Surface Complexation-Based Biocompatible Magnetofluorescent

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ACS Applied Materials & Interfaces

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Surface Complexation Based Biocompatible 8

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Magnetofluorescent Nanoprobe for Targeted 12 13 14 15

Cellular Imaging 16 17 18 20

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Satyapriya Bhandari, † Rumi Khandelia, † Uday Narayan Pan †and Arun Chattopadhyay †‡ * 21 2 24

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Department of Chemistry, ‡ Centre for Nanotechnology,

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Indian Institute of Technology Guwahati, Guwahati-781039, Assam, India. 28 29 30

*E-mail: [email protected] 31 32 34

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KEYWORDS. Magnetic nanoparticle, Quantum dots, Photoluminescence, Complexation 36

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reaction, Targeted cellular imaging. 37 39

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ABSTRACT. We report the synthesis of a magnetofluorescent biocompatible nanoprobe – 41

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following room temperature complexation reaction between Fe3O4-ZnS nanocomposite and 842 43

hydroxyquinoline (HQ). The composite nanoprobe exhibited high luminescence quantum yield, 4 46

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low rate of photobleaching, reasonable excited-state life time, luminescence stability especially 48

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in human blood serum, superparamgnetism and no apparent cytotoxicity. Moreover, the 49 50

nanoprobe could be used for spatio-controlled cell labeling in the presence of an external 53

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magnetic field. The ease of synthesis and cell labeling in vitro make it a suitable candidate for 5

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targeted bioimaging applications. 56 57 58 59 60 ACS Paragon Plus Environment

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Multifunctional nanostructures, with potential for synergy of action of their components, are 5

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an emerging class of materials being proposed - over unifunctional entities - for simultaneous 7

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targeting, imaging and therapeutic applications in the field of biomedical science. 1-10 Among 10

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others, magnetofluorescent bi-functional units, such as superparamagnetic iron oxide 12

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nanoparticle (SPION) - quantum dot (Qdot) composites, are popular choice in targeted bio13 14

imaging.1-10 The superparamgnetism of SPIONs is useful for magnetic resonance imaging (MRI) 17

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in vivo and for targeting tissues guided by an external magnetic field.1-11 On the other hand, 19

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Qdots are preferred over traditional organic dyes in cellular and in vivo imaging due to their 20 2

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unique optical properties, especially photo-stability, large Stokes-shifted emission and size24

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tuneable luminescence.1-13 Thus a combination of the two i.e. SPION-Qdot composite would 25 26

provide the best of both options. However, concerns regarding cyto-toxicity of (especially heavy 27 29

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metal based) Qdots, their dispersibility in aqueous medium, low luminescence quantum yield 31

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(QY), ease of functionalization for targeted delivery and stability in blood and circulation life 3

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time (even for the composite) have limited their application potential.1-13 For example, the use of 36

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Fe3O4–ZnS SPION-Qdot composite has been restricted due to low luminescence QY, which 38

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makes optical imaging difficult in the presence of cellular auto-fluorescence.14-15 39 40 41

Surface functionalization of the nanocrystals with appropriate ligand or compound may hold 4

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the key to colloidal and circulation stability, targeted delivery and even improvement in QY 46

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through passivation or other means.16-17 Recent results from our laboratory suggest that reaction 47 48

of a molecule/ligand with the cations on the surface of a Qdot leads to drastic change in its 51

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optical property via the formation of complex on the surface, referred to as quantum dot complex 53

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(QDC). As a result, optical properties (such as emission maximum, QY and excited state life 54 5

time), colloidal and thermal stabilities of the Qdot are greatly improved.18-21 If the idea could be 57

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extended to the magnetofluorescent composite then their practical utility could be enhanced 5

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using some of the properties mentioned above. 6 7 8

Herein we report the formation of a magnetofluorescent composite, based on the 1

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complexation reaction between as-synthesized Fe3O4-ZnS (SPION-Qdot) composite and 813

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hydroxyquinoline (HQ), and referred to here as SPION-QDC composite. The composite particles 14 16

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exhibited superior optical property with red-shifted emission maximum, in comparison to the 18

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parent SPION-Qdot, and without the loss of magnetic property or morphology. Furthermore, the 20

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stability in human blood serum and non-cytotoxicity made it an important candidate for cellular 21 23

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imaging. Importantly, spatially directed luminescent labeling of mammalian cancer cells (in cell 25

