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Manganese-doped carbon dots for magnetic resonance/ optical dual-modal imaging of tiny brain glioma Zhe Ji, Penghui Ai, Chen Shao, Tingjian Wang, Changxiang Yan, Ling Ye, and Wei Gu ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.7b01008 • Publication Date (Web): 07 May 2018 Downloaded from http://pubs.acs.org on May 8, 2018

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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ACS Biomaterials Science & Engineering

Manganese-doped carbon dots for magnetic resonance/optical dual-modal imaging of tiny brain glioma Zhe Ji,

⊥,

‡

Penghui Ai,

⊥,

§

Chen Shao, # Tingjian Wang, ₤ Changxiang Yan,*, ₤ Ling Ye,† and Wei Gu*, †

†

School

Pharmaceutical

Sciences,

Capital

Medical

University,

No.

10

Youanmenwaixitoutiao, Beijing 100069, P.R. China ‡

School of Basic Medical Sciences, Capital Medical University, No. 10

Youanmenwaixitoutiao, Beijing 100069, P.R. China §

Department of Stroke Center, People's Hospital of Puyang, No. 252 Shengli Middle

Street, Puyang, Henan, 457000, P. R. China #

Department of Pharmacy, Xuanwu Hospitial of Capital Medical University, No. 45

Changchun Street, Beijing 100053, P.R. China ₤

Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical

University, No.50 Xiangshanyikesong, Beijing 100093, P. R. China

* Corresponding authors E-mail: [email protected], [email protected]

⊥

These authors contributed equally to this work. 1

ACS Paragon Plus Environment

ACS Biomaterials Science & Engineering 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

Abstract Brain gliomas are the life-threatening diseases with low survival rate. Early detection and accurate intraoperative location of brain gliomas is vital to improving the prognosis. Herein, we synthesized manganese (Mn)-doped carbon dots (CDs) as magnetic resonance (MR)/optical dual-modal imaging nanoprobes by a one-pot green microwave-assistant route. These ultrasmall-sized Mn-doped CDs possess distinct excitation-dependent photoluminescent emissions, high r1 relaxivity, and low cytotoxicity. The in vivo MR imaging and ex vivo optical imaging of mouse brain with tiny glioma demonstrate that the Mn-doped CDs could lead to an enhanced MR T1 contrast effect in the tiny brain glioma region, disclosing the great promise of these Mn-doped CDs as MR/optical dual-modal imaging nanoprobes for detection and intra-operative location of tiny brain gliomas.

Keywords: carbon dots (CDs), Mn doping, dual-modal, MR imaging, optical imaging, tiny brain gliomas

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Introduction Brain gliomas are the most aggressive intracranial tumors with poor prognosis 1. Anatomical and

functional imaging

techniques

enable

accurate

detection,

pre-operative planning, intra-operative location, and on-demand evaluation of the response to a treatment, thus play an important role in improving outcomes of brain gliomas. Magnetic resonance (MR) imaging is the dominate imaging modality for brain glioma diagnosis and intra-operative imaging

2,3

. Recently, optical imaging has

been applied as a promising tool for intra-operative image-guided resection

4-6

.

Nevertheless, either MR or optical imaging has its own inherent limitations and disadvantages. Obviously, new and improved imaging tools can overcome the limitations of its predecessors. However, it usually requires a vast amount of efforts for clinical translation. Alternatively, it is more practical and economical to maximize the capability of each imaging tool by utilization of nanoprobes. In this context, it becomes essentially important to design MR/optical dual-modal nanoprobes, which can take advantages of the high soft-tissue contrast and spatial resolution with MR imaging and the fast data acquisition and high sensitivity with optical imaging, to confer more accurate diagnosis and effective treatment according to the complementary imaging information

7,8

. Currently, most MR/optical dual-modal

nanoprobes reported in literature rely on a step-by-step synthesis fashion, that is, in each step, only one imaging modality is incorporated

9,10

. Such multiple-step

preparation is time-consuming and may cause accumulated toxicity. Preparation of MR/optical dual-modal nanoprobes by a one-step and green method is thus 3



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continually being pursued. During the past few years, carbon dots (CDs) have emerged as attractive novel optical nanoprobes for bio-imaging due to their distinct merits, such as tunable emissions, photostability, and low toxicity

11-15

. These features make CDs superior

substitutes to conventional organic dyes and quantum dots in bio-applications. Moreover, it has been demonstrated that CDs could pass the blood-brain barrier (BBB) due to their ultrasmall size 16. In the mean time, CDs can serve as an ideal platform to construct MR/optical dual-modal imaging nanoprobes simply by doping of paramagnetic ions. For instance, a number of gadolinium (Gd)-doped CDs have been constructed as efficient MR/optical dual imaging nanoprobes

17-21

. Nevertheless, Gd

ions are known to be nephrotoxic, leading to nephrogenic systemic fibrosis

22

.

