4 (1%) was similar, but further increase of HAuCl4 (2.0 mL) resulted in the significant hump at 500-700 nm. Owing to the overlap between emission of Cr3+0.004:ZnGa2O4@MPA and absorption of Au nanoparticles, the energy transfer happened and resulted in the decreased emission intensity of Cr3+0.004:ZnGa2O4@MPA@Au against Cr3+0.004:ZnGa2O4@MPA (Figure 1b). However, compared with the raw Cr3+0.004:ZnGa2O4, the Cr3+0.004:ZnGa2O4@MPA@Au synthesized with 1.0 and 1.5 mL HAuCl4 (1%) exhibited higher emission intensity. It was reported that the plasmon resonance of Au nanoparticles could enhance the luminescence efficiency of the nanophosphor if the distance of Au nanoparticles and nanophosphor was around 10 nm.13 In our case, the Cr3+0.004:ZnGa2O4 and Au nanoparticles were only separated by MPA, thus the distance was too close to enhance the emission efficiency. But we did find the higher emission intensity of Cr3+0.004:ZnGa2O4@MPA@Au than Cr3+0.004:ZnGa2O4 when 1.0 or 1.5 mL of HAuCl4 was used, which was most possibly because of the much better aqueous dispersibility of Cr3+0.004:ZnGa2O4@MPA@Au over Cr3+0.004:ZnGa2O4. As for the Cr3+0.004:ZnGa2O4@MPA@Au synthesized from 2.0 mL HAuCl4, the absorption of Au nanoparticles

at

500-700

nm

was

too

strong,

which

absorbed

most

energy

of

Cr3+0.004:ZnGa2O4@MPA, thus resulted in the lower emission intensity (Figure 1b). The 695 nm afterglow decay curves of the aqueous dispersions (1 g·L-1) of Cr3+0.004:ZnGa2O4, Cr3+0.004:ZnGa2O4@MPA and Cr3+0.004:ZnGa2O4@MPA@Au (Figure 1c) displayed nearly the 10


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same tendency. In the first 150 s, the Cr3+0.004:ZnGa2O4@MPA@Au synthesized from 1.5 mL HAuCl4 (1%) exhibited relatively higher afterglow intensity than others, thus 1.5 mL HAuCl4 (1%) was used for preparation of Cr3+0.004:ZnGa2O4@MPA@Au. 3+

Cr Cr

b 10000

0.004

:ZnGa2O4

0.004

:ZnGa2O4@MPA

3+

1.2

8000

+1.5 mL HAuCl4 +1.0 mL HAuCl4

0.8 0.6 0.4

3+

Cr

+2.0 mL HAuCl4

1.0

Cr

0.004 3+

c

:ZnGa2O4

Cr

8000


6000

10000

3+

Cr

:ZnGa2O4@MPA 0.004

Intensity (a.u.)

1.4

Intensity (a.u.)

a Absorbance (a.u.)

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

ACS Sensors

+1.0 mL HAuCl4

4000

0.004 3+

:ZnGa2O4

0.004

:ZnGa2O4@MPA


6000

+1.0 mL HAuCl4

4000 2000

2000

0.2

0 0.0 200

300

400 500 600 Wavelength (nm)

700

800

0 400

500

600 700 Wavelength (nm)

800

0

100

200

1000 1100 1200 Time (s)

Figure 1. (a) UV-vis spectra; (b) PL emission spectra and (c) 695 nm afterglow decay of the aqueous dispersion (1 g·L-1) of Cr3+0.004:ZnGa2O4, Cr3+0.004:ZnGa2O4@MPA and Cr3+0.004:ZnGa2O4@MPA@Au synthesized from adding 1.0, 1.5 and 2.0 mL of HAuCl4 (1%). The emission spectra were recorded under the constant excitation of 254 nm. The afterglow decay curves were recorded after the stoppage of 5 min irradiation of a 254 nm UV lamp (6W).

Characterization

of


Nanoparticles.

