Dual-mode Fluorescence and Magnetic Resonance Imaging

Subscriber access provided by Northwestern Univ. Library

Article

Dual-mode Fluorescence and Magnetic Resonance Imaging Nanoprobe Based on Aromatic Amphiphilic Copolymer Encapsulated CdSe@CdS and Fe3O4 Xiaohong He, Xue Shen, Dongming Li, Yiyao Liu, Kun Jia, and Xiaobo Liu ACS Appl. Bio Mater., Just Accepted Manuscript • DOI: 10.1021/acsabm.8b00240 • Publication Date (Web): 10 Jul 2018 Downloaded from http://pubs.acs.org on July 11, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

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.

Page 1 of 30 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 Applied Bio Materials

Dual-mode Fluorescence and Magnetic Resonance Imaging Nanoprobe Based on Aromatic Amphiphilic Copolymer Encapsulated CdSe@CdS and Fe3O4 Xiaohong He, Xue Shen, Dongming Li, Yiyao Liu, Kun Jia*, Xiaobo Liu* Research Branch of Advanced Functional Materials, School of Materials and Energy, University of Electronic Science and Technology of China, Chengdu, 611731, P.R. China

ABSTRACT: Nanoparticles exhibiting good biocompatibility and multi-functional optical, magnetic as well as reactive properties are essential materials for the construction of next generation theranostics platforms. The core-shell structured CdSe@CdS is few of semiconductor quantum dots (QD) that shows ideal photoluminescence for biological application including unity quantum yields, identical photoluminescence for ensembles and single dot, non-blinking and anti-bleaching. However, the overcome of toxicity concerns from Cd2+ is still a great challenge for promoting the practical medical application of the CdSe@CdS QD. Besides, the high quality luminescent and superparamagnetic nanoparticles at present are basically hydrophobic, which implies that the phase transfer of these functional nanoparticles into aqueous phase is the primary step to enable their biomedical

ACS Paragon Plus Environment

ACS Applied Bio Materials 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

application. Herein, we have developed a facile protocol to fabricate highly biocompatible nanoparticles showing both modulated luminescent and magnetic properties via a one-step self-assembling of amphiphilic block co-polyarylene ether nitriles (amPEN), oleic acid stabilized CdSe@CdS QD and Fe3O4 superparamagnetic nanoparticles (SP) in microemulsion system. Benefiting from the aromatic backbone structure of amPEN and its strong hydrophobic interaction with surface capping agent of QD/SP, the fabricated hybrid nanoprobe exhibits quite competitive colloids stability as well as fluorescent/magnetic properties, which ensures its application for in-vitro fluorescence and magnetic resonance (MR) imaging of cancer cells.

KEYWORDS: amphiphilic block copolymer; quantum dots; superparamagnetism; self-assembling; fluorescence bioimaging; magnetic resonance imaging


Page 2 of 30

Page 3 of 30 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


1. INTRODUCTION Thanks to their modulated fluorescence emission and superparamagnetism, fluorescent magnetic nanoparticles (FMNP) based on semiconductor quantum dots (QD) and small sized superparamagnetic nanoparticles (SP) have witnessed increasing research interests in the development of multi-modal biomedical theranostics and advanced functional devices1-5. For instance, fluorescent QD showing intriguing feature such as upconversion and size-dependent emission can provide versatile pathways to construct advanced in-vitro detection probe6,7, while the superparamagnetic Fe3O4 NPs are widely combined with various luminescent probe to enhance the detection sensitivity and drug delivery efficiency8-10. The conventional protocols to prepare the FMNP that hold both fluorescent and magnetic properties can be roughly divided into covalent conjugation and non-covalent encapsulation, and the latter one is considered as the preferred method to prepare FMNP, given that the fluorescence emission of many QD could be obviously quenched during the covalent modification of magnetic nanoparticles11. In addition, the majority of high quality fluorescent QD and magnetic nanoparticles have been synthesized via solvothermal process in organic solvents of high boiling point, thus these small-sized nanoparticles (NP) are basically hydrophobic due to the presence of non-polar surface capping agent12,13. Therefore, the phase transfer of these hydrophobic NP into aqueous solution while maintaining their fluorescent/magnetic properties is the indispensable step to ensure their effective application in biomedical scenarios14,15.



Page 4 of 30

Amphiphilic organic materials have been intensively employed as soft templates to enable the phase transfer of hydrophobic QD/SP into aqueous solution16. Compared with the diverse surfactants of small organic molecules, the amphiphilic block copolymers are able to provide more effective stabilization of hydrophobic QD/SP in aqueous solution, which is mainly due to the much stronger intermolecular interaction derived from hydrophobic interaction and chain entanglement between block copolymer and non-polar surface capping agent of QD/SP17-19. For this reason, a great range

of

amphiphilic

block

copolymers

including

polymaleic

anhydride-alt-tetradecene (PMAT), PEG grafted diblock/triblock copolymers, amphiphilic

polyethyleneimine,

polystyrene-co-maleic

anhydride

have

been

synthesized and further employed in aqueous phase transfer of hydrophobic NP, and the obtained copolymer-NP conjugates have been successfully utilized in bio-imaging20, in-vitro/vivo diagnostics, cancer therapy, etc21-25. In addition, the amphiphilic block copolymer with appropriate molecular design can be employed to encapsulate various different functional entities including drugs, photosensitizer, imaging probe, etc. into single system to realize the multi-mode biomedical platform.26-29

However, the molecular interaction between hydrophobic segment of

conventional co-polyolefin and aliphatic capping agent of hydrophobic QD/SP is limited and would be declined in aggressive conditions, which results to the deterioration of long term stability of colloids solution as well as fluorescent/magnetic properties30. Besides, the surface charge and further bio-modification of the amphiphilic copolymer encapsulated NP need to be carefully controlled to ensure


