Enabling Prussian Blue with Tunable Localized Surface Plasmon

Enabling Prussian Blue with Tunable Localized Surface Plasmon Resonances: Simultaneously Enhanced Dual-Mode Imaging and Tumor Photothermal Therapy Xiaojun Cai,†,‡ Wei Gao,§ Linlin Zhang,†,‡ Ming Ma,† Tianzhi Liu,†,‡ Wenxian Du,†,‡ Yuanyi Zheng,§ Hangrong Chen,*,† and Jianlin Shi† †

State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 200050 Shanghai, P. R. China ‡ University of Chinese Academy of Sciences, 100049 Beijing, P. R. China § Shanghai Sixth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200233 Shanghai, P. R. China S Supporting Information *

ABSTRACT: Prussian blue (PB) has been used as a photothermal conversion agent to generate heat to induce localized damage to tumor. However, its therapeutic efficiency is far from satisfactory. One of the major obstacles is that the maximum NIR absorption peak of PB within 690−720 nm cannot be optimized near the wavelength of the laser to enhance its therapeutic efficiency. Herein, we report that the integration of Gd3+ into PB nanocrystals (GPB NCs) enables PB with tunable localized surface plasmon resonances (LSPRs) from 710 to 910 nm, achieving the maximum NIR peak near the wavelength of the laser. Concurrently, the efficiency of dual-mode imaging including photoacoustic imaging and magnetic resonance imaging has been greatly improved. These enhancements in dual-mode imaging and photothermal therapy enable PB with low nanomaterial dose and laser flux. Additionally, it is found that GPB NCs show the capability of not only acting as a chemical probe with tunable sensitivity but also scavenging reactive oxygen species. The integration of functional ions into a photothermal conversion agent is an efficient strategy to improve the synergy of nanoagent, enchancing tumor theranostic efficiency. KEYWORDS: Prussian blue, tunable localized surface plasmon resonances, magnetic resonance imaging, photoacoustic imaging, photothermal therapy, reactive oxygen species scavenger

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as a smart and versatile theranostic platform, could realize ultrasound (US)/photoacoustic (PA) dual-mode imaging guided synergistic chemo-photothermal therapy for tumors.16 However, the maximum NIR absorption peak of PB is generally located within 690−720 nm and is almost independent of the change of the fundamental physical characteristics such as size, structure, and morphology. The tunable localized surface plasmon resonances (LSPRs) in the NIR enable plasmonic nanocrystals (NCs) used in bioimaging and PTT for cancer as they fall in the “therapeutic window” in which light has a large penetration depth in tissue.17

hotothermal therapy (PTT) is well known as a noninvasive efficient treatment of cancer since it can convert near-infrared (NIR) light into heat to cause localized necrosis and apoptosis to tumor cells, which shows great potential for precise tumor treatment.1,2 Prussian blue (PB), with excellent biocompatibility and biosafety, has been a clinical antidote for the treatment of thallium poisoning proved by U.S. Food and Drug Administration,3−6 which has attracted much interest in many fields,7−10 especially in cancer theranostics.11−13 Due to the strong absorbance in the NIR, PB can serve as multifunctional contrast agent and photothermal conversion agent for the accurate diagnosis and PTT treatment.11−14 In addition, PB nanoparticles with low cost possess good photostability.15,16 Our previous research has demonstrated that hollow mesoporous PB nanoparticles (HMPB) loading with both perfluoropentane and doxorubicin, © 2016 American Chemical Society

Received: September 5, 2016 Accepted: November 14, 2016 Published: November 14, 2016 11115

DOI: 10.1021/acsnano.6b05990 ACS Nano 2016, 10, 11115−11126

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ACS Nano Scheme 1. Schematic of Gd3+ Simultaneously Optimizing the Properties of PB NCsa

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With the incorporation of Gd3+ ions, PB NCs presented tunable NIR LSPRs and simultaneously enhanced capability of tumor diagnosis (MRI and PA imaging) and therapy (PTT), providing an ingenious solution for accurate early tumor diagnosis and real-time imaging during tumor therapy. In addition, the GPB NCs can also be used as an efficient chemical probe with high sensitivity of their optical response to their immediate surrounding environment.

strated that gradient gadolinium ironhexacyanoferrate nanoparticles with a higher concentration of gadolinium toward the outer layers can be used as a multifunctional particle design easily combining MRI contrast (the longitudinal relaxivity value r1 of 12.3 mM−1 s−1) and PTT for cancer theranostics.28 However, it is worth noting that Gd3+ ions only locate in the interstitial site in their work, and almost no changes for the NIR absorbance of PB could be found. Furthermore, PB could be an excellent photoacoustic contrast agent.14 MRI is a powerful noninvasive technique for cancer early detection, which possesses high spatial resolution and deep tissue penetration but poor sensitivity.29 PA imaging is a newly developed noninvasive diagnostic technology, which possesses the advantages of both optical imaging and ultrasound imaging, with excellent sensitivity, high resolution, and the capability of real-time imaging.30−32 Nevertheless, the problem of limited tissue penetration depth still exists. The combination of MRI and PA imaging will achieve not only high spatial resolution and sensitivity but also deep tissue penetration and real-time imaging, which are much meaningful and useful for clinically precise and efficient diagnosis. Thus, it is of great significance but a big challenge to tune the maximum absorbance in the NIR of PB, together with simultaneously enhanced MRI and PA capabilities, for meeting the demands of precise and high efficient multimode imaging. Herein, we propose an efficient but simple strategy for enabling PB with tunable near-infrared LSPRs and simultaneously enhancing dual-mode imaging and PTT of tumors by incorporating Gd3+ ions into the different lattice sites of PB