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culture Petri plate) could be achieved in the presence of an external magnetic field, thus 26 27

providing evidence for potential application in targeted delivery. 28 29 31

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Experimentally, cysteine-capped Fe3O4-ZnS composite was synthesized using 7.3 ± 2.3 nm 32 3

water dispersible Fe3O4 NP (which was synthesized based on the modification of reported 34 35

protocols)22-24 as seed and onto which cysteine capped ZnS Qdots were grown, based on an 38

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earlier method,21 the details of which are in the experimental section of the Supporting 39 40

Information (SI). The transmission electron microscopic (TEM) and high resolution TEM 41 43

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(HRTEM) images confirmed the formation of 7.3 ± 2.3 nm cubic inverse spinel Fe3O4 NPs 45

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(Figure S1). The powder x-ray diffraction (XRD) pattern of the solid Fe3O4-ZnS composite 46 48

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(obtained following magnetic separation) showed the presence of the characteristic peaks of 50

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cubic inverse spinel Fe3O4 with diffractions at 35.6o, 45.2o, 53.5o, 60.4o and 66.2o, corresponding 52

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to (311), (400), (422), (511) and (440) planes and cubic ZnS with diffractions at 28.8o, 48.2o and 53 54

57.0o, corresponding to (111), (220) and (311) planes, thus confirming the formation of the 57

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composite material (SI, Figure S2).21-25 Also, as is clear from the high resolution TEM image, 3.2 58 59 60 ACS Paragon Plus Environment

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+ 0.6 nm ZnS Qdots were formed surrounding the Fe3O4 NPs (Figure 1 A). It is to be mentioned 5

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here that the high resolution TEM image and the inverse fast Fourier transform (IFFT) patterns 6 8

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in Figure 1A evidenced the presence of ZnS Qdots surrounding the Fe3O4 NPs (>10 nm). 10

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Interestingly, the presence of cross pattern, which occurred due to the overlap of lattice fringes of 1 12

(311) plane of inverse spinel Fe3O4 NPs (0.28 nm) and (111) plane of cubic ZnS Qdots (0.3 nm) 13 15

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(Figure 1 A and Figure 1B-C), clearly indicated the presence of both the crystals in the Fe3O417

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ZnS composite.21-25 Importantly, the closeness of the lattice spacing of ZnS Qdot with that of 18 19

cubic inverse spinel Fe3O4 NP might have favored fusion of the Qdot on the NP. Additionally, 20 2

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literature report suggests formation of amorphous overlayer of ZnS on the Fe3O4 NP surface 24

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prior to fusion of the Qdot with the NP.14 In a similar vein, the selected area electron diffraction 25 27

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(SAED) analysis of the composite also supported the presence of both the crystals (Figure 1 D). 29

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The growth of ZnS nanocrystals on the surface of the Fe3O4 NPs was accompanied by the change 31

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in zeta potential from –52.0 + 0.5 mV (for Fe3O4 NPs) to –31.1 + 0.1 mV (for the composite, SI, 32 3

Table S1). 35

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Figure 1. (A) High resolution TEM (HRTEM; scale bar-5 nm), (1, 2) corresponding inverse fast 39 41

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Fourier transform (IFFT) images of Fe3O4-ZnS composite obtained following focusing on the 43

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Fe3O4 NP, which had size greater than 10 nm, so that 3.2 nm ZnS Qdots could easily be observed 4 45

simultaneously; (B) high resolution TEM (HRTEM; scale bar-5 nm) and (C) corresponding 46 48

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inverse fast Fourier transform (IFFT) images of the Fe3O4-ZnS composite obtained following 50

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focusing on another zone, where Fe3O4 NPs and ZnS Qdots were of similar sizes; (D) selected 51 52

area electron diffraction (SAED) pattern (scale bar: 5 nm-1) of the Fe3O4-ZnS composite 5

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(corresponding to the image in Figure 1B). 56 57 58 59 60 ACS Paragon Plus Environment

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Figure 2. (A) Photographs of the aqueous dispersion of SPION-QDC in (a) absence and (b) 49

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presence of an external magnetic field under (1) white and (2) UV light (365 nm). (B) UV-vis 51

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and (C) emission spectra of the aqueous dispersion of (a) Fe3O4 (pH-9.5; 52

ex-320

nm); (b) Fe3O4-

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ZnS (pH-6.8; 56

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ex-320

nm); and (c) SPION-QDC (pH-6.8;

ex-365

nm). (D) Schematic

representation of the formation of SPION-QDC composite. 57 58 59 60 ACS Paragon Plus Environment

