Supramolecular Self-Assembly Bioinspired Synthesis of Luminescent

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Supramolecular self-assembly bioinspired synthesis of luminescent gold nanocluster-embedded peptide nanofibers for temperature sensing and cellular imaging Wensi Zhang, Dongmei Lin, Haixia Wang, Jingfeng Li, Gerd Ulrich Nienhaus, Zhiqiang Su, Gang Wei, and Li Shang Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.7b00312 • Publication Date (Web): 08 Aug 2017 Downloaded from http://pubs.acs.org on August 12, 2017

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

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Bioconjugate Chemistry

Supramolecular self-assembly bioinspired synthesis of luminescent gold nanocluster-embedded peptide nanofibers for temperature sensing and cellular imaging Wensi Zhanga, Dongmei Lina, Haixia Wangb, Jingfeng Lic, Gerd Ulrich Nienhausb,d,e, Zhiqiang Sua*, Gang Weic*, and Li Shangf* a State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China. E-mail: [email protected] b Institute of Applied Physics, Karlsruhe Institute of Technology, D-76131 Karlsruhe, Germany c Faculty of Production Engineering, University of Bremen D-28359 Bremen, Germany. E-mail: [email protected] d Institute of Nanotechnology and Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany e Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801 f Center for Nano Energy Materials, School of Materials Science and Engineering, Northwestern Polytechnical University, Xi'an 710072, China. E-mail: [email protected] KEYWORDS supramolecular self-assembly; bioinspiration; gold nanoclusters; peptide nanofibers; temperature sensing; cell imaging

ABSTRACT: Metal nanoclusters (NCs) hold great potential as novel luminescent nanomaterials in many applications, while synthesis of highly luminescent metal NCs still remains challenging. In this work, we report self-assembling peptides as a novel bioinspired scaffold capable of significantly enhancing the luminescence efficiency of gold nanoclusters (AuNCs). The resulting AuNCs capped with motif-designed peptides can self-assemble to form nanofiber structures, in which the luminescence of AuNCs is enhanced by nearly 70-fold, with 21.3% quantum yield. The underlying mechanism responsible for the luminescence enhancement has been thoroughly investigated by the combined use of different spectroscopic and microscopic techniques. The resultant highly luminescent AuNC-decorated protein nanofibers exhibit physicochemical properties that are advantageous for biological applications. As a proof of concept, we demonstrate the use of these nanoconstructs as fluorescent thermometers and for imaging living cells, both showing very promising results.

Metal nanoclusters (NCs), consisting of a few to hundreds of atoms, are an important type of materials bridging molecular and bulk metal electronic structures.(1, 2) One of the most striking features of metal materials in this size range is the emergence of strong photoluminescence, which makes them attractive for applications such as biological imaging, fluorescent sensing, photoelectrocatalysis and light-emitting devices.(3-7) Over the past decade, many different types of luminescent metal NCs have been developed, mainly including Au, Ag, Cu and Pt. Among these, AuNCs are less toxic, more chemically stable and easier to synthesize, thus considered as more promising for biological and biomedical applications.(8-10) However, a drawback that limits further application of AuNCs as luminescent probes is their relatively low quantum yield compared with organic dyes and fluorescent proteins. Despite great efforts to develop new strategies,(11-

14)

creating AuNCs with enhanced luminescence still remains challenging.

Herein, we report a new approach to boost the luminescence of AuNCs by deploying self-assembled peptide nanostructures as ‘bio-amplifiers’. Molecular selfassembly is a powerful way to construct novel supramolecular architectures.(15, 16) In nature, biomolecules, including peptides, proteins and lipids, interact and selforganize to form well-defined functional structures. Inspired by these natural self-assembly processes, materials chemists have attempted to fabricate versatile advanced materials through self-assembly of biomolecules.(17, 18) In particular, peptides have been recognized as attractive building blocks for creating self-assembling nanostructures for biological applications due to their inherent biocompatibility and biodegradability, chemical design versatility as well as their ability to adopt specific secondary structures.(19-21) In this work, we found that self-

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assembling peptides can provide a novel bioinspired scaffold capable of significantly enhancing the luminescence efficiency of AuNCs. The resulting AuNCs capped with motif-designed peptides can self-assemble to form nanofiber structures, in which the luminescence of AuNCs is enhanced by nearly 70-fold. The resultant highly luminescent AuNC-decorated peptide nanofibers exhibit physicochemical properties that are advantageous for biological applications. As a proof of concept, we demonstrate the use of these nanoconstructs as fluorescent thermometers as well as for bioimaging, both showing very promising results.