Therefore, the use of Gd-doped CDs in patients with renal impairment is limited. Alternatively, manganese (Mn)-based nanoparticles has been used as an efficient MR nanoprobe. More importantly, Mn-based MR nanoprobes exhibit better performance in detection of brain diseases 23-26. Nevertheless, the preparation of Mn-doped CDs as MR/optical dual-modal nanoprobe for brain glioma imaging remains unexplored so far. Herein, Mn-doped CDs were prepared by a one-step and green microwave-assisted route using citric acid, urea, and manganese chloride as the starting materials. The as-prepared Mn-doped CDs illuminate unique excitation wavelength-dependant photoluminescent (PL) emissions while the doped Mn ions afford the CDs an efficient r1 relaxivity for MR imaging. In vivo MR and ex vivo optical imaging of mouse brain

4


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with tiny glioma were performed to explore the applicability of these Mn-doped CDs as a novel MR/optical dual-modal nanoprobe for tiny brain glioma detection.

Results and discussion Characterization The Mn-doped CDs were prepared by the one-step microwave-assisted carbonation of citric acid in the presence of urea and Mn ions. Specifically, citric acid simultaneously serves as the carbon source and the coordination agent to bind Mn ions through carboxyl groups. Urea acts as the nitrogen dopant to afford the tunable PL of Mn-doped CDs. Note that the preparation of Mn-doped CDs by this method is reproducible. The morphology and size of the Mn-doped CDs were examined by TEM. The TEM image of Mn-doped CDs reveals that the Mn-doped CDs are well-separated with a size less than 5 nm (Fig 1A). Meanwhile, the DLS measurement indicates that the hydrodynamic diameter distribution of Mn-doped CDs is relatively narrow, which is in the range of 3-5 nm (Fig. 1B). Clearly, the hydrodynamic diameter of Mn-doped CDs is well agreed with that observed on the TEM image. Moreover, the high-resolution TEM image shows that the individual Mn-doped CD possesses observable lattice spacing of 0.24 nm (inset, Fig. 1A), which can be referred to the 001 in-plane lattice of graphene. In addition, the content of Mn in CDs as determined by ICP-OES is about 20 µg Mn per mg CDs.

5



A

B

0.24 nm

30 Number (%)

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20

10

0 1

2

3 4 5 Size (d.nm)

6

7

Fig. 1 (A) TEM image and (B) size distribution histogram of Mn-doped CDs measured by DLS. Inset shows the HRTEM image of an individual Mn-doped CD.

The crystalline nature of the Mn-doped CDs was examined by XRD. The XRD pattern shown in Fig. 2A presents a reflection centered at 22°, which is due to turbostratic graphitic carbon phase

27

. However, the broad and noisy characteristics

suggest the amorphous nature of the Mn-doped CDs. Additionally, to probe the surface functional groups as well as the chemical composite of Mn-doped CDs, FTIR spectrum was acquired. According to the IR spectrum of Mn-doped CDs shown in Fig. 2B, a number of oxygen-containing functional groups are identified. For example, the bands in the range of 3300-3500 cm-1 and at 1650 cm-1 suggest the presence of surface O-H and C=O groups, respectively. Meanwhile, the IR bands at 1380 and 1120 cm-1 originated from the respective bending mode of N–H and C–N confirm the nitrogen doping. Moreover, both aromatic and aliphatic CH stretching vibration bands are observed, which can be attributed to the CH attached to the carbon core and surface functional groups, respectively. 6


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A

Counts (a.u.)