Page 5 of 30 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


their future application in biomedicine31. Therefore, it is still a great challenge to enable the phase transfer of hydrophobic FMNP and maintain their long term functionality and bio-modification via the facile self-assembling of amphiphilic block copolymers. Polyarylene ether nitrile (PEN) is one typical member of the high performance polyarylene ethers thermoplastics family, which are traditionally used as the ideal matrix for advanced engineering composites, mainly due to their promising mechanical properties and outstanding thermal stability derived from aromatic backbone structure and strong intermolecular interaction32. In our previous works, we have discovered that PEN is also an intrinsically fluorescent non-conjugated polymer and can be employed to establish fluorescence sensors for heavy metal ions detection33-35. Very recently, we have synthesized a novel amphiphilic block co-PEN, which is further employed as the macromolecular agent to enable phase transfer of hydrophobic organic photocatalyst into aqueous solution for photocatalytic degradation of dyes36. On the basis of these previous works, we herein have developed a facile protocol to co-encapsulate the hydrophobic fluorescent QD and magnetic SP into single polymeric nanospheres to obtain the FMNP with long term stability, which can be further employed as a multi-modal cancer cells bio-imaging (fluorescence and magnetic resonance imaging) agent due to their modulated sizes, magnetic and fluorescent properties. 2. EXPERIMENTAL SECTION 2.1 Reagents



Cadmium oxide (CdO), sodium sulfide nonahydrate (Na2S·9H2O) and selenium powder (Se) were obtained from Aladdin (Shanghai, China). Oleic acid (OA), liquid paraffin, dichloromethane (DCM), tetrahydrofuran (THF), chloroform and toluene were purchased from J&K Scientific Ltd (Beijing, China). Hydroquinone monosulfonic acid potassium salt (SHQ) and 2, 6-difluorobenzonitrile (DFBN) were obtained from Sigma Aldrich. Bisphenol A (BPA), potassium carbonate (K2CO3), ferric chloride hexahydrate (FeCl3·6H2O), ferrous chloride tetrahydrate (FeCl2·4H2O) and ammonium hydroxide (NH3·H2O, 25%~28%) were acquired from Chengdu Haihong Chemical. Furthermore, PBS buffer powders, fetal bovine serum (FBS), penicillin and streptomycin were purchased from Gibco (Thermo Fisher Scientific, Waltham, MA, USA). All the reagents were used without further purification. 2.2 Preparation of amphiphilic block co-polyarylene ether nitrile (amPEN) The amPEN was synthesized via block copolymerization of a hydrophobic oligomer 1 and a hydrophilic oligomer 2. The oligomer 1 and oligomer 2 were prepared via the nucleophilic substitution between DFBN/BPA and DFBN/SHQ, respectively. Importantly, the stoichiometric ratios of monomers for oligomers synthesis were controlled to assure that oligomer 1 and oligomer 2 was end-capped with phenolic hydroxyl and fluoro group, respectively. Specifically, the mixture of BPA (14.383 g, 63 mmol), DFBN (3.346 g, 60 mmol), K2CO3 (12.749 g, 92.25 mmol), NMP (36 mL) and toluene (12 mL) was heated to 140°C and maintained for 3h to obtain oligomer 1, while the oligomer 2 was prepared via a similar step using SHQ (13.680 g, 60 mmol), DFBN (8.763 g, 63 mmol) and K2CO3 (12.749 g, 92.25


Page 6 of 30

Page 7 of 30 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


mmol) dispersed in the mixture of NMP (36 mL) and toluene (12 mL). Next, the two oligomers were freely cooled, followed by thorough mixing and gradually heated to 175 °C for 5 h to obtain the crude product, which was completely washed with hot ethanol and ddH2O for three times to remove the excess reactants. Finally, the acquired white powder was dried at 80 °C in a vacuum oven to obtain purified amPEN. The intrinsic viscosity of the as-prepared amPEN was determined to be 1.02 dL/g by an Ubbelohde viscometer, and its chemical structure was verified by FTIR (KBr, cm-1) and 1H NMR (DMSO-d6, 400 MHz). (FTIR and 1H NMR spectra were shown in Figure S1 of the supporting information). 2.3 Preparation of OA-capped CdSe@CdS QD The OA-capped quantum dots of CdSe@CdS were prepared via a one-pot continuous precursor injection method based on our previously work with slight modification33. In a typical synthesis, 0.25 g cadmium oxide was dissolved in the mixture of oleic acid (2 mL) and liquid paraffin (8 mL) at 180 °C to obtain light yellow cadmium precursor solution, then 1 mL of the precursor solution was rapidly injected into 9 mL liquid paraffin solubilized with 4 mg selenium powder at 240 °C under rapidly stirring for 5 min. Subsequently, the acquired CdSe-core colloidal solution was cooled quickly, followed by introducing 12 mg Na2S·9H2O and reacted at 80 °C for 30 min, then washed by the mixed solvents of chloroform/methanol and centrifuged for 3 times to obtain the final OA-capped CdSe@CdS QD. 2.4 Synthesis of OA-capped Fe3O4 nanoparticles



The OA-capped Fe3O4 nanoparticles were prepared by a chemical co-precipitation route. Typically, 6.76 g FeCl3·6H2O and 3.32 g FeCl2·4H2O were added to a three-necked flask with 50 mL deionized water (deoxidized previously) under nitrogen atmosphere at 60 °C for 1 h, then injected with 16.6 mL NH3·H2O (25%~28%) while continuously stirring the mixture for 5 min. Next, the extra 1.5 mL NH3·H2O (25%~28%) and 2 mL OA were added into the mixture in succession, followed by a further reaction of 5 min and subsequently heated to 80 °C for 3 h under nitrogen atmosphere. Finally, the entire solution was magnetically separated and washed with deionized water to be neutral and dried at 60 °C in a vacuum oven to obtain the OA-capped Fe3O4 powder. 2.5 Fabrication of QD/Fe3O4/amPEN fluorescent magnetic nanoparticles (FMNP) The FMNP of QD/Fe3O4/amPEN were prepared by a facile microemulsion self-assembly process. Briefly, 50 μL as-synthesised OA-capped CdSe@CdS QD and OA-capped Fe3O4 (0 - 2.5 mg) nanoparticles were dispersed into the mixed solvents of dichloromethane (DCM) and tetrahydrofuran (THF) (different volume ratio, the total volume is 1 mL) supplemented with 5 mg amPEN, then the mixture was added into 10 mL aqueous solution containing 30 mg SDS as surfactant. Next, the formed emulsion was stirred for 12 h at room temperature to completely evaporate the organic solvents along with the self-assembling of QD/Fe3O4/amPEN via hydrophobic interactions. The obtained products were washed by ddH2O for 3 times


