Article Cite This: Chem. Mater. 2018, 30, 775−780
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Magneto-Fluorescent Yolk−Shell Nanoparticles Sandip K. Pahari,† Shunit Olszakier,†,‡ Itamar Kahn,‡ and Lilac Amirav*,† †
Schulich Faculty of Chemistry and ‡The Ruth and Bruce Rappaport Faculty of Medicine, Technion−Israel Institute of Technology, Haifa 32000, Israel S Supporting Information *
ABSTRACT: We present a new strategy for the fabrication of magneto-fluorescent nanoparticles designed for bimodal imaging. These hybrid nanostructures comprise an optically active semiconductor nanoparticle quantum dot core with tunable fluorescence, encapsulated within a hollow paramagnetic iron oxide shell that serves as an MRI contrast agent. The yolk−shell morphology enables incorporation of the semiconductor and magnetic domains into a single structure, while avoiding direct contact between them, which typically results in quenching of the desired optical fluorescence. We successfully demonstrate utilization of the ultrasmall (15 nm hydrodynamic size) magneto-fluorescent CdSe@CdS@Hollow-Fe2O3 nanoparticles for multimodal imaging of cells at the intracellular level.
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INTRODUCTION Designing effective nanoparticles that can passively or actively label fine biological structures in various functional states is a central goal of medicine-oriented nanotechnology development.1,2 Because each established imaging modality has its own drawbacks, integration of different techniques into multimodal imaging can provide complementary information. Hence, fabrication of materials that simultaneously contain more than one functional component, and may serve as bifunctional markers, is highly desirable.3−5 Magnetic nanoparticles may serve as markers for magnetic resonance imaging (MRI) and may be utilized for manipulation and direction of cells toward specific sites.6,7 Integrating the magnetic particles with other functional components into one single entity will result in hybrid nanostructures that exhibit several features synergistically. In particular, magneto-fluorescent particles have been recognized as an emerging class of materials that have potential in advanced applications.6−9 Here, quantum dots are considered preferable fluorescent components due to their high temporal stability and resistance to photobleaching compared with dyes.10 Typical synthetic strategies for the fabrication of such magneto-fluorescent materials include heterostructure crystal growth, coencapsulation into organic structures (for example, oil droplet, lipid micelle, and block copolymer) or inorganic materials (for example, silica), template-based synthesis via either chemical bonding or physical attachment, or conjugation of separate nanoconstructs.8,11−21 The performance of such magneto-fluorescent nanoparticles will strongly depend on their size, which must be tunable, the magnetic and optical signal, long-term stability, and versatility of surface functionality. In particular, care must be taken to prevent undesirable © 2017 American Chemical Society
interactions within the hybrid that could abrogate the respective properties. For example, different reports reveal that direct contact between the semiconductor and magnetic domain, typical of traditional heterodimer structures, can lead to strong electronic coupling, diminishing the desired optical fluorescence. This can be minimized or prevented entirely if effective separation is achieved.22−25 Recently, Bawendi and co-workers26 presented colloidal superstructures comprised of close-packed magnetic nanoparticle cores that were fully surrounded by a shell of fluorescent quantum dots. These silica-coated core−shell structured supernanoparticles exhibit high magnetic content and fluorophore loading (with about 2000 nanocrystals), with an overall diameter of about 100 nm.26 Weller and co-workers reported on polystyrene coated iron oxide and quantum dot/ quantum rod nanoparticles, where the fluorescence and magnetism of the separate components were preserved, and with tuned diameters ranging from 74 to 150 nm (based on DLS).24 Although these few recently developed hybrids have been successful in combining the magnetic and fluorescent components into functional multimodal markers, their diameters might restrict imaging of the intracellular environment. Size was found to be a critical criterion that decides the exact mechanism by which nanomaterial gets internalized into the cell, with influence on the cellular uptake efficiency and kinetics, and implications on the subcellular distribution, saturation concentrations, and toxicity.27−31 Imaging of the Received: October 9, 2017 Revised: December 14, 2017 Published: December 22, 2017 775
DOI: 10.1021/acs.chemmater.7b04253 Chem. Mater. 2018, 30, 775−780
Article
Chemistry of Materials intracellular environment is necessary if we were to fully characterize brain structural and functional integrity in health and disease, where compromising events occur at this level. Hence, the synthetic strategy of choice is critical for appropriate functionality of the hybrid structure and its relevance to the desired application. Here we present a general strategy and a promising novel hybrid structure that comprises a florescent quantum dot (QD) core encapsulated inside a hollow magnetic shell, which provides the MRI contrast agent. This architecture results in an ultrasmall magneto-fluorescent nanoparticles (on the order of 10 nm particle size, and 15 nm hydrodynamic size), high level of tunability with respect to size, composition, and surface functionalization, and compatibility with multimodal (magnetic resonance and optical) imaging of biological cells at the intracellular level in vtiro and in vivo. These structures offer a novel platform for structural intracellular labeling in vivo with significant applications in noninvasive disease-related diagnostic imaging.