1200

800

400

0 10

20

30

40

50

60

70

80

2θ

B

100 80

Transmittance (%)

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


60 40 20 0 4000

3500 3000

2500

2000

1500 1000 -1

Wavenumber(cm )

Fig 2 (A) XRD pattern and (B) IR spectrum of the Mn-doped CDs.

Optical properties The Mn-doped CDs are highly water dispersible and no notable aggregation or precipitation was observed for the aqueous dispersion over a 4-week storage period at ambient conditions. Fig 3A presents the UV-vis absorption spectrum of Mn-doped CDs dispersed in water. The band at 260 nm is attributed to the π−π* transition, 7



manifesting the presence of aromatic ring structure in the CDs. The formation of aromatic ring structure occurs during the microwave-assistant carbonization process through the reactions between various functional groups (e.g. the hydroxyl, carboxyl, and amino groups) from the starting materials. Additionally, the relatively strong and narrow peak at 340 nm and the relatively weak and broad band centered at 410 nm are due to the n–π* electronic transition, which is attributed to the trapping of excited state energy by the surface oxygen-based functional groups of the Mn-doped CDs. Next, the PL emission spectra of the Mn-doped CDs were acquired under different excitation wavelengths. It is found that the Mn-doped CDs exhibit excitation wavelength-dependent PL emissions (Fig. 3B). The excitation wavelength-dependent emission is common to CDs, which may result from the inhomogeneous chemical structure, various surface emissive traps, or an unknown mechanism. Nevertheless, it is noted that the behavior of excitation-wavelength-dependent PL emission becomes less significant with the increase of excitation wavelength. As a consequence, the Mn-doped CDs illuminate a green PL emission when excitation wavelength is in the range of 400 to 460 nm and the most intensive green emission is observed when the excitation wavelength is 420 nm. The surface COOH and OH groups are reported as the general origin for the green PL of CDs because these oxygen-containing groups act as molecule-like states known as edge states

28

. Note that the longer

excitation/emission wavelength is favored in bio-imaging as it allows a deeper detection of Mn-doped CDs in biological tissues. The QY of green PL as directly determined by the integrating sphere is about 10 %. Another PL feature of the

8


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Mn-doped CDs is a blue/green dual-emission when excitation in the range of 360 to 400 nm, which suggests that the Mn-doped CDs have diverse PL centers. It is worthwhile to note that both UV-vis spectrum and PL emission spectra of Mn-doped CDs resemble to that of undoped CDs, suggesting the Mn doping has little impact on the optical properties of CDs. In addition, the decay curve Mn-doped CDs (Fig. 3C) reveals that when excited at 400 nm, the Mn-doped CDs possess two lifetimes, that is, 3.97 and 7.12 ns ( χ2 = 1.297), further confirming the presence of multiple emission centers. It is reported recently that the carbon-core and surface domain mainly corresponds to the multiple emission centers in CDs derived from the citric acid. Specifically, the blue PL is due to the radiative recombination of electron-hole pairs from the carbon core, whereas the green PL is a result of the radiative relaxation from the excited state to ground state due to the presence of different oxygen-containing groups on the surface of CDs 29

.

9



A

Abs (a.u.)

0.4

0.2

0.0 250

300

350

400

450

Wavelength（ nm）

B

FL 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

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8000

320 nm 340 nm 360 nm 380 nm 400 nm 420 nm 440 nm 460 nm

6000

4000

2000

0 350

400

450

500

550

600

Wavelength (nm)

10


650

700

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C 3000

Counts (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


2000

1000

0 5

10 Time (ns)

15

20

Fig. 3 (A) UV-vis absorption spectrum, (B) PL emission spectra, and (C) decay curve of the Mn-doped CDs (λex = 400 nm).

Relaxivity The relaxivity of nanoprobe has a critical impact on the quality of MR imaging. To determine the r1 relaxivity of Mn-doped CDs, the T1 relaxation times of Mn-doped CDs with increased Mn concentrations from 0 to 0.5 mM were first measured on a 7 T MR scanner. Then, the linear fitting of 1/T1 against the Mn concentration was conducted. The slope of the line represents the r1 relaxivity of Mn-doped CDs, which is found to be 6.23 mM-1 s-1 (Fig. 4A). Although this r1 value is not as high as the r1 of Gd-doped CDs obtained in our previous work 21, it is comparable to most Mn-based nanoparticles reported in the literatures 23,26,30,31. It is known that the spin-lattice effect contributes to T1 relaxation enhancement and a direct contact of the surface paramagnetic ions with the nearby water is thus necessary. Obviously, a shorter 11