Page 8 of 30

Page 9 of 30 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


to remove the excess reactants and then dispersed in pure water for further experiments. 2.6 Cytotoxicity assay The cytotoxicity of the as-prepared amPEN nanospheres, QD@amPEN and QD/Fe3O4/amPEN nanoparticles were evaluated by EMT6 cells using cell counting kit-8 (CCK-8) assay. Typically, EMT6 cells with a density of 5×104 cells/mL containing 10% fetal bovine serum (FBS) were seeded in a 96-well plate and allowed to adhere for 24 h. After incubation for 24 h at 37 °C, the cells were treated with different concentrations of the as-prepared amPEN nanospheres, QD@amPEN and QD/Fe3O4/amPEN NPs (0 – 100 μg /mL, 0 as control group) for another 24 h, respectively. Next, the culture medium was discarded and the cells were washed with PBS buffer (pH7.4) for three times to remove the free nanospheres, then 10 μL of CCK-8 dye and 100 μL minimum essential medium contained with 10 % FBS and antibiotics (100 units/mL penicillin and 100 μg/mL streptomycin) were added into each well. After additional 2 h incubation at 37 °C, the optical density of each well was recorded using a microplate reader (ELX808, BioTek) at a wavelength of 450 nm to evaluate the cell viability and the resulted cytotoxicity data are the average value from four parallel tests. 2.7 In vitro cellular imaging For in-vitro cellular imaging, EMT6 cells (5×104 cells /mL) were cultured in minimum essential medium with 10% FBS and antibiotics (100 units/mL penicillin and 100 μg/mL streptomycin) in a humidified incubator containing 5% CO2, then the



Page 10 of 30

cells were treated with the water-dispersed QD@amPEN and QD/Fe3O4/amPEN fluorescent probes at a concentration of 60 μg/mL, respectively. After incubated in the mixture for 3 h, 6 h and 12 h, the cells were washed with PBS buffer for three times to remove the non-specifically bound probes. Finally, the samples incubated for different time and stained with QD@amPEN and QD/Fe3O4/amPEN probes were captured using a confocal laser scanning microscopy (FV1000, Olympus) with an excitation wavelength of 405 nm, respectively. 2.8 MR imaging MR imaging experiments were carried out on a 3.0 T clinical GE MR750 scanner equipped with a coil for small animal. Specifically, T2 relaxation times of the as-prepared QD/Fe3O4/amPEN FMNP emulsion with different concentrations of Fe (0-0.50 mM) were measured using a T2 mapping sequence, from which the repetition time (TR) and echo time (TE) are 1000 ms and 10 – 80 ms (with an interval of 10 ms) respectively, the slice thickness is 4 mm and the flip angle is 90°. Next, the T2 relaxation times were calculated by the formula of

(

)

(

)

from the obtained data, where S means the signal intensity of the MRI pixel. Finally, the T2 relaxation rate of the synthesized FMNP was acquired based on the slope of the linear regression of the 1/T2 (S-1) versus Fe concentrations. 2.9 Characterization Fourier transform infrared spectroscopy (FT-IR, Shimadzu 8400S, KBr) and 1H nuclear magnetic resonance spectrometer (1H NMR, Bruker AMX-400, relative to DMSO-d6, δ =2.50) were employed to verify the chemical structures of the


Page 11 of 30 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


synthesized amPEN. The morphologies and the sizes of the obtained QD, Fe3O4, QD@amPEN, Fe3O4@amPEN and QD/Fe3O4/amPEN HNPs were acquired using a scanning electron microscope (SEM, JEOL, JSM 6490LV) and a transmission electron microscope (TEM, JEOL, JEM 2100F, accelerating voltage at 200 kV). The crystallization properties and magnetic performance of the as-prepared Fe3O4, amPEN nanospheres and Fe3O4@amPEN nanoparticles were characterized by means of an X-ray diffractometer (XRD, ShimadzuXRD-7000, 40 kV, Cu-Kα) and a vibrating sample magnetometer (VSM, DJM-13, Quantum Design, room temperature), respectively. In addition, the UV-Visible absorption and steady state fluorescence spectra of the prepared samples were recorded with a Persee TU-1901 UV-Vis spectrophotometer and a home-made laser microspectral analyzer based on an optical microscope (Motic, BA410E) equipped with a 405 nm laser and a portable spectrophotometer, respectively. Furthermore, the images of real samples under white light, 365 nm ultraviolet lamp and 405 nm laser were captured by a phone camera. 3. RESULTS AND DISCUSSION 3.1 Synthesis and characterization of QD@amPEN, Fe3O4@amPEN nanospheres As demonstrated in Scheme 1, the amphiphilic block co-polyarylene ether nitrile (amPEN) was firstly synthesized via block copolymerization of a hydrophobic oligomer 1 end-capped with hydroxyl and a hydrophilic oligomer 2 end-capped with fluorine, among which, oligomer 1 and oligomer 2 were prepared through nucleophilic substitution between DFBN/BPA and DFBN/SHQ, respectively, and the chemical structure of the obtained amPEN was verified via the FT-IR spectrum and



1

H NMR spectrum (see Figure S1 in supporting information). Meanwhile, the oleic

acid (OA)-capped CdSe@CdS QD was synthesized via a one-pot continuous precursor injection method in liquid paraffin and oleic acid as surface ligand, while the OA-capped superparamagnetic Fe3O4 nanoparticles were prepared by a chemical co-precipitation route using ammonium hydroxide as precipitant. Next, as shown in Scheme 1, the synthesized QD and Fe3O4 nanoparticles were both encapsulated into amPEN nanospheres via a facile one step microemulsion self-assembling owing to the hydrophobic interaction of amPEN with the oil-soluble surface capping agent of nanoparticles. Finally, the morphology as well as properties of the obtained QD@amPEN and Fe3O4@amPEN core-shell nanospheres was fully explored for further application.