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RESULTS AND DISCUSSION Construction of nanoparticles of increasing chemical complexity is now facilitated via a series of sequential colloidal synthetic procedures, with separately optimized steps, in a manner resembling molecular synthesis. Here, the production of the magneto fluorescent hybrid structures comprises four stages, as illustrated in Figure 1. The reaction commences with the wellestablished synthesis of a CdSe core (illustrated in red), followed by the formation of CdS shell (illustrated in yellow), for improved fluorescence. The CdSe@CdS QD nanoparticles from a representative synthesis are seen in the TEM micrograph in Figure 1B. During CdS shell growth, the average particle diameter increased from 3.2 nm for the CdSe core to 4.8 nm, which corresponds to shell thickness of 0.8 nm. These values are consistent with the optical measurements, which also demonstrate relatively narrow size distribution. Note that the CdSe core and CdS shell thickness are tunable and their synthesis is well-established in the literature.32 In the following step, metallic iron (illustrated in gray) is deposited on the surface of the purified CdSe@CdS core−shell nanoparticles via thermal decomposition of Fe(CO)5 in the presence of oleylamine. The deposition of metallic iron results with spherical hybrid nanoparticles (i.e., formation of a QD@ Fe core−shell structure) with an average diameter of 7.4 nm. The Fe shell can be clearly seen in the TEM micrograph (Figure 1C) due to its lower contrast. Hollow nanocrystals are formed with a mechanism analogous to void formation in the Kirkendall effect, where the mutual diffusion rates of two components in a diffusion couple differ by a considerable amount.33,34 Nested nanoparticles, also referred to as “yolk−shell” structures, are created when the starting metallic particle to be oxidized encapsulates another material, as is the case here. Hence, controlled oxidation of the iron with O2/Ar mixture resulted with formation of hollow Fe2O3 iron oxide shell (also illustrated in gray), encapsulating the CdSe@ CdS QD. After complete oxidation of the metallic iron shell the structures outer diameter increased to 9.9 nm, while the average CdSe@CdS core size remained unchanged. Finally, the CdSe@ CdS@hollow-Fe2O3 hybrids were functionalized with Tiron (disodium 4,5-dihydroxy-1,3-benzenedisulfonate)35 for their incorporation to cells, resulting in stable and well-suspended water-dispersed nanoparticles of 14−16 nm hydrodynamic particle size (determined by dynamic laser scattering analysis).
Figure 1. (A) Illustration of the multistep sequential synthesis producing the magneto-fluorescent hybrid structures. (B−E) TEM micrographs of the building blocks from which the magneto fluorescent structures are composed: (B) CdSe@CdS fluorescent core. (C) Intermediate step with metallic iron shell. (D) Complete CdSe@CdS@hollow-Fe2O3 nanostructure. (E) Enlarged image of D.