Scheme 1 Schematic illustration of the sequence of (a) the designed peptide structure and (b) the procedure for the two-step synthesis of peptide nanofiber (PNF)-AuNCs. As shown in Scheme 1, a motif-designed 28-mer peptide molecule with a symmetric amino acid sequence of RGDAEAKAEAKCCYYCCAEAKAEAKRGD was employed as a multi-functional template for constructing PNFAuNC suprastructures. In this sequence, domain 1 (RGD) possesses a relatively high binding affinity towards integrin-rich tumor cells;(22, 23) domain 2 (AEAKAEAK) consists of alternating hydrophobic and hydrophilic residues that assume beta-sheet secondary structure and aggregate into highly water-soluble fibril architectures.(24) Domain 3 (CCY) can reduce Au3+ ions into clusters via the phenolic group of tyrosine (Y) and capture the formed AuNCs with the -SH group of cysteine (C).(25) In a first step, we synthesized peptide-stabilized AuNCs (peptide-AuNCs) by utilizing the CCY domain-biomimetic reduction of AuCl4– ions to AuNCs. Subsequently, the peptide-AuNCs undergo controlled supramolecular self-assembly to form PNF-AuNCs.

Figure 1 Typical HRTEM and AFM images of (a-c) peptideAuNCs and (d-f) PNF-AuNCs. The inset in a shows diameter distribution statistics of peptide-AuNC based on HRTEM images, and the HRTEM of PNF-AuNCs with an enlarged region shown in the inset. The height of selected field in figure b and e are displayed in c and f, respectively.

The morphology and size of the peptide-AuNCs was characterized by high-resolution transmission electron microscopy (HRTEM) and atomic force microscopy (AFM). The as-obtained AuNCs are well dispersed and possess a narrow size distribution (Figure 1a), with an average diameter of (1.8 ± 0.2) nm. Preliminary experiments confirmed that our designed peptides can indeed self-assemble and form fibrous structures after incubating in an ethanol/water system (3/4, v/v) at 37°C for 5 days as expected (Figure S1, ESI). Interestingly, peptide-AuNCs still preserve the unique ability of PNF forming peptide nanofibers under similar self-assembly conditions as for the peptide (ethanol/water = 3/4, v/v; 37 °C; 5 days). Formation of fibrous structures with typical lengths over a few 100 nm and homogenously distributed Au particles are observed in the TEM image (Figure 1c). Notably, the size of the Au particles in the PNF structures was (3.6 ± 0.9) nm, much larger than that of the peptide-AuNCs before PNF assembly. The size change of the AuNCs upon PNF formation was further supported by AFM (Figure 1b, c, e and f), where the average size of Au particles also significantly increased after peptide self-assembly. The height of AuNCs measured by AFM is smaller than the one measured in TEM, which is possibly due to the PNFAuNCs undergoing tapping forces during AFM probing. Apparently, the hydrophobic force, controlled by the concentration of ethanol, drives the AEAKAEAK domains to the ordered organization of peptide-AuNCs to a fibrous structure.(26) The size distribution of PNF-AuNCs was measured by dynamic light scattering (DLS) technique. Result reveals that those nanofibers possess a wide dis-


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persion with a Z-average length of 575.4 nm, polydispersity index: 0.796 (Figure S10 and Table S2), which is in accord with the TEM and AFM morphology of PNF-AuNCs.

Figure 2 Optical spectroscopy and XPS characterization of peptide-AuNCs and PNF-AuNCs. (a) Absorption spectra of PNF-AuNCs in aqueous solution. The inset shows images of as-prepared PNF-AuNC solution under ambient light (left) and UV illumination (365 nm, right). (b) Luminescence excitation (black, emission at 660 nm), emission spectra of peptide-AuNCs (blue, amplified by 10-fold for visualization) and PNF-AuNCs (red) aqueous solution upon excitation at 480 nm. XPS spectra showing photoemission of (c) Au and (d) S atoms before (black) and after (red) assembly.