Page 12 of 30

Page 13 of 30 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


Scheme 1. The synthesis process of the amPEN, OA capped QD and OA capped Fe3O4 as well as the illustration for fabrication of QD/Fe3O4/amPEN nanospheres via microemulsion self-assembling. The sizes of the synthesized QD nanoparticles calculated to be around 5 nm from the transmission electron microscope (TEM) image in Figure 1A, and the QD exhibits a strong yellow-green emission at 555 nm (Figure 1B and inset) when excited by a 405 nm laser. After being encapsulated into the prepared amPEN nanospheres via a microemulsion self-assembly process, the morphology of the hybrid QD@amPEN nanospheres was captured with a scanning electron microscope (SEM). According to Figure 1C and Figure S2A, the SEM image shows the majority sizes of the monodispersed isotropic nanospheres are mainly about 90-120 nm, which implies that these colloids could be readily endocytosed into cells. In addition, the fluorescence behaviors of the hybrid QD@amPEN synthesized with different volume ratios of dichloromethane (DCM) and tetrahydrofuran (THF) were explored to modulate their fluorescence emission and the results were displayed in Figure 1D. It was clear from the fluorescence spectra that two major emission peaks were detected at 435 nm and 555 nm, which were attributed to the π-π transition of amPEN macromolecule and the photoluminescence of the encapsulated CdSe@CdS QD, respectively. Meanwhile, the fluorescence intensity of the former emission band was gradually increased along with the increasing volume of THF against DCM (total volume is 1 mL) during the preparation process, whereas the emission peak at 555 nm demonstrated a contrary tendency, which can be also intuitively observed from the inset that the emission



colors of sample tubes were changed from yellow-green to light blue. The specific reason for the fluorescence variation is mostly attributed to the enhanced energy transfer between amPEN donor and QD acceptor. Since amPEN has higher solubility in THF than DCM, thus the increased content of THF in mixed solvents will lead to a stronger intermolecular interaction between amPEN and surface capping agent of QD, finally contribute to a more compacted encapsulation and declined local distance between amPEN and QD. For the application to fluorescence imaging, we chose the QD@amPEN nanospheres synthesized without THF for further preparation of the dual-mode imaging nanoprobes.

Figure 1. The HR-TEM image (A) and the absorption as well as emission spectrum (B) of the as-prepared QD of 555 nm as well as the SEM image (C) and fluorescent emission spectra (D) of the synthesized QD@amPEN nanospheres. Shown in insets of panel B and D are the vials containing fluorescent QD and QD@amPEN colloids.


Page 14 of 30

Page 15 of 30 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


According to the results discussed in the above paragraph, the Fe3O4@amPEN core-shell nanospheres were prepared via microemulsion self-assembly with 1 mL DCM as organic solvent, meanwhile amPEN nanospheres were prepared using the same method as the control. Firstly, the morphology of the prepared OA-capped Fe3O4 nanoparticles could be observed in the TEM image in Figure 2A, which displayed that the size of the Fe3O4 nanoparticles were mainly about 10-15 nm. Next, after being encapsulated into the amPEN nanospheres, the X-ray diffraction patterns were carried out to identify the crystalline properties of the OA-capped Fe3O4, pure amPEN and the Fe3O4@amPEN nanospheres. As exhibited in Figure 2B, the pristine amPEN nanospheres presented a diffraction broad peak at around 22.2°, indicating that the amphiphilic PEN copolymer has an amorphous nature. Meanwhile, the OA-capped Fe3O4 nanoparticles showed diffraction peaks at 2θ = 30.2°, 35.6°, 43.1°, 53.6°, 57.1°and 62.9°, which corresponded to the (220), (311), (400), (422), (511) and (440) crystal faces of Fe3O4 according to Joint Committee on Powder Diffraction Standards (JCPDS) card No. 19-0629

37

. Furthermore, the XRD pattern of the

Fe3O4@amPEN nanospheres revealed that the diffraction peaks were consisted of both amPEN and Fe3O4 nanoparticles, indicating the possible embedding of Fe3O4 into the amPEN shell structure. Next, the SEM image was recorded to characterize the morphology features of the magnetic hybrid amPEN nanospheres and the result was shown in Figure 2C and Figure S2B, from which we can see that the synthesized nanospheres were mono-dispersed and had a uniform size around 90±20 nm without any other small-sized impurities, confirming the completely capsulation of Fe3O4 into



the hydrophobic pocket of amPEN nanospheres. Finally, to estimate whether the nanospheres could satisfy the requirements for MR imaging, the magnetic properties of the prepared OA-capped Fe3O4 and Fe3O4@amPEN hybrid nanospheres were characterized by a vibrating sample magnetometer (VSM) and the hysteresis loops were shown in Figure 2D. At 298 K, the saturation magnetizations of the OA-capped Fe3O4 particles and the prepared Fe3O4@amPEN hybrid nanospheres were 52 emu·g-1 and 30 emu·g-1 at 4600 Oe, respectively, which is a sufficient magnetization for MR imaging, and the decrease of the magnetic hybrid nanospheres against the pristine Fe3O4 is most likely attributed to the existence of the antimagnetic amPEN shell capped on the Fe3O4 nanoparticles resulting the reduction of magnetic moment. In addition, as displayed in the inset Figure 2D, both the OA-capped Fe3O4 and the self-assembled nanospheres exhibited a quite low coercive force of 22 Oe, which implied that both nanoparticles were typical superparamagnetic materials. Therefore, the superparamagnetic Fe3O4@amPEN nanospheres were potential materials for MR imaging probes.