The

prepared

Cr3+0.004:ZnGa2O4@MPA@Au powder was characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM), and energy dispersive spectroscopy (EDS). The XRD pattern of Cr3+0.004:ZnGa2O4@MPA@Au exhibited the typical peaks ascribed to the spinel phase of ZnGa2O4 (JCPDS 38-1240) as Cr3+0.004:ZnGa2O4 and Cr3+0.004:ZnGa2O4@MPA, and the cubic phase of Au (JCPDS 65-8601) (Figure 2a). TEM image revealed there were many Au nanoparticles (the dark dots) attached on the surface of Cr3+0.004:ZnGa2O4@MPA (Figure 2b). The EDS of Cr3+0.004:ZnGa2O4@MPA@Au nanoparticle confirmed the element compositions (Figure 2c), in which Zn, Ga, O and Au peaks were clearly observed (the Cu peak was generated by the 11


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copper grid). The line scanning in HAADF-STEM image (Figure 2d) further ascertained that the coexistence of the Zn, Ga and Au, as the peaks of three elements displayed the same tendency at the same position, indicating that the Au nanoparticles were indeed linked onto the surface of Cr3+0.004:ZnGa2O4. Besides, the little changes in the measurements of dynamic light scattering (DLS), PL and UV-vis spectra (Figure S5) over time (0-8 h) indicated the fine stability and aqueous-dispersity of the Cr3+0.004:ZnGa2O4@MPA@Au, which ensured the potential application as optical probes.

a

b

20 nm

d

c

20 nm

Figure

2.

(a)

XRD

patterns

of

Cr3+0.004:ZnGa2O4,

Cr3+0.004:ZnGa2O4@MPA

and

Cr3+0.004:ZnGa2O4@MPA@Au powders. (b) TEM image of Cr3+0.004:ZnGa2O4@MPA@Au. (c) EDS spectrum of Cr3+0.004:ZnGa2O4@MPA@Au. (d) HAADF-STEM image and Zn (red curve), Ga (blue curve) and Au (pink curve) distribution of Cr3+0.004:ZnGa2O4@MPA@Au.

Cr3+0.004:ZnGa2O4@MPA@Au-Based FAPα Assay. As mentioned above, the special 12


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structure of Cr3+0.004:ZnGa2O4@MPA@Au enabled the convenient construction of a desired ARET-based sensor by using some sulphydryl compounds as the acceptors. To design an ARET-based sensor for FAPα assay, we introduced the Cy5.5-KGPNQC-SH as the acceptor, wherein the thiol group was involved for binding to Au nanoparticles; the NIR dye of Cy5.5 with the absorbance overlapped with the emission of Cr3+0.004:ZnGa2O4 was for the energy acceptor; and the short peptide sequence KGPNQC acted as the linker and recognition site of FAPα. In that way, the ARET between Cr3+0.004:ZnGa2O4@MPA@Au and Cy5.5-KGPNQC-SH would result in the quenched afterglow of Cr3+0.004:ZnGa2O4@MPA@Au, while the selective cleavage of the Pro-X (X stands for other amino acids) site by FAPα could lead to the inhibition of ARET and afterglow restoration of Cr3+0.004:ZnGa2O4@MPA@Au. The quenching response of Cr3+0.004:ZnGa2O4@MPA@Au to Cy5.5-KGPNQC-SH was first examined. As shown in Figure S6a, the PL intensity of Cr3+0.004:ZnGa2O4@MPA@Au was maximally quenched by Cy5.5-KGPNQC-SH (5 µM) after one hour interaction, thus 1 h incubation time was used for testing the quenching response of Cr3+0.004:ZnGa2O4@MPA@Au to various amounts of Cy5.5-KGPNQC-SH. The PL spectra from in-situ excitation of 254 nm (Figure

S6b)

and

the

afterglow

spectra

from

pre-excitation

(Figure

3a)

of

Cr3+0.004:ZnGa2O4@MPA@Au in the presence of various amounts of Cy5.5-KGPNQC-SH were recorded respectively. The reliability of afterglow measurements was ascertained by 11 measurements (the RSD of the afterglow intensity at 695 nm was 2.3-4.0%, Figure S7). The linear quenching response of Cr3+0.004:ZnGa2O4@MPA@Au to Cy5.5-KGPNQC-SH was observed in both ARET and PRET (Figure 3b and Figure S6c). The linear relationships between the quenching efficiency ∆A/A0 (∆P/P0) (∆A=A-A0, ∆P=P-P0, A (P) and A0 (P0) were the afterglow (PL) intensity 13