The optical absorption spectrum of PNF-AuNCs in aqueous solution is essentially featureless in the visible range, as is the case for peptide-AuNCs prior to assembly (Figure 2a). The absence of a strong plasmon resonance peak near 520 nm is characteristic of metal particles with less than 2 nm in diameter.(3, 27) The aqueous solution of as-prepared PNF-AuNCs is almost colorless at ambient light but displays strong red luminescence under UV lamp illumination (365 nm, inset in Figure 2a). The emission spectra show an intense emission band centered on 650 nm upon excitation at 480 nm (Figure 2b). The emission spectrum stays essentially constant upon excitation wavelength variation from 405 nm to 510 nm (Figure S2, ESI). Remarkably, the luminescence intensity of PNFAuNCs is enhanced by nearly 70-fold compared with that of peptide-AuNCs, whereas the peak emission wavelength of peptide-AuNCs remains identical upon formation of PNF structures. Since the emission wavelength of noble metal NCs strongly depends on their core sizes,(28) this result implies that the core size does not change during this process. Consequently, the apparent size increase of AuNCs in the PNF structure observed by TEM is the result of local clustering of several individual AuNCs upon peptide assembly, giving rise to an aggregation induced enhancement of the luminescence of AuNCs.(29, 30) The quantum yield (QY) of PNF-AuNCs has been measured and determined to be 21.3±1.8%, by using carboxytetra-

methylrhodamine (68% in water solution) as the reference. Previous studies revealed that the fluorescence of the thiol-Au system stems from the Au(0) core and from Au(I)-S complexes.(31) It mainly comes from the charge transfer from the S to the Au core. To further elucidate the mechanism underlying the enhanced luminescence of peptide-AuNCs after self-assembly, we designed another similar but shorter sequence, RGDAEAKAEAKAEAKCCY (Pep II), to compare the capping and stabilizing ability of capping motifs in preparing luminescent AuNCs. Although Pep II possessed self-assembly ability, the resultant nanofibers were shorter than the PNFs we adopted in this work. (Figure S3 (a)) Then we employed Pep II to synthesize PNF-AuNCs under the same conditions. As a result, there was almost no fluorescence observed from the solution and a lot of Au nanoparticles were observed under the TEM (Figure S3 (b)). Compared to Pep II, the peptide sequence in this work have a longer capping motif (CCYYCC), and a longer assembly motif, which helps in the formation of the –S-Au-S-Au-S-Au- structures, leading to NIR emission. (31, 32) We also investigated the valence states of Au and S in the peptide structures by using X-ray photoelectron spectroscopy (XPS) (Figure S4-S6, ESI). As shown in Figure 2c, the Au 4f7/2 binding energy (BE) of the peptide-AuNCs was 84.0 eV, which falls between Au(0) BE (83.8 eV) and Au(I) BE (85.0 eV), suggesting coexistence of Au(0) and Au(I) in the AuNCs.(33, 34) However, after peptide assembly, the BE of Au4f2/7 shifted to 83.4 eV, suggesting that a certain fraction of Au(I) ions were converted to Au(0) during assembly. As a result, the ratio of Au(0) increased from 32.6% to 82.2%, while the fraction of Au (I) decreased, which reveals the further reduction of AuNCs during the self-assembly process. This behavior is reminiscent of our previous finding that protein adsorption can significantly enhance the luminescence of AuNCs, for which the binding energy of Au 4f7/2 was also observed to shift to lower energy.(35) The BE shift may be related to the influence of the oxidation (electronic) state of the AuNCs, or different structural arrangements on the surface of the particles upon formation of supramolecular PNF structures. We also observed significant changes of the BE of S2p (Figure 2d and S6). The doublet band of S2p3/2 of peptide-AuNCs at 162.7 eV is assigned to sulfur atoms bound to Au surfaces as thiolate species and shifts to 162.0 eV upon self-assembly.(36) The band representing oxidized sulfur also blue-shifts from 168.6 eV to 168.3 eV, further confirming that the bonding states of AuNCs within the surrounding peptides were significantly modified.(37) Particularly, quantitative analysis revealed that the area ratio of oxidized sulfur to thiolate species decreased from 3.19 to 0.98, suggesting that a greater fraction of sulfur atoms directly bound to Au atoms (i.e., via Au-S bonds) upon peptide fibril structure formation. The XPS analysis suggests the formation of Au(0) during selfassembly. One reasonable explanation is that the ratio change between Au(0) and Au (I) comes from the self-assembly