The capping ligand of the fluorescent QD core was found to affect the quality of iron deposition on the surface, and hence the morphology of the yolk−shell system. Various capping ligands were examined including trioctylphosphine oxide (TOPO), octadecyl ammine, and oleylamine. Oleylaminecapped nanoparticles resulted with the highest quality structure. Alternative synthetic procedures that were examined resulted with poor iron deposition on the core, or aggregation. We examined various CdSe core sizes ranging from 2.7 to 3.9 nm, with corresponding CdSe@CdS size range of 3.2 to 5.2 nm. Variations in the iron oxide shell thickness were not examined. The gap between the internal QD core and surrounding Fe2O3 hollow shell is clearly seen in the high-angle annular dark-field (HADDF) micrograph in Figure 2A. X-ray diffraction (XRD) confirmed the presence of wurtzite CdSe@CdS core, and γ-Fe2O3, that seems to be polycrystalline. X-ray photoelectron spectroscopy (XPS) analysis (Figure S7) validates presence of γ-Fe2O3. Though we cannot fully eliminate potential presence of small contribution from Fe3O4, we note that this phase will likely oxidize further in the cell environment. Composition is also confirmed by elemental analysis from an energy-dispersive X-ray spectroscopy (EDS) line scan preformed over the hybrid structure, as indicated by the red line in Figure 2C. Elemental analysis taken at two different positions along the particle profile clearly indicates the 776
DOI: 10.1021/acs.chemmater.7b04253 Chem. Mater. 2018, 30, 775−780
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Figure 2. (A) HAADF micrograph of core CdSe@CdS sphere (white) embedded inside a hollow iron oxide shell (gray); (B) XRD pattern of CdSe, CdSe@CdS and CdSe@CdS@Fe2O3 along with indexed pattern assignments; (C) distribution of components obtained by elemental line-scan analysis using EDS/STEM (along the red arrow over the inset). I and II elemental analysis taken at different positions along the particle profile.
presence of Cd, Se, and S above the core, and only Fe and O above the external side of the hybrid structure. The optical and magnetic properties of our CdSe@CdS@ Fe2O3 nanoparticles are visually demonstrated in Figure 3B. The magnetic nature of the overall structure was evident immediately after its production and was utilized for cleaning the nanoparticles in lieu of precipitation in a centrifuge. The particles were easily collected by a strong hand-held magnet and showed fluoresce under ultraviolet light. The absorption of the separate building blocks of the hybrid along with that of the complete structure are presented in Figure 3A. The fluorescent spectra of the iron oxide-coated CdSe@CdS QD has identical peak maxima to that of the pure QD, indicating that the average core size was preserved despite the oxidation procedure (though size distribution has broadened). A comparison of the two spectra is presented in Figure S2. Fluoresce quantum efficiency was typically found to be around 16% (measured in buffered aqueous medium), which was sufficient for imaging of 3D cell culture under optical microscope, as seen in Figure 3C−F. The wide-field optical microscopy images show a drop of 3D cell culture derived from mouse cortical tissue in Matrigel scaffold, on a 32 mm cell culture dish. The cells were taken from embryonic Sprague− Dawley rats, 13 days in vitro and 6 days after introducing the CdSe@CdS@Fe2O3 nanoparticle markers to the culture. Full experimental details regarding the cells culturing are included in the Supporting Information. A bright-field channel permits recognition of cells that appear to be darker than the background (Matrigel is transparent). A bright-field image (Figure 3C) displaying all cells in the drop is presented alongside a red fluorescence image (Figure 3D), under optical excitation at 548 nm, and through a Rhodamine filter. These images are merged together in Figure 3E, which clearly indicates the florescence signal produced via the magnetofluorescent CdSe@CdS@Fe2O3 that are embedded in the cell
Figure 3. (A) Absorption spectra of hollow Fe2O3 (black), CdSe@ CdS QD (red) and CdSe@CdS@hollow Fe2O3 (blue) along with the hybrid structure’s photoluminescence (PL) spectra (purple). (B) Optical and magnetic properties of iron oxide-QD core−shell. The CdSe@CdS@Fe2O3 were easily collected by a strong hand-held magnet and show fluoresce under ultraviolet light. Optical microscopy. Optical microscopy. (C−F) Microscopy images showing a 3D cell culture, 13 days in vitro (DIV) and 6 days after introducing to the CdSe@CdS@Fe2O3. (C) Bright-field image displaying all cells, (D) red fluorescence image indicating the QD in the nanoparticles, which are exclusively localized using a Rhodamine filter, (E) the merged image, (F) enlargement of (E) showing few individual cells. The blue spot (Hoechst stain) demarcate the nuclei of the cells. The close proximity of the nanoparticles (red spots) to the nuclei suggests that the nanoparticles are localized inside the cells.