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at 695 nm in the presence or absence of Cy5.5-KGPNQC-SH respectively) and the concentration of Cy5.5-KGPNQC-SH in two assays had the similar slopes, which was ascribed to that the quenching

response

was

primarily

caused

by

the

energy

transfer

between

Cr3+0.004:ZnGa2O4@MPA@Au and Cy5.5-KGPNQC-SH. The inhibition of the above PRET and ARET by FAPα was evaluated. In the presence of 2 mg L-1 FAPα, the PL of the PRET system was gradually recovered and reached the maximal intensity after 1 h incubation (Figure S6d), thus 1 h incubation time was used for recording the FAPα concentration-dependent inhibition effect. Both the afterglow from ARET (Figure 3c) and the PL from PRET (Figure S6e) systems were gradually restored with the increase of FAPα concentration. The inhibition efficiency defined as ∆A/A0 (∆P/P0) (∆A=A-A0, ∆P=P-P0, A (P) and A0 (P0) were the afterglow (PL) intensity of the ARET (PRET) system at 695 nm in the presence or absence of FAPα respectively) was linearly related to the concentration of FAPα (0.1-2.0 mg L-1, Figure 3d and Figure S6f). However, the sensitivity (slope of the linearity) of the ARET inhibition assay (0.4407) was higher than that of the PRET inhibition assay (0.2309), and the limit of detection (LOD, calculated from 3σ/S, where σ was the standard deviation of 11 measurements of ∆A/A0 (∆P/P0) at 0.1 mg L-1 of FAPα, and S was the slope of linearity) of the ARET inhibition assay (11

µg L-1) was lower than that of PRET inhibition assay (27 µg L-1), demonstrating the merit of ARET assay over PRET. The relative standard deviation (RSD) of 0.5 mg L-1 FAPα in ARET inhibition was 3.9% (n=5). In the aspect of linearity and LOD, the proposed ARET assay of FAPα was superior or comparable with other methods (Table S1).31-32

14


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a

60000

40000

-0.2

∆A/A0= − 0.1197C − 0.0719 2

(R = 0.9908)

30000

(A-A0)/A0

Intensity (a.u.)

b

0 1 2 µM 3 4 5

50000

20000 10000

-0.4

-0.6

0

675


750

1

2 3 4 CCy5.5-KGPNQC-SH (µM)

5

1.4 40000

d

2.0 1.5 1.0 -1 0.5 mg L 0.1 0

30000

20000

1.2

∆A/A0= 0.4407 C + 0.4306 2

(R = 0.9967)

1.0 (A-A0)/A0

c

Intensity (a.u.)

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

ACS Sensors

0.8

10000 0.6 0 0.4 675


750

0.0

0.5

1.0

1.5

2.0 -1

FAPα concentration (mg L )

Figure 3. ARET-based FAPα assay: (a) Afterglow spectra of 15 mg·L-1 Cr3+0.004:ZnGa2O4@MPA@Au in the presence of 1-5 µM Cy5.5-KGPNQC-SH for 1 h incubation; (b) Quenched efficiency (A-A0)/A0 (A and A0 were the afterglow intensity at 695 nm in the presence or absence of Cy5.5-KGPNQC-SH respectively)

of

15

mg·L-1


against

the

concentration

of

Cy5.5-KGPNQC-SH; (c) Afterglow spectra of the ARET in the presence of 0.1-2.0 mg L-1 FAPα for 1 h incubation; and (d) ARET inhibition efficiency (A-A0)/A0 (A and A0 were the afterglow intensity at 695 nm of the ARET in the presence or absence of FAPα respectively) against the concentration of FAPα. The afterglow spectra were recorded immediately after the stoppage of 5 min irradiation of 254 nm by Xe light (75 W) of fluorometer.