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process, which would significantly raise local concentration of Au(0) and stable motif in the nanofiber. Besides, the secondary structure of peptide enhances the possibility of inter-chain charge transfer, which may be another potential advantage of self-assembly.(31) As revealed by circular dichroism spectroscopy (CD), the percentage of antiparallel and parallel β-pleated sheets in the secondary structure of the peptides decreased after assembly of peptide-AuNCs (see Figure S7 and Table S1, ESI), whereas the content of disordered (random-coil) structures increased significantly. Apparently, after peptide assembly, intermolecular peptide structures around AuNCs are more disordered, thereby presumably providing a more favorable environment for luminescence generation of AuNCs. In a recent study, Tian and co-workers also found that AuNCs anchored to two-dimensional, ultrathin MgAl nanosheets showed enhanced luminescence.(14) The excited electrons/holes of AuNCs could be confined by interacting substrates such as nanosheets, resulting in enhanced luminescence. The remarkable luminescence enhancement of AuNCs in PNFs observed in our work may also be partially ascribed to the 1D nanostructureinduced effective electron confinement of AuNCs.(14) From the spectroscopic characterization, we conclude that the self-assembly of peptide-AuNCs to form PNF structures significantly affects the luminescence process of AuNCs, resulting in the remarkably enhanced luminescence yield. This is particularly advantageous for practical application of AuNCs, where brighter probes are favorable for achieving superior performance.(38) For example, with ultra-small size, excellent biocompatibility and colloidal stability, metal NCs are considered as attractive probes for developing highly robust fluorescent nanothermometer.(39-41) Thus, the potential utilization of our highly luminescent PNF-AuNCs as an optical thermometer was then evaluated.

Figure 3 Temperature sensing of PNF-AuNCs in PBS: (a) Luminescence emission spectra (excitation 480 nm) at different temperatures in the range of 10 - 45 °C (top to bottom); (b) Luminescence intensity at 650 nm versus temperature

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(symbols) and the corresponding linear regression (line); (c) Average luminescence lifetime versus temperature (symbols) and the corresponding linear regression (line); (d) Temperature dependence of the lifetimes of the three exponentials required to fit the luminescence decay curves. Error bars denote standard deviations from three separate measurements.

As shown in Figure 3a, there is a strong temperature dependence of the steady state emission spectra of PNFAuNCs in phosphate-buffered saline (PBS) solution. With temperature increasing from 10 to 45°C, their luminescence intensity decreased by 52%. Further quantitative analysis revealed a good linear relationship between the intensity and the solution temperature in the investigated range (Figure 3b). Assuming that an intensity change of 0.5% °C-1 is required to resolve a temperature difference, the temperature resolution is ca. 0.3 °C in this temperature range. This value is comparable or even superior to the one reported for other optical thermometers.(42-45) Also, we note that the emission maximum of AuNCs does not shift with temperature, in agreement with previous reports.(44) Concomitant with the intensity, the luminescence lifetime of PNF-AuNCs decreases with increasing temperature. The characteristic luminescence decay can be fitted with a sum of three exponentials, with a short (τ1 ≈ 4 ns), medium (τ2 ≈ 95 ns), and long lifetime (780 ns < τ3 < 990 ns). A good linear relationship was observed between the average lifetime of PNF-AuNCs and the surrounding temperature (Figure 3c); the fit yielded a correlation coefficient of 0.97. The long lifetime component exhibits more significant changes than the other two components (Figure 3d). Although the detailed luminescence mechanism of metal NCs is still in dispute, the long lifetime component is believed to be closely associated with gold (I)thiolate complexes on the AuNC surfaces.(30, 46) Apparently, this type of complex is mostly responsible for the thermal response of PNF-AuNCs. Therefore, not only the emission intensity, the lifetime of the PNF-AuNCs but also the lifetime of the PNFAuNCs changes sensitively with temperature. For thermometry applications, the luminescence lifetime is more attractive than the intensity as an observable because it is independent of the probe concentration and excitation conditions.(47) Moreover, the long luminescence lifetime of AuNCs is easily separated from background fluorescence, especially in biological samples.(42, 48) Another distinct feature of our AuNC-based thermometer is that their photophysical properties are inert to environmental changes such as biomolecular adsorption. Control experiments showed that the luminescence intensity of PNFAuNCs stayed essentially constant upon mixing with 100 µM HSA or cell culture medium complemented with 10% fetal bovine serum (Figure S8, ESI), which is particularly favorable for their application in quantitative studies of samples in complex biological medium.