distance between the surface paramagnetic ions and the neighboring water protons is crucial for improved relaxivity. The ultrasmall size and hydrophilic nature of Mn-doped CDs endow a shorter distance between the surface Mn ions and the surrounding water protons and this ultimately results in a relatively high r1 relaxivity, making the Mn-doped CDs suitable for acting as efficient T1 nanoprobes. The applicable of Mn-doped CDs as effective MR T1 nanoprobes was additionally supported by the corresponding T1-weighted MR images of Mn-doped CDs dispersions with increasing Mn concentrations (Fig. 4B), which clearly verifies the enhancement in brightness as Mn concentration increases.

A

4

3

R1 (s-1)

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

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2

r1 = 6.23 mM-1 s-1

1

0.0

0.1

0.2

0.3

0.4

0.5

Mn concentration (mM)

B

Fig. 4 (A) linear fitting of 1/T1 against Mn concentration for r1 relaxivity measurement and (B) corresponding T1-weighted MR images of aqueous dispersions of Mn-doped 12


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CDs with increased Mn concentrations.

Cytotoxicity Next, we performed the standard cell viability MTT assay to ensure that the Mn-doped CDs have low cytotoxicity for bio-related applications. The C6 cells were incubated with the Mn-doped CDs for 24 h at various concentrations up to 0.6 mg/mL and the corresponding MTT assay result is plotted in Fig. 5. It is noted that the survival of C6 cells depends on the concentration of incubated Mn-doped CDs. However, incubation of C6 cell with the Mn-doped CDs at the highest tested concentration still results in a satisfactory cell viability ( > 80 %). This thus validates the low cytotoxicity of Mn-doped CDs. Nonetheless, the biocompatibility of Mn-doped CDs requires further investigations.

100

Cell Viability (%)

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


80 60 40 20 0 0.0

0.1

0.2

0.3

0.4

0.5

0.6

Concentration (mg/mL) Fig. 5 MTT assay of C6 cells upon incubation of Mn-doped CDs at different concentrations. 13



In vivo MR imaging of mouse brain with tiny glioma Given the decent r1 relaxivity and the good cytocompatibility, the feasibility of Mn-doped CDs as MR T1 contrast agents for tiny brain glioma imaging was tested. The mouse brain with tiny glioma was imaged pre- and post-injection of Mn-doped CDs (at a dosage of 0.4 mg Mn-doped CDs per kg body weight) and the obtained MR images are presented in Fig. 6. Compared to the pre-injection MR image, a marked enhancement in the tiny brain glioma region at 30 min post-injection of Mn-doped CDs is evidenced and the enhanced MR contrast lasts at least for 2 h, confirming that the Mn-doped CDs can enter brain, travel across the BBB, and eventually accumulate in the glioma region. This is most likely due to the ultrasmall size (3-4 nm) of Mn-doped CDs, which enables them to effectively penetrate the intact or disrupted BBB and extravasate across the leaky tumor vasculature of gliomas via the enhanced permeability and retention (EPR) effect. Although further work should be conducted to confirm that whether the CDs are internalized by tumor cells or retained in the blood vessels, the enhanced MR contrast demonstrates the potential of the Mn-doped CDs for detection of tiny brain gliomas, which is of essential importance for improving the outcomes.

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A

C

B

Fig. 6 in vivo T1-weighted MR images of mouse brain with tiny glioma obtained pre-injection (A), and 30 min (B), 2 h (C) post-injection of the Mn-doped CDs.