Page 16 of 30

Page 17 of 30 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


Figure 2. The TEM image of the synthesized Fe3O4 NPs (A), XRD patterns (B) of the OA capped Fe3O4 NPs, amPEN nanospheres and Fe3O4@amPEN. The SEM (C) of Fe3O4@amPEN as well as the hysteresis curves (D) of the as prepared Fe3O4 NPs, and Fe3O4@amPEN. 3.2 Preparation, characterization and cytotoxicity of the QD/Fe3O4/amPEN dual-mode imaging nanoprobes Based on the modulated properties of the QD@amPEN and Fe3O4@amPEN nanospheres shown above, we confirmed that amPEN nanospheres embedded with QD had great potential as probes for fluorescence imaging, while the amPEN copolymers encapsulated with Fe3O4 NPs could serve as probes for magnetic resonance (MR) imaging. Therefore, to realize the fluorescence/MR dual modality



imaging, QD and Fe3O4 were co-encapsulated into the amPEN via the emulsion self-assembly to obtain the QD/Fe3O4/amPEN fluorescent magnetic nanospheres (FMNP). Firstly, the fine morphology of QD/Fe3O4/amPEN FMNP was characterized by the SEM and TEM, respectively. From the SEM image shown in Figure 3A and the size distribution histograms in Figure S2C, we can see the sizes of the mono-dispersed FMNP were mainly in the range of 130-160 nm, a larger size than that of QD@amPEN and Fe3O4@PEN, which was ascribed to the co-encapsulation of QD and Fe3O4 into single amPEN nanospheres. Then, it was clear from the TEM image in Figure 3B that both QD and Fe3O4 NP were well-organized into the polymeric nanospheres, which further confirmed the successfully encapsulation of the QD and Fe3O4 NPs inside amPEN matrix. Furthermore, the TGA curves and the corresponding differential curves displayed in Figure S3A and Figure S3B also indicated that QD and Fe3O4 NPs have been successfully co-encapsulated into amPEN carriers. Next, the FMNP with different contents of Fe3O4 at the same amount of QD were synthesized and the fluorescence properties of the samples were studied. As demonstrated in Figure 3C, the fluorescence intensity of the FMNP was gradually decreased along with the increasing content of introduced Fe3O4, which was mainly attributed to the fact that the synthesized Fe3O4 NPs had quenching effects to the fluorescence of QD. Nevertheless, we can still detect the photoluminescence under a 405nm laser excitation even at a dosage of Fe3O4 up to 2.5 mg, indicating that the amPEN nanospheres co-encapsulated with QD and Fe3O4 NPs could also be used as fluorescent imaging probes.


Page 18 of 30

Page 19 of 30 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


Finally, to evaluate the potentials of QD/Fe3O4/amPEN FMNP to be used as in vitro dual-mode bio-imaging probes, EMT6 cell viabilities exposed to different concentrations of amPEN, QD@amPEN and QD/Fe3O4/amPEN nanospheres for 24 h were measured using cell counting kit-8 (CCK-8) cytotoxicity assay, and the detailed procedure of CCK-8 assay was given in the experimental section. According to the results shown in Figure 3D, we could see the control group showed cell viability nearly 100%, while the cells incubated with different concentrations of amPEN nanospheres presented similar biological activities, which demonstrated that amPEN nanospheres had good biocompatibility and can be used as carriers to encapsulate functional nanoparticles. As for cells incubated with QD@amPEN nanospheres, they also showed cell viabilities nearly 100%. Given that CdSe@CdS QD shows well-known toxicity, thus the good biocompatibility of QD@amPEN obtained in this work unambiguously confirms that aromatic amPEN is an outstanding template to effectively

eliminate

the

toxicity

of

luminescent

QD.

In

addition,

for

QD/Fe3O4/amPEN nanospheres, although the cell vitality decreased to some degree, we could see that over 90% cells still had cellular activity under different concentrations of QD/Fe3O4/amPEN nanospheres. These results demonstrated the good biocompatibility and low cytotoxicity of the FMNP, therefore, QD@amPEN and QD/Fe3O4/amPEN FMNP could be utilized as good dual-mode agent for cancer cells bioimaging.



Page 20 of 30

Figure 3. The SEM (A), TEM (B, inset: HRTEM) image and the emission spectra (C) of the QD/Fe3O4/am-PEN nanospheres. Shown in panel (D) is the cytotoxicity evaluation

of

the

synthesized

amPEN

nanospheres,

QD@amPEN

and

QD/Fe3O4/amPEN NP with different concentrations in EMT6 cells after incubated for 24 h.

3.3 In vitro fluorescence and magnetic resonance (MR) imaging To explore the functionality of QD/Fe3O4/amPEN nanoprobes for cellular imaging in vitro, the uptake of nanoprobes into EMT6 cells were observed via confocal laser scanning microscopy with an excitation wavelength of 405 nm in different time intervals, while the cells cultivated with QD@amPEN nanospheres were investigated as the control. Before recording the confocal images, the cells were washed carefully