In PRET inhibition assay, the cleavage of acceptors from binding with donors set apart the donors and acceptors, and thereby restored the PL of the donors. However, the cleaved acceptors were still in PRET systems, thus could absorb the excitation and/or emission energy of donors and in turn offset part of the PL restoration.42 In the case of ARET assay, the absorption of excitation 15


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energy by the inhibitors and cleaved acceptors was decreased or eliminated, thus the afterglow restoration (or ARET inhibition) efficiency was enhanced. Consequently, besides suppressing the interference of the autofluorescence and scattering light of the sample matrix,3 the ARET-based sensors enabled decreasing or eliminating the absorption of excitation energy by the inhibitors, cleaved acceptors and coexistences.

Selectivity of FAPα Assay. To test the selectivity of the proposed sensor, human dipeptidyl peptidase-IV (DPPIV), the most closely related prolyl peptidase family member of FAPα,31-32, 37 and human serum albumin (HSA), the most abundant protein in human serum, were selected. Figure 4 compared the ARET or PRET inhibition efficiency of FAPα, DPPIV and HSA. Only FAPα could inhibit the ARET or PRET between 15 mg·L-1 Cr3+0.004:ZnGa2O4@MPA@Au and 5 µM Cy5.5-KGPNQC-SH. The presence of DPPIV and HSA could not lead to the inhibition of the ARET and PRET, but resulted in further quenching of the afterglow (Figure 4a) and PL (Figure 4b) of Cr3+0.004:ZnGa2O4@MPA@Au, elucidating the fine selectivity of the proposed probe. Compared to the PRET assay (Figure 4b), the ARET assay (Figure 4a) gave the higher inhibition efficiency of the target analyte FAPα, whereas the lower quenching interference of DPPIV and HSA. These data further proved the merit of ARET assay for enhancing the response of the target analyte but lowering the interference of the coexisted substances.

16


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a

FAPα DPPIV HSA

1.0 0.8

0.8

(P-P0)/P0

0.6

0.4 0.2 0.0

FAPα DPPIV HSA

1.0

b

0.6 (A-A0)/A0

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

ACS Sensors

2.0

10.0

2.0

10.0

0.4 0.2 0.0

2.0

-0.2

2.0

10.0

10.0

2.0

2.0

-0.2

-0.4

-0.4 -1

-1

Concentration (mg L )

Concentration (mg L )

Figure 4. (a) ARET and (b) PRET inhibition efficiency of FAPα, DPPIV and HSA (A (P) and A0 (P0) were the afterglow (PL) intensity at 695 nm in the presence or absence of the corresponding protein respectively). 15 mg·L-1 Cr3+0.004:ZnGa2O4@MPA@Au and 5 µM Cy5.5-KGPNQC-SH was used. The afterglow spectra were immediately measured after the stoppage of 5 min irradiation of 254 nm by Xe light (75 W) of fluorometer. The PL spectra were recorded with constant illumination of 254 nm.

In Vitro Cell Imaging. The FAPα-positive U87MG, MDA-MB-435 and FAPα-negative AD293 cells30-32 were involved for cell imaging. The expression of FAPα by the three kinds of cells was first ascertained via flow cytometry (Figure 5a), wherein the anti-FAPα antibody strongly stained U87MG and MDA-MB-435 cells, whereas the AD293 was not stained (Figure 5a). To make sure the cells healthy, the cytotoxicity of the CZMA-based probe was first evaluated. U87MG, MDA-MB-435 and AD293 cells were incubated with different concentration of CZMA-based probe for 24 h. The cell viabilities for the three kinds of cells incubated with 100 mg L-1 CZMA-based probe were over 90% (Figure S8) and the live/dead cell images (Figure S9) further showed high viability of cells after incubation with different probe concentrations, indicating the ignorable cytotoxicity of the CZMA-based probe. Figure 5b showed the in vitro imaging of U87MG, MDA-MB-435 and AD293 cells respectively by 10 mg L-1 CZMA-based probe. For AD293 cells which are not supposed to express FAPα,31 the CZMA-based probe was 17


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dark. In contrast, the U87MG and MDA-MB-435 cells with high expression of FAPα30-31 were lightened by the red signal of CZMA-based probe (Figure 5b).