culture. An enlarged image, presented in Figure 3F, shows a few individual cells. Hoechst stain (blue) was used to identify the nuclei of the cells. The close proximity of red fluorescent nanoparticles (620 nm peak) to the nuclei suggests that the nanoparticles are likely to be localized inside the cells. To verify nanoparticle cellular uptake, we traced their presence from 24 h to 12 days after they were first introduced to the cell culture, using both fluorescent microscopy and MRI. The cultures were washed once every 2 days. Figure 3F validates the nanoparticles uptake in the cells after 6 days. Data for longer periods (not shown) confirm uptake for at least 12 days. This was the longest period examined, because of the fact that the cell culture is not viable after about 14 days. The relatively high fluorescent quantum yield of the hybrid system suggests that the gap between iron oxide shell and CdSe@CdS core in the nested morphology restricts charge or 777
DOI: 10.1021/acs.chemmater.7b04253 Chem. Mater. 2018, 30, 775−780
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overall size, surface characteristics and magnetic properties. CdTe may be pushed further into the red by altering its size, thus minimizing the spectral overlap between the absorption of the core and that of the hollow shell. The functionality of the hybrid nested nanoparticles as markers for MRI is demonstrated in Figure 5A, which reveals a
energy transfer between the two materials. To examine this suggestion, we monitored the fluorescence of the encapsulated CdSe@CdS core throughout the oxidation process of the solid iron into the hollow iron oxide shell (Figure S1). We found that for the initial metallic Fe-coated CdSe@CdS, where iron is in direct contact with the core, the fluorescent quantum yield is negligble. The fluorescence quantum yield improved progressively in direct correlation with the oxidation process of the Fe shell, resulting from gradual separation of the CdSe@CdS core from the shell and the formation of a physical gap. To further confirm our hypothesis regarding the role of the gap, we compared the fluorescent quantum yield of a CdSe@hollow Fe2O3 nested structure to that of CdSe QD grown directly on top of an iron oxide hollow sphere. While the nested structure resulted in relatively weak fluorescence, it was not fully quenched, in contrast to the structure with direct contact between the CdSe and iron oxide, which resulted in a barely measurable signal (Figure S5). This is despite the fact that each Fe2O3 hollow nanoparticle was decorated with a few CdSe QDs, as seen in Figure 4A.
Figure 5. (A) Upper panel: MRI phantoms. Lower panel: Plot of transverse relativity R2 (1/T2) versus iron concentration, R2 relaxation rates as a function of iron concentration in CdSe@CdS@ Fe2O3. The linear correlation suggests good MRI sensitivity toward the nanoparticles. (B) Magnetic resonance (MR) T2-weighted (left) and R2 mapping (right) cell imaging. Color-scale quantitative map demonstrating R2 relaxation time for a drop of 3D cell culture before and after the introduction of CdSe@CdS@Fe3O2 bifunctional markers.
Figure 4. (A) TEM micrograph of CdSe nanoparticles grown directly on top of hollow Fe2O3 nano sphere; (B) CdSe-Fe2O3 complex absorption, and photoluminescence spectra enhanced 20-fold, along with corresponding spectra of CdTe@CdS@hollow Fe2O3; (C, D) TEM micrographs of CdTe@CdS@hollow Fe2O3.