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The aqueous dispersion of Fe3O4-ZnS composite upon complexation reaction with HQ (refer 5

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to SI) exhibited a strong green luminescent color (Figure 2A), following irraditaion with UV 6 7

(365 nm) light. This was in contrast to the as-synthesized Fe3O4-ZnS composite and Fe3O4 NPs, 10

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which showed no such emission (SI, Figure S3). On the other hand, dispersions of Fe3O4 NPs 12

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and Fe3O4-ZnS composite (following HQ treatment too) were dark and light brown color 13 14

respectively in daylight (SI, Figure S3 and Figure 2A). Importantly, the product of the reaction 17

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could be separated using a magnet (Figure 2A) and could again be redispersed in water with 19

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retention of luminescence (not shown). 20 21 23

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The UV-vis spectrum of the composite following complexation consisted of an excitonic peak 25

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at 320 nm (due to the Qdot) and a peak at 365 nm, assigned to ZnQ2 complex formed on the 27

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surface of the Qdot (Figure 2B).18-21 The luminescence spectrum of the Fe3O4-ZnS composite 30

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consisted of a broad emission centered at 440 nm (upon excitation at 320 nm) – which occurred 32

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possibly due to the coupling of surface defect states with the core state of the ZnS Qdots.26-27 On 3 34

the other hand, following complexation the emission peak at 440 nm disappeared and a new and 37

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intense emission peak appeared at 500 nm (Figure 2C). The excitation maximum for the peak at 39

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500 nm appeared at 365 nm (SI, Figure S4). The results are consistent with previous 40 41

observations of formation of ZnQ2 complex on the surface of ZnS Qdot.18-21 However, Fe3O4 4

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nanocrystals did not have any clear emission peak even in the presence of HQ, thus discounting 45 46

the possibility of the peak at 500 nm due to any product (associated with Fe) from the reaction 47 49

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(SI, Figure S5). It is to be mentioned here that the formed surface ZnQ2 complexes act as 51

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quencher of the Qdot emission and the green emission of the attached ZnQ2 complex to Qdot 52 54

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originates due to the electronic transition from the electron rich phenoxide ring (HOMO; highest 56

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occupied molecular orbital) to the electron deficient pyridyl ring (LUMO; lowest unoccupied 57 58 59 60 ACS Paragon Plus Environment

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molecular orbital) of HQ moiety of the surface attached ZnQ2 complexes.18-21 Overall, the results 5

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suggest that several ZnS nanocrystals grew on each Fe3O4 (although, considering the size 6 7

similarity of the crystal sizes smaller number of attached ZnS crystals per Fe3O4 particle cannot 10

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be ruled out); the complexation reaction led to the formation of ZnQ2 on the surface of the ZnS 12

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Qdots. Earlier results suggested the bonding of the complex with the dangling sulphide ions 13 15

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present on the surface, while the sixth coordinate may be occupied by H2O and the attached 17

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ZnQ2 complexes provide the chemical stability and solubilty to the composite.18-21 We define the 19

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new composite as SPION-QDC (SPION – Qdot – complex), the formation of which is 20 2

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schematically shown in Figure 2D. It is to be mentioned here that the optimum amount of HQ 24

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required for the reaction was calculated by monitoring the saturation in emission intensity at 500 25 26

nm (SI, Figure S6A). It was found to require 0.03 mM HQ for a 2.0 mL of Fe3O4-ZnS composite 29

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dispersion (with an absorbance value of 0.20-0.25 at 320 nm). That the luminescence at 500 nm 31

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was due to the formaton of a complex was further supported by the retention of emission 32 3

following centrifugation of the product and redispersion into the same medium (SI, Figure S6B). 36

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Furthermore, there was no significant change in pH of the reaction medium after complexation, 38

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which ruled out the effect of pH on the changes in the luminescence. 39 40 41

Fourier transform infrared (FTIR) spectroscopy results showed that SPION-QDC contained 4

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the functional groups corresponding to the octahedral ZnQ2 complexes, which were absent in 46

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Fe3O4-ZnS (SPION-Qdot) composite.18-21 The details are described in the SI, Figure S7. 47 48

Additionally, the elemental analysis, from atomic absorption spectroscopy (AAS), showed 51

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constancy of Fe:Zn content, thus indicating that there was no discernible depletion of metal ions 53

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from the composite due to complexation reaction (SI, Table S2). However, the changes in the 54 56