Page 21 of 30 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


with PBS buffer for three times to remove unbound nanoprobes, and the obtained images were displayed in Figure 4A and Figure 4B as well as Figure S4 in supporting materials. As shown in Figure S4 (I), when incubated with QD@amPEN and QD/Fe3O4/amPEN nanoprobes for 3 h, respectively, the weak green fluorescence signals (DOX FRET channel) were observed in the EMT6 cells and mainly concentrated on the cell membrane, indicating the initial stage of the nanocarriers uptake by cells. After 6 h of incubation, as presented in Figure 4A and Figure 4B, an obvious increase of green fluorescence signal could be observed in cell cytoplasm, and the nanoprobes gradually transferred into cell nucleus. While after incubation for 12 h, strong fluorescence signals could be observed in cells, which indicated most of the nanoprobes were fed into the EMT6 cells as shown in Figure S4 (II). Moreover, the QD@amPEN stained cell samples always showed a stronger green fluorescence signals than cells tagged with QD/Fe3O4/amPEN nanoprobes, which was attributed to the higher fluorescence intensity of QD@PEN. Nevertheless, the fluorescence signal intensity in both cases should meet the acquirements of in vitro cell imaging. Thereafter, since superparamagnetic Fe3O4 nanoparticles have been proved to be an excellent T2 contrast agent for MR imaging, to evaluate the potential of the low-cytotoxic and superparamagnetic QD/Fe3O4/amPEN nanoprobes to be diagnostic MR contrast agents, the MR signals of QD/Fe3O4/amPEN emulsion with different Fe concentrations were detected using a 3.0T clinical MRI scanner. As shown in Figure 4C, we could see that T2-weighted signal intensity was significantly decreased along with the increased Fe concentrations, which was attributed to the interaction of



magnetic moments between the Fe3O4 NPs in the nanospheres and protons in water. Specifically, the shorter spin-spin relaxation time would lead to the lower MR signals38. Furthermore, the transverse 1/T2 relaxation rates of the QD/Fe3O4/amPEN nanoprobes in deionized water related to the Fe concentrations were shown in Figure 4D. It is clear that a linear relationship is detected between relaxation rates and Fe concentrations, and the relaxation value is up to 65.2 mM−1s−1, which is much larger than that of the recently reported dual functional MRI nanoprobes39, 40, demonstrating that the synthesized QD/Fe3O4/amPEN nanospheres can be served as efficient T2-weighted MRI probe.

Figure 4. The confocal images of EMT6 cells labeled with QD@amPEN (A) and QD/Fe3O4/amPEN (B) nanospheres at a concentration of 60 μg/mL and incubated for 6h under green channel and bright field. The T2-weighted magnetic resonance images phantoms (C) and T2 relaxation rate (D) of the QD/Fe3O4/amPEN FMNP emulsion with different concentrations of Fe at a 3.0 T MRI spectrometer.


Page 22 of 30

Page 23 of 30 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


4. CONCLUSIONS In this work, we have synthesized an amphiphilic diblock copolymer (amPEN) with aromatic backbone structure and pendant hydrophilic sulfonate groups, which was further employed as a template to encapsulate both semiconductor CdSe@CdS quantum dots (QD) and Fe3O4 superparamagnetic nanoparticles (SP) via a facile one-step microemulsion self-assembling, finally leading to the fabrication of fluorescent magnetic nanoparticles (FMNP) with modulated fluorescent and magnetic properties. Thanks to the good biocompatibility and strong hydrophobic interaction inherited from aromatic chemical structures, the synthesized amPEN is able to firmly encapsulate the oleophilic QD and SP together, which not only effectively eliminates the toxicity concerns of fluorescent QD but also allows easy modulation of the fluorescent and magnetic properties of the obtained FMNP. Based on their good biocompatibility, green fluorescence emission as well as desirable magnetic properties, the obtained FMNP exhibited promising dual mode fluorescence imaging and magnetic resonance imaging capacity for cancer cells. Basically, the preliminary results in this work open the way for construction of multifunctional biomedical agents using amphiphilic block copolymer with aromatic backbone structures, and the future work will dedicated to modification of macromolecular chemical structures to introduce more reaction groups such as carboxyl, amino, hydroxyl, etc, which will expand the targeted theranostics applications of the FMNP after immobilization of various biomolecular recognition components. ASSOCIATED CONTENT



Supporting Information The following files are available free of charge. The FTIR spectrum, 1H NMR spectrum, size distribution histograms, TGA analysis and the confocal images of the synthesized samples. AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] * E-mail: [email protected]

ORCID Xiaohong, He: 0000-0002-3946-3833 Kun, Jia: 0000-0002-7906-8109 Xiaobo, Liu: 0000-0001-5921-8491 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENTS The authors gratefully thank the financial support from the National Natural Science Foundation of China (Project 51403029), the Fundamental Research Funds for the Central Universities (ZYGX2016J040) and the Scientific Research Foundation


Page 24 of 30

Page 25 of 30 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


for the Returned Overseas Chinese Scholars from State Education Ministry (LXHG5003). REFERENCES (1) Pradhan, N.; Adhikari, S. D.; Nag, A.; Sarma, D. D. Luminescence, Plasmonic and Magnetic Properties of Doped Semiconductor Nanocrystals: Current Developments and Future Prospects. Angew. Chem., Int. Ed. 2017, 56, 7038-7054.. (2) Li, M.; Luo, Z.; Zhao, Y. Self-Assembled Hybrid Nanostructures: Versatile Multifunctional Nanoplatforms for Cancer Diagnosis and Therapy. Chem. Mater. 2018, 30, 25-53. (3) Pahari, S. K.; Olszakier, S.; Kahn, I.; Amirav, L. Magneto-Fluorescent Yolk–Shell Nanoparticles. Chem. Mater. 2018, 30, 775-780. (4) Purbia, R.; Paria, S. Yolk/Shell Nanoparticles: Classifications, Synthesis, Properties, and Applications. Nanoscale 2015, 7, 19789-19873. (5) Ye, Y.; Xing, J.; Zeng, L.; Yu, Z.; Chen, T.; Hosmane, N. S.; Lu, G.; Wu, A. Fluorescent/Magnetic Nanoprobes of High Specificity for Detection of Triple Negative Breast Cancer. J. Biomed. Nanotechnol. 2017, 13, 980-988. (6) Wei, Y.; Chen, Q.; Wu, B.; Xing, D. Excitation-Selectable Nanoprobe for Tumor Fluorescence

Imaging

and

near-Infrared

Thermal

Therapy.