The absorption spectra of hollow iron oxide and pure CdSe@CdS (Figure 3A) revels that the iron oxide shell strongly absorbs in the same optical wavelength as the QD core. This overlap limits the actual intensity that can excite the core, and to some extent also the detected fluorescence. Consequently, it restricts the optimal quantum yield that may be obtained with this particular composition. It is noteworthy that the morphology of a fluorescent core nested inside a hollow magnetic shell is general and flexible with regards to the composition of the separate components. To conceptually demonstrate this flexibility, we synthesized a similar hybrid structure with a CdTe@CdS as the fluorescent core (Figure 4C, D). Note that the core may be altered with no effect on
linear correlation between the contrast enhancement efficiency (transverse relativity R2 = 1/T2) and nanoparticle concentration. This indicates good MRI sensitivity toward the nanoparticles. The T2-weighted MR contrast is enhanced with relaxivity of r2 = 304 mM−1 S−1 at 9.4T. This relaxivity is in good agreement with the literature,26,36 and enhanced compared with commercial contrast agents such as SHU555C (r2* = 69mM−1 S−1), or Fe3O4 NPs (r2* = 26.8 mM−1 S−1). Similar exotic hollow Fe2O3 nanostructures were recently explored for their potential use in nanomedicine as agents for controlled drug delivery.36−38 Of significance is the fact that the hollow magnetic nanoparticles were reported to exhibit an 778
DOI: 10.1021/acs.chemmater.7b04253 Chem. Mater. 2018, 30, 775−780
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improved MR contrast enhancement, arguably due to the larger interface between the iron oxide and water phase. As noted above, this morphology is flexible with regards to the composition of the individual components, and in principle the magnetic shell may also be altered, tuned, and optimized. Once we confirmed that the hybrid nanoparticles serve as contrast enhancement markers, we examined with MRI the 3D cell culture that was imaged via optical microscope. Figure 5B shows the MR detected image, with darker areas that presumably correspond to higher concentration of CdSe@ CdS@hollow Fe2O3 nanoparticles. The pattern observed in the MRI is in good agreement with that obtained from the cells using the optical microscope (refer to Figure S9 for an overlap of the images from the different methodologies). We conclude that our novel CdSe@CdS@hollow Fe2O3 nanoparticles serve as bifunctional markers for both optical microscopy and MRI. We estimated the biocompatibility of our hybrid nanoparticles by determination of cell viability via XTT assay method in both neuronal primary culture, and HeLa cells (Figure S8). In HeLa cells no noticeable degradation in cell viability was obtained throughout the examined nanoparticle concentration range. In the neuronal primary culture, the magneto-fluorescent nanoparticles show low toxicity up to a concentration of 20 μg/mLs. In this low concentration range, the viability percentage was not fully consistent with nanoparticle concentration, suggesting that another parameter is affecting the cells viability. High toxicity was obtained for concentrations above 50 μg/mL, which are considerably higher than the required labeling concentration. We note that although at the moment our markers contain Cd in the core composition, it is fully encapsulated and is separated from the intracellular environment. The encapsulation of the core might prove to be essential for biocompatibility and toxicity.
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CONCLUSIONS
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ASSOCIATED CONTENT
Article
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Lilac Amirav: 0000-0002-0539-0488 Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was carried out in the framework of the Russell Berrie Nanotechnology Institute (RBNI) and the Lorry I. Lokey Interdisciplinary Center for Life Sciences & Engineering at the Technion. Dr. Pahari expresses his gratitude to Israel Council for Higher Education for the PBC postdoctoral fellowship. We thank Dr. Yaron Kauffmann for his assistance with HAADF and EDS characterization. We are grateful to Prof. Shai Berlin for his valuable advice and help with the fluorescent validations in vitro and Dr. Alexandra Kavushansky and Dr. Ronit Heinrich for their valuable contribution to this work.
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In summary, a novel general strategy for the fabrication of ultrasmall (15 nm hydrodynamic size) magneto-fluorescent nanoparticles, designed for multimodal imaging of cells at the intracellular level, was presented. These hybrid nanostructures are comprised of an optically active semiconductor nanoparticle quantum dot core with tunable fluorescence, encapsulated within a hollow paramagnetic iron oxide shell that serves as an MRI contrast agent. The yolk−shell morphology prevents undesirable interactions within the hybrid that could abrogate the respective properties of the semiconductor and magnetic domains. Furthermore, this architecture offers high level of tunability with respect to size, composition, and surface functionalization. The resulting hybrid nanoparticles present a unique platform for structural intracellular labeling in vtiro and in vivo with significant applications in noninvasive diseaserelated diagnostic imaging.
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemmater.7b04253. Detailed information on the synthesis and sample characterization with information on the imaging methodologies utilized (PDF) 779
DOI: 10.1021/acs.chemmater.7b04253 Chem. Mater. 2018, 30, 775−780
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