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Bioconjugate Chemistry luminescence compared with the peptide-AuNCs before assembly, which is advantageous for luminescence-based applications. These PNF-AuNCs can be harnessed for diverse applications in physicochemical analytics and biomedicine including the ones shown here, sensitive monitoring of temperature variations and efficient imaging of living cells. Moreover, we envisage that the present strategy can be easily extended to the fabrication of other fluorescent nanocomposites and even more advanced functional materials thanks to the high chemical design versatility and abundant functionalization capabilities of the peptide building blocks.

SUPPORTING INFORMATION Supporting Information Available: Experimental details, supporting figures, and a table. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/ Figure 4 Cellular imaging of PNF-AuNCs. Confocal (a-c) and corresponding bright field (d) images of HeLa cells upon internalization of PNF-AuNCs for 2 h: (a) PNF-AuNCs, red; (b) nuclear staining, blue; (c) overlay of red and blue channels. Scale bar: 20 µm.

Potential utilization of PNF-AuNCs for biological imaging was also investigated. Figure 4 shows typical confocal fluorescence microscopy images of HeLa cells after incubation with PNF-AuNCs for 2 h. With a RGD motif in our peptide constructs, these PNF-AuNCs are expected to be capable of specifically targeting integrin-rich tumor cells, i.e., HeLa cells.(17) Indeed, bright luminescence from PNF-AuNC nanohybrids can readily be observed inside the cells, indicating successful labeling of the HeLa cells. We note that the red features in the cells are mostly large aggregates. Co-staining the cell nucleus with Hochest 33342 revealed the absence of any colocalization between AuNCs and the nucleus (Figure 4b and c). Together, these observations suggest that AuNC nanohybrids are likely internalized via endocytosis, similar as many other engineered nanomaterials.(49-51) Furthermore, we did not observe any morphological changes of HeLa cells upon PNF-AuNCs internalization, as inferred from the corresponding bright-field image (Figure 4d), suggesting a good biocompatibility. Indeed, further quantitative viability evaluation by MTT (thiazolyl blue tetrazolium bromide) assays showed that the cell viability was not affected after incubation with PNF-AuNCs in the concentration range of 0 - 100 μg/mL for 24 h (Figure S9, ESI). The facile cellular labelling via simple endocytosis and low toxicity towards HeLa cells demonstrate that PNF-AuNCs are promising ﬂuorescent probes for advanced diagnostics and imaging of cellular processes. In summary, we have reported a novel approach for preparing highly luminescent AuNCs by combining biomineralization and supramolecular self-assembly of motif-designed peptide constructs, with high QY of ~21.3%. The resultant PNF-AuNCs show remarkably enhanced

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] (Z. Su) *E-mail: [email protected] (G. Wei) *E-mail: [email protected] (L. Shang)

Author Contributions The manuscript was written through contributions of all authors. / All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENT We gratefully acknowledge the financial supports from the National Natural Science Foundation of China (NSFC, Grant No. 51573013) and the Deutsche Forschungsgemeinschaft (DFG) under grant WE 5837/1-1. Financial support from the National 1000 Young Talent Program (LS) is also acknowledged. Research in the Nienhaus lab is supported by the KIT within the context of the Helmholtz Program STN and by Deutsche Forschungsgemeinschaft (DFG) grant GRK 2039.

ABBREVIATIONS NCs, nanoclusters; AuNCs, gold nanoclusters; PNF, peptide nanofibers; TEM, transmission electron microscopy; HRTEM, high-resolution transmission electron microscopy; AFM, atomic force microscopy; CD, circular dichroism spectroscopy; BE, binding energy; MTT, thiazolyl blue tetrazolium bromide.

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In this work, we report self-assembling peptides as a novel bioinspired scaffold capable of significantly enhancing the luminescence efficiency of gold nanoclusters. 101x101mm (96 x 96 DPI)


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Supramolecular Self-Assembly Bioinspired Synthesis of Luminescent

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