J.

Biomed.

Nanotechnol.2016, 12, 91-102. (7) Li, Q. L.; Ding, S. N. Multicolor Electrochemiluminescence of Core-Shell Cdse@Zns Quantum Dots Based on the Size Effect. Sci. China Chem. 2016, 59, 1-5. (8) Xiao, X.; Yang, H.; Jiang, P.; Chen, Z.; Ji, C.; Nie, L. Multi-Functional Fe3O4@mSiO2-AuNCs Composite Nanoparticles Used as Drug Delivery System. J. Biomed. Nanotechnol. 2017, 13, 1292-1299. (9) Yang, H.; Liu, M.; Jiang, H.; Zeng, Y.; Jin, L.; Luan, T.; Deng, Y.; He, N.; Zhang, G.; Zeng, X. Copy Number Variation Analysis Based on Gold Magnetic Nanoparticles and Fluorescence Multiplex Ligation-Dependent Probe Amplification. J. Biomed. Nanotechnol. 2017, 13, 655-664.



(10) Yang, H.; Jiang, P.; Chen, Z.; Nie, L. Magnetic Fe3O4@Mesoporous Silica Composite Microspheres: Synthesis and Biomedical Applications. Nanosci. Nanotech. Lett. 2017, 9, 1849-1860. (11) Li, Z.; Sun, Q.; Zhu, Y.; Tan, B.; Xu, Z. P.; Dou, S. X. Ultra-Small Fluorescent Inorganic Nanoparticles for Bioimaging. J. Mater. Chem. B 2014, 2, 2793-2818. (12) Leng, Y.; Wu, W.; Li, L.; Lin, K.; Sun, K.; Chen, X.; Li, W. Magnetic/Fluorescent Barcodes Based on Cadmium-Free near-Infrared-Emitting Quantum Dots for Multiplexed Detection. Adv. Funct. Mater. 2016, 26, 7581-7589. (13) Wen, C.-Y.; Xie, H.-Y.; Zhang, Z.-L.; Wu, L.-L.; Hu, J.; Tang, M.; Wu, M.; Pang, D.-W. Fluorescent/Magnetic Micro/Nano-Spheres Based on Quantum Dots and/or Magnetic Nanoparticles: Preparation, Properties, and Their Applications in Cancer Studies. Nanoscale 2016, 8, 12406-12429. (14) Liu, H.; Qian, X.; Wu, Z.; Yang, R.; Sun, S.; Ma, H. Microfluidic Synthesis of QD-Encoded PEGDA Microspheres for Suspension Assay. J. Mater. Chem. B 2016, 4, 482-488. (15) Pellegrino, T.; Manna, L.; Kudera, S.; Liedl, T.; Koktysh, D.; Rogach, A. L.; Keller, S.; Rädler, J.; Natile, G.; Parak, W. J. Hydrophobic Nanocrystals Coated with an Amphiphilic Polymer Shell: A General Route to Water Soluble Nanocrystals. Nano. Lett. 2004, 4, 703-707. (16) Bollhorst, T.; Rezwan, K.; Maas, M. Colloidal Capsules: Nano- and Microcapsules with Colloidal Particle Shells. Chem. Soc. Rev. 2017, 46, 2091-2126. (17) Cho, M.-J.; Park, S.-Y. Preparation of Poly(Styrene)-B-Poly(Acrylic Acid)-Coupled Carbon Dots and Their Applications. ACS Appl. Mater. Interfaces 2017, 9, 24169-24178. (18) Lees, E. E.; Nguyen, T.-L.; Clayton, A. H. A.; Mulvaney, P. The Preparation of Colloidally Stable, Water-Soluble, Biocompatible, Semiconductor Nanocrystals with a Small Hydrodynamic Diameter. ACS Nano 2009, 3, 1121-1128. (19) Wang, X.; Zhang, Q.; Zhao, J.; Dai, J. One-Step Self-Assembly of Znpc/NaGdF4:Yb,Er Nanoclusters for Simultaneous Fluorescence Imaging and Photodynamic Effects on Cancer Cells. J. Mater. Chem. B 2013, 1, 4637-4643.


Page 26 of 30

Page 27 of 30 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


(20) Wang, J.; Lv, F.; Liu, L.; Ma, Y.; Wang, S. Strategies to Design Conjugated Polymer Based Materials for Biological Sensing and Imaging. Coordin. Chem. Rev. 2017, 354. (21) Ostermann, J.; Merkl, J.-P.; Flessau, S.; Wolter, C.; Kornowksi, A.; Schmidtke, C.; Pietsch, A.; Kloust, H.; Feld, A.; Weller, H. Controlling the Physical and Biological Properties of Highly Fluorescent Aqueous Quantum Dots Using Block Copolymers of Different Size and Shape. ACS Nano 2013, 7, 9156-9167. (22) Park, J.; Lee, J.; Kwag, J.; Baek, Y.; Kim, B.; Yoon, C. J.; Bok, S.; Cho, S.-H.; Kim, K. H.; Ahn, G. O.; Kim, S. Quantum Dots in an Amphiphilic Polyethyleneimine Derivative Platform for Cellular Labeling, Targeting, Gene Delivery, and Ratiometric Oxygen Sensing. ACS Nano 2015, 9, 6511-6521. (23) Wang, Q.; Zhang, P.; Xu, J.; Xia, B.; Tian, L.; Chen, J.; Li, J.; Lu, F.; Shen, Q.; Lu, X.; Huang, W.; Fan, Q. NIR-Absorbing Dye Functionalized Supramolecular Vesicles for Chemo-Photothermal Synergistic Therapy. ACS Applied Bio Mater. 2018, DOI: 10.1021/acsabm.8b00014. (24) Wu, F.; Su, H.; Cai, Y.; Wong, W.-K.; Jiang, W.; Zhu, X. Porphyrin-Implanted Carbon Nanodots for Photoacoustic Imaging and in Vivo Breast Cancer Ablation. ACS Applied Bio Mater. 2018, DOI: 10.1021/acsabm.8b00029. (25) Wang, Y.; Li, S.; Zhang, P.; Bai, H.; Feng, L.; Lv, F.; Liu, L.; Wang, S. Photothermal-Responsive Conjugated Polymer Nanoparticles for Remote Control of Gene Expression in Living Cells. Adv. Mater. 2018, 1705418. (26) Peng, J.; Xiao, Y.; Li, W.; Yang, Q.; Tan, L.; Jia, Y.; Qu, Y.; Qian, Z. Photosensitizer Micelles Together with Ido Inhibitor Enhance Cancer Photothermal Therapy and Immunotherapy. Adv. Sci. 2018, 5, 1700891. (27) Li, J.; Zhu, Y.; Li, W.; Zhang, X.; Peng, Y.; Huang, Q. Nanodiamonds as Intracellular Transporters of Chemotherapeutic Drug. Biomaterials 2010, 31, 8410-8418. (28) Zhang, X.; Wang, K.; Liu, M.; Zhang, X.; Tao, L.; Chen, Y.; Wei, Y. Polymeric AIE-Based Nanoprobes for Biomedical Applications: Recent Advances and Perspectives. Nanoscale 2015, 7, 11486-11508.