Ex vivo optical imaging The accumulation of Mn-doped CDs in the brain glioma was further supported by ex vivo optical imaging of the excised mouse brain with tiny glioma. The acquired images clearly show that the glioma site exhibits intensive fluorescence as compared to normal brain issue (Fig. 7). Moreover, the location of the glioma identified by optical imaging is consistent with the result of MR imaging, suggesting that the Mn-doped CDs are potentially useful for intra-operative location of gliomas. In addition, the ex vivo optical imaging of major organs discloses that detectable fluorescence signals are found in the lung, kidney, and liver as well, whereas almost no fluorescence signals are observed in the heart and spleen (Fig. 7). This suggests that the Mn-doped CDs could rapidly circulate in blood after intravenous injection, and consequently be captured by organs either with high levels of blood flow (e.g. lung) or high levels of blood flow plus processing (e.g. liver). In addition, the presence of Mn-doped CDs in kidneys infers that the Mn-doped CDs could be

15



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excreted by urine. High

Brain

Spleen

Heart

Lung

Kidney

Liver Low

Fig. 7 ex vivo optical imaging of tiny glioma-bearing mouse brain and major organs after injection of Mn-doped CDs.

Overall, the in vivo MR and ex vivo optical imaging results demonstrate that the applicability of Mn-doped CDs as MR/optical dual-modal nanoprobes for the imaging of tiny brain glioma. Compared to other MR/optical dual-modal nanoprobes reported in literature, the one-step microwave-assisted preparation of Mn-doped CDs is easy, cost-effective, and environmentally friendly. Moreover, the ultrasmall size facilitates the BBB crossing and accumulation of Mn-doped CDs in tumor sites. However, to fully realize their potential as dual-modal nanoprobes, the Mn-doped CDs with tunable PL emissions that extend to red or near-infrared regions are highly desirable.

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Conclusion In sum, the Mn-doped CDs with a size less than 5 nm were prepared by one-pot microwave-assisted carbonization of citric acid in the presence of urea and Mn ions. These Mn-doped CDs feature distinct excitation-dependent PL emissions, high r1 relaxivity, and low cytotoxicity. In vivo MR and ex vivo optical imaging of mouse brain with tiny glioma demonstrate that the Mn-doped CDs can lead to enhanced MR/optical contrast in the glioma region, providing the possibilities for detection and intra-operative location of tiny brain gliomas.

Experimental Synthesis of Mn-doped CDs A green, one-step microwave-assistant carbonation method was adopted to synthesize the Mn-doped CDs. Briefly, to 10 ml of distilled water, 1.00 g of citric acid, 3.00 g of urea, and 1.00 g of MnCl2 were added. The mixture was placed in a household microwave oven (750W, Glanz, China) and heated for 3.5 min. The formed Mn-doped CDs were re-dispersed in distilled water and subjected to centrifugation at 4000 rpm for 10 min. Afterwards, the Mn-doped CDs collected from the supernatant were dialyzed against distilled water for 24 h with a cellulose ester membrane (MWCO = 100-500 Da), followed by freeze-drying to obtain the Mn-doped CDs powder for further use. In vivo MR imaging of mouse brain with tiny glioma The protocols evaluated and approved by the ethical committee of Capital Medical 17



University were followed to perform the animal experiments in this study. The tiny brain glioma (less than 2 mm in diameter) model was established using the protocol reported elsewhere.23 The Mn-doped CDs dispersed in 0.2 mL of saline (2 mg/ml) were injected via tail vein. In vivo MR imaging of the tiny glioma bearing brain was conducted on a 7 T MR scanner (Bruker Pharmascan, Germany) and the same sequence reported in our previous work was applied. 23 Ex vivo optical imaging After in vivo MR imaging, the brain with tiny glioma and other major organs including heart, liver, spleen, lungs, and kidneys were excised. Ex vivo optical imaging of these organs was performed on a Berthold imaging system (NightOwl LB 983, German) with 475/520 nm excitation/emission filter sets.

Acknowledgements The authors gratefully acknowledge the financial supports from Natural Science Foundation of Beijing Municipality (7162023), the Key Project from Beijing Commission of Education (KZ201610025022), the National Natural Science Foundation of China (81271639), and the Basic-clinical Key Research Grant (16JL46). The technical supports from the Core Facilities Center (CFC) at Capital Medical University are also acknowledged.

Supporting Information The Supporting Information is available free of charge on the ACS Publications

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website at DOI: xxx/xxx. Experimental details (PDF)

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For Table of Contents Use Only

Manganese-doped carbon dots for magnetic resonance/optical dual-modal imaging of tiny brain glioma Zhe Ji,

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Penghui Ai,

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Chen Shao, # Tingjian Wang, ₤ Changxiang Yan,*, ₤ Ling Ye,† and Wei Gu*, †

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