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zeta potential indicated modification of the SPION-Qdot surface following complexation (SI, 57 58 59 60 ACS Paragon Plus Environment

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Table S1). Also, the preservation of morphological characteristics of the Fe3O4-ZnS composite 5

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following complexation with HQ was confirmed by XRD, TEM and SAED analyses (SI, Figure 7

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S8-S9). 21-25 9

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Figure 3. (A) Photostability ( 46

ex-365

nm) - under continuous irradiation of light - of (a) SPION-

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QDC (in water;

em-500

nm) and (b) rhodamine 6G organic dye (in ethanol;

em-570

nm). (B)

Luminescence (

ex-365

nm) stability of SPION-QDC composite in human blood serum as

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measured at different time intervals; Inset- emission spectrum ( 5

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ex-365

nm) of only human

blood serum. (C) M–H hysteresis curves of the solid particles of (a) Fe3O4, (b) Fe3O4-ZnS 56 57 58 59 60 ACS Paragon Plus Environment

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(SPION-Qdot), and (c) SPION-QDC. (D) MTT based cell viability assay of HeLa cells after 24 h 5

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treatment with varying concentrations of SPION-QDC composite. 6 7 8

The as-synthesized Fe3O4-ZnS (SPION-Qdot) composite had a photoluminescence QY of 0.6 1

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% (at 320 nm excitation). On the other hand, the SPION-QDC resulted in a QY of 5.9 % (with 13

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excitation at 365 nm) and 0.8 % (with excitation at 320 nm, SI, Table S3). The significant 14 16

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enhancement of QY and the red-shift of the excitation maximum, due to the formation of 18

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complex on the surface of Qdot is expected to make the SPION-QDC more attractive for 20

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bioimagning, especially against the background of strong cellular autofluorescence.13, 21

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Additionally, the average excited-state lifetime of the SPION-QDC was measured to be 12.54 ns, 25

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also enhancing their potential for bioimaging (SI, Figure S10 and Table S4).18 Furthermore, the 26 27

HQ treated Fe3O4-ZnS composite was found 5 times more photostable than an organic dye (here 30

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rhodamine 6G). For example, the decrease in luminescence intensity for HQ treated Fe3O4-ZnS 32

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and rhodamine 6G were observed to be 0.003 and 0.014% per sec (Figure 3A and SI, Table S5), 3 35

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supporting the superiority of the composite. Moreover, the stability of the luminescence (at 37

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365 nm and 38

em-500

ex-

nm) of the SPION-QDC in human blood serum (as measured for 24 h)

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indicated its clinical application potential (Figure 3B). Additionally, the zeta potential of the 42

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aqueous dispersion of the SPION-QDC was measured to be –25.5 ± 0.6 mV, indicating its 4

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colloidal stability in water, which is required for biological applications (SI, Table S1).18-21 45 47

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Furthermore, the stability and long-term storage in solid forms were confirmed by preservation 49

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of the bright green fluorescence, even after 15 days, as observed under fluorescence microscope 50 51

(SI, Figure S11). 52 53 5

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The vibrating sample magnetometric (VSM) analysis of Fe3O4, Fe3O4-ZnS and SPION-QDC 57

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showed magnetization saturation values of 26.4, 3.88 and 3.81 emu/g, respectively and the 58 59 60 ACS Paragon Plus Environment

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measurements supported their super-paramagnetic nature at room temperature (Figure 3C and SI, 5

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Table S6).3, 14-15 The decrease in magnetic saturation of Fe3O4-ZnS composite compared to Fe3O4 6 8

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NPs (per unit weight) may be due to the diamagnetic ZnS nanocrystals formed surrounding the 10

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Fe3O4 NPs.14 Additionally, the treatment of HQ to Fe3O4-ZnS composite did not significantly 1 12

change its magnetic saturation. Furthermore, the SPION-QDC showed magnetic saturation value 13 14

of 3.81, which is sufficient for magnet guided imaging applications.3 The MTT based cell 17

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viability assay, performed using different concentrations (with a maximum 0.36 mg/mL) of the 19

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SPION-QDC, showed that more than 90% of the cervical cancer HeLa cells were viable after 24 20 2

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h of incubation (Figure 3D). This clearly indicated that the composite was nontoxic to the 24

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mammalian cells and thus makes it suitable for biological applications. 25 27

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Additionally, the SPION-QDC composite exhibited bright green luminescence under confocal 28 30