Page 28 of 30

(29) Hu, D.; Chen, L.; Qu, Y.; Peng, J.; Chu, B.; Shi, K.; Hao, Y.; Zhong, L.; Wang, M.; Qian, Z. Oxygen-Generating Hybrid Polymeric Nanoparticles with Encapsulated Doxorubicin

and

Chlorin

E6

for

Trimodal

Imaging-Guided

Combined

Chemo-Photodynamic Therapy. Theranostics 2018, 8, 1558-1574. (30) Wong, C. K.; Mason, A. F.; Stenzel, M. H.; Thordarson, P. Formation of Non-Spherical Polymersomes Driven by Hydrophobic Directional Aromatic Perylene Interactions. Nat. Commun. 2017, 8, 1240. (31) Kim, J.; Biondi, M. J.; Feld, J. J.; Chan, W. C. W. Clinical Validation of Quantum Dot Barcode Diagnostic Technology. ACS Nano 2016, 10, 4742-4753. (32) Tong, L.; Jia, K.; Liu, X. Novel Phthalonitrile-Terminated Polyarylene Ether Nitrile with High Glass Transition Temperature and Enhanced Thermal Stability. Mater. Lett. 2014, 128, 267-270. (33) Jia, K.; He, X.; Zhou, X.; Zhang, D.; Wang, P.; Huang, Y.; Xiaobo, L. Solid State Effective Luminescent Probe Based on Cdse@Cds/Amphiphilic Co-Polyarylene Ether Nitrile Core-Shell Superparticles for Ag+ Detection and Optical Strain Sensing. Sensor. Actuat. B: Chem. 2018, 257, 442-450. (34) Jia, K.; Wang, P.; Yuan, L.; Zhou, X.; Chen, W.; Liu, X. Facile Synthesis of Luminescent Silver Nanoparticles and Fluorescence Interactions with Blue-Emitting Polyarylene Ether Nitrile. J. Mater. Chem.C 2015, 3, 3522-3529. (35) Wang, P.; Zhao, L.; Shou, H.; Wang, J.; Zheng, P.; Jia, K.; Liu, X. Dual-Emitting Fluorescent Chemosensor Based on Resonance Energy Transfer from Poly(Arylene Ether Nitrile) to Gold Nanoclusters for Mercury Detection. Sensor. Actuat. B: Chem. 2016, 230, 337-344. (36) Zhou, X.; Jia, K.; He, X.; Wei, S.; Wang, P.; Liu, X. Microemulsion Self-Assembling of Novel Amphiphilic Block co-Polyarylene Ether Nitriles and Photosensitizer Znpc Towards Hybrid Superparticles for Photocatalytic Degradation of Rhodamine B. Mater. Chem. Phys. 2018, 207, 212-220. (37) Wang, Y.; Pang, X.; Wang, J.; Cheng, Y.; Song, Y.; Sun, Q.; You, Q.; Tan, F.; Li, J.; Li, N. Magnetically-Targeted and near Infrared Fluorescence/Magnetic Resonance/Photoacoustic Imaging-Guided Combinational Anti-Tumor Phototherapy


Page 29 of 30 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


Based on Polydopamine-Capped Magnetic Prussian Blue Nanoparticles. J. Mater. Chem. B 2018, 6, 2460-2473. (38) Su, X.; Chan, C.; Shi, J.; Tsang, M.-K.; Pan, Y.; Cheng, C.; Gerile, O.; Yang, M. A Graphene Quantum Dot@Fe3O4@SiO2 Based Nanoprobe for Drug Delivery Sensing and Dual-Modal Fluorescence and MRI Imaging in Cancer Cells. Biosens.Bioelectron.2017, 92, 489-495. (39) Luo, Y.; Du, S.; Zhang, W.; Liao, Z.; Zuo, F.; Yang, S. Core@Shell Fe3O4@Mn2+-doped

NaYF4:Yb/Tm

nanoparticles

for

triple-modality

T1/T2-weighted MRI and NIR-to-NIR upconversion luminescence imaging agents. RSC Adv. 2017, 7, 37929-37937. (40) Alipour, A.; Soran-Erdem, Z.; Utkur, M.; Sharma, V. K.; Algin, O.; Saritas, E. U.; Demir, H. V. A New Class of Cubic SPIONs as a Dual-mode T1 and T2 Contrast Agent for MRI. Magn. Reson. Imaging 2018, 49, 16-24.



Graphic Abstract 240x84mm (300 x 300 DPI)


Page 30 of 30

Dual-mode Fluorescence and Magnetic Resonance Imaging

Recommend Documents