Figure 5. (a) Flow cytometry detection of FAPα in U87MG, MDA-MB-435 and AD293 cells using anti-FAPα antibody and secondary antibody containing PE. The cells without incubating with anti-FAPα antibody and secondary antibody were used as the corresponding control. (b) In vitro cell imaging of FAPα in U87MG, MDA-MB-435 and AD293 cells incubated with 10 mg L-1

CZMA-based probe. The blue color stands for DAPI and the red color represents CZMA-based probe. Quantitative Analysis of FAPα α Expressed by Living Cells in Complete Medium and Human Serum. Besides differentiating the FAPα-positive and negative cells, the proposed ARET 18


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sensor could quantitatively analyze FAPα expressed by living cells. Figure 6a described the afterglow spectra of CZMA-based probe incubated with various amounts of U87MG cells in complete medium. The afterglow intensity at 695 nm was linearly recovered against the cell numbers of U87MG (Figure 6b). To further validate the ARET-based assay, we measured the five U87MG and MDA-MB-435 cells spiked human serum samples. Table 1 showed 0.66 mg L-1 and 0.51 mg L-1 of FAPα expressed by five U87MG and MDA-MB-435 cells respectively. Each cancer cells-spiked sample was further spiked by known FAPα concentrations of 0.4, 0.8 and 1.2 mg L-1, respectively, and the spike recoveries were in 95.6-103% (Table 1). All these outcomes further demonstrated the high specificity and good feasibility of the proposed CZMA-based probe for imaging and quantitative determination of FAPα. 50000

25 20 15 cell number 10 5 CZMA-based probe Medium

40000 30000 20000

b 1.2 1.0 (A-A0)/A0

a

Intensity (a.u.)

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

ACS Sensors

0.8 0.6

10000 0.4 0 0.2 675


750

5

10

15 20 Cell number

25

Figure 6. The ARET assay of FAPα expressed by the living U87MG cells in complete medium: (a) Afterglow spectra of CZMA-based probe incubated with various numbers of living U87MG cells and (b) the recovered efficiency (A-A0)/A0 (A and A0 were the afterglow intensity at 695 nm of the ARET in the presence or absence of U87MG cells respectively) against the numbers of U87MG cells.

19


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Table 1 Spike recoveries of the proposed ARET sensor for quantitative analysis of FAPα in human serum Cell lines

Content in 5 cells (mg L-1)

U87MG

MDA-MB-435

Spiked (mg L-1)

0.66

0.51

Recovery (%)

0.4

96.7 ± 1.8

0.8

98.0 ± 1.1

1.2

103 ± 2.6

0.4

102 ± 2.4

0.8

95.6 ± 3.2

1.2

102 ± 1.3

CONCLUSION In summary, we presented an ARET assay and a simple strategy of decorating PLNPs with gold nanoparticles for functionalizing PLNPs as reliable ARET donors for imaging and quantitative detection of FAPα expressed by live cells. The ARET assay gave higher sensitivity, lower LOD of FAPα, and better anti-interference capability than the PRET assay, illustrating great merits of the ARET assay in decreasing or eliminating absorption of the excitation energy by the cleaved acceptors, inhibitors and coexisted interferences. Besides the optical probing and imaging, the simple strategy of decorating PLNPs with gold nanoparticles would find potential applications in surface-enhanced Raman scattering, photodynamic therapy and photothermal therapy without external illumination. Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 21575070, 21435001) and the Open Funds of the State Key Laboratory of Electroanalytical Chemistry (SKLEAC201805). Supporting Information 20


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The Supporting Information is available free of charge on the ACS Publications website. Chemicals and Materials, Apparatus, preparation of Cr3+0.004:ZnGa2O4 nanoparticles, cell cytotoxicity assay and live/dead cell staining, preparation of cell suspension and additional figures and tables (PDF)

21


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Afterglow Resonance Energy Transfer Inhibition for Fibroblast

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