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microscope, using 405 nm diode laser (Figure 4A), while no such green fluorescence was 32

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observed in control HeLa cells (SI, Figure S12). Importantly, the magnetic property of the 34

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composite offered the opportunity for labelling of cells with spatial control, by using external 35 37

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magnetic field. In order to achieve this, HeLa cells were cultured onto two cover slips - placed 39

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inside a cell culture Petri plate and then were incubated with the SPION-QDC composite for 4 h. 40 41

A small magnet was placed below the Petri plate and closer to one of the cover slips (Figure 4B). 4

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When viewed using a microscope, strong green luminescence was observed for the cells on the 46

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cover slip which was near to magnet (Figure 4B; right panel), while the cells on the other one 47 48

(away from the magnet) showed negligible luminescence (Figure 4B; left panel). On the other 51

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hand, in the absence of any magnet strong green luminescence from the cells attached to both the 53

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cover slips could be observed (SI, Figure S13). This means that the magnetic property of the 54 5 56 57 58 59 60 ACS Paragon Plus Environment

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composite could be used to direct the same for cell labelling with spatial control. This may auger 5

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well for targeted cellular imaging and drug delivery. 6 7 8 9 10 1 12 13 14 15 16 17 18 19 20 21 2 23 24 25 26 27 28 29 30 31 32 3 34 35 36 37 38 39 40 41 42 43 4 45 46 47 48 49 50 52

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Figure 4. (A) Confocal laser scanning microscopic images (scale bar - 25 m) of HeLa cells 53 5

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following 4 h incubation with SPION-QDC. (B) Fluorescence microscopic images (scale bar 56 57 58 59 60 ACS Paragon Plus Environment

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100 m) of HeLa cells – which were cultured on two cover slips placed inside a Petri plate and 5

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incubated with SPION-QDC for 4 h. A magnet was placed below one cover slip during 6 8

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incubation. The images are for cells on the cover slip (I) away from the external magnet (left 10

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panel) and (II) the other one closer to magnet (right panel). The image for the set-up is in the 12

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second column. 13 14 16

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In conclusion, a new composite has been developed based on the complexation reaction of 18

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Fe3O4-ZnS composite nanocrystals with HQ, leading to the formation of luminescent ZnQ2 on 19 20

the 23

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surface

of

the

Qdot.

The

high

photoluminescence

QY,

photo-stability

and

superparamgnetism of the SPION-QDC composite were used to demonstrate cellular labeling 25

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with spatial control using an external magnetic field. Furthermore, the luminescence stability in 26 27

human blood serum, non-toxicity and magnet guided specific cell imaging properties of the 30

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biocompatible SPION-QDC would make it a suitable candidate for targeted bioimaging. 32

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Moreover, the complexation based QY enhancement of multifunctional materials can be 3 35

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expected to bring new excitement in biodiagnostics in near future. 36 38

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ASSOCIATED CONTENT 39 40 41

Supporting Information (SI). Experimental details, synthesis and characterization of Fe3O4 4

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nanoparticles, Fe3O4-ZnS (SPION-Qdot) composite, HQ treated Fe3O4-ZnS (SPION-QDC) 46

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composite, fluorescence images of HeLa cells incubated with SPION-QDC composite (in 47 48

absence of magnetic field), Figure S1-S14 and Table S1-S6. This material is available free of 51

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charge via the Internet at http://pubs.acs.org. 52 53 54 5 56 57 58 59 60 ACS Paragon Plus Environment

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AUTHOR INFORMATION 5

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Corresponding Author. 6 7 8

*Email: [email protected] 10

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ACKNOWLEDGMENT 13 15

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We thank the Department of Electronics and Information Technology (No. 5(9)/2012-NANO 16 17

(Vol. II)), Government of India, for fund. Assistances from CIF, IIT Guwahati, Shilaj Roy, 20

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Sabyasachi Pramanik, Dr. Anupam Banerjee, Dr. Subhojit Das, Amaresh Kumar Sahoo, Partha 2

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Maity and Puspal Mukherjee are acknowledged. S.B. and R. K. thank the CSIR for fellowships 23 24

(09/731(0115)/2011-EMR-I, 09/731(0105)/2010-EMR-I). 26

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Table of Contents Graphic 4 6

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A new biocompatible magnetofluorescent nanocomposite, based on surface complexation 7 8

reaction, for magnet driven cellular imaging is described here. 10

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Surface Complexation-Based Biocompatible Magnetofluorescent

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