For example, gold nanorods, the most common plasmonic nanomaterials, possess tunable LSPRs in the NIR, good biocompatibility, and easy functionalization, and have widely been used in many biomedical applications including biosensors, tumor diagnostics, and therapy.18−21 Recently, the discovery of LSPRs in doped semiconductor NCs, including copper selenide, tungsten oxide, indium oxide, copper telluride, germanium telluride, and zinc oxide, has opened up another regime in plasmonics.22−24 Combining Au nanoparticles and semiconductor to form a core@shell structure is an efficient way to take advantage of plasmon-enhanced absorption.17,25 Ding et al. constructed a dual plasmonic hybrid nanosystem Au−Cu9S5 with well-controlled interfaces, which could enhance the optical absorption cross-section and high photothermal transduction efficiency for tumor PTT.17 However, there are still several drawbacks for plasmonic NCs in the medical field, such as the complicated preparation process, generation of reactive oxygen species (ROS) induced by nanoparticles causing DNA damage, mitochondrial damage, and lipid peroxidation.26 Therefore, it is of great significance to explore another kind of NCs with tunable NIR LSPRs to further enhance the effect of plasmonic NCs on cancer theranostics. In addition, Mohammadreza et al. reported that PB NCs could be used as an effective T1-weighted cellular magnetic resonance imaging (MRI) contrast agent with the longitudinal relaxivity value r1 of 0.14 mM−1 s−1 at 7 T. Nevertheless, its longitudinal relaxivity value is approximately 1 order of magnitude lower than those found in the typical commercial Gd3+-based T1-weighted contrast agents.27 Li et al. demon11116


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Figure 1. Tunable strong absorbance in the NIR of GPB NCs. (a−d) TEM images and size distribution histograms of GPB NCs prepared under the same pH value with an increasing amount of Gd source. (e) Corresponding STEM-EDS elemental mappings of GPB-3. (f) XRD patterns and (g) FTIR spectra of the prepared GPB NCs with different Gd/Fe molar ratios. (h−k) Schematic diagrams of Gd3+ ions in the GPB NCs with various Gd/Fe molar ratios.

(Scheme 1). The site and concentration of Gd3+ ions in the structure of PB, which can be controlled by changing the concentration of the H+ and Gd3+ sources, have a great influence on the properties of PB. When the site of Gd3+ in the structure of PB changes from the interstitial site to the lattice site, the NIR LSPR peaks can be well-tuned from 710 to 910 nm. Additionally, the sensitivity of optical response to their immediate surrounding environment can be well controlled, endowing PB as chemical probes. Thanks to the tunable NIR LSPRs of PB and the excellent MRI nature of Gd3+ ions, the performances of PA, MRI, and PTT of PB achieve great enhancement concurrently, which is of great importance for the improvement of tumor theranostic efficacy (Scheme 1). Importantly, these prepared Gd-containing Prussian blue (GPB) NCs can efficiently scavenge ROS to protect normal cells instead of inducing damage by generating ROS, showing good biosafety of GPB, which will be also of great interest in the studies of anti-inflammation, Alzheimer’s disease, diabetes, and so on.

RESULTS AND DISCUSSION GPB NCs were constructed with a tunable Gd/Fe molar ratio in order to control the maximum absorbance in the NIR. GPB NCs with uniform particle sizes were synthesized by mixing the iron source, gadolinium source, and polyvinylpyrrolidone (PVP) in the hydrothermal condition. The Gd/Fe molar ratio and particle sizes of GPB can be controlled by changing either the ratio of iron to gadolinium or the value of pH (Figures S1 and S2; the detailed mechanism of GPB formation can be seen in the Supporting Information). It is worth noting that when the pH value remains invariant, the Gd/Fe molar ratio can be tuned by different amounts of Gd source but with approximately the same sizes. As shown in Figure 1a−d, with the increased concentration of Gd source under the same pH value of 2, the Gd/Fe molar ratio of GPB NCs gradually increases from 0.026:1 to 0.84:1 with similar particle sizes of around ∼270 nm. Their hydration diameters and zetapotentials are about ∼345 nm and −28 mV, respectively (Figures S3 and S4). As shown in Figure 1e, Gd, Fe, C, N, and K elements distribute uniformly in the structure of GPB NCs. 11117


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Figure 2. [F(R∞)hν]2 versus hν curves of (a) GPB-1, (b) GPB-2, (c) GPB-3, and (d) GPB-4 NCs. Horizontal dashed black line marks the baseline; the other dashed red lines are the tangents of the curves. (e) Tunable LSPR of GPB NCs with similar particle sizes. (f) Absorbance peak blue-shift of various GPB NCs with increasing solvent refractive index. (g) Plots of 1/T1 vs Gd3+ concentrations at a magnetic field strength of 7 T for GPB-1, GPB-2, GPB-3, and GPB-4 NCs. (h) Corresponding T1-weighted MR phantom images of GPB-1, GPB-2, GPB-3, and GPB-4 NCs of varied Gd3+ concentrations using a 7 T scanner.

First, we investigated the optical band gaps of GPB NCs, which can be estimated from the Tauc plot [i.e., the curve of converted [F(R∞)hν]r versus hν from the UV−vis spectrum, in which F(R∞), h, and ν are the functions of Kubelka−Munk, Planck constant, and light frequency, respectively, r = 2 for a direct band gap material, and r = 1/2 for an indirect band gap material]. As shown in Figure 2a−d, all four kinds of GPB NCs (GPB-1, GPB-2, GPB-3, and GPB-4) with different Gd/Fe molar ratios show good linear fit when using r = 2, indicating that GPB NCs are a direct band gap material (no good linear fit is obtained for r = 1/2). The Eg values of GPB NCs (GPB-1, GPB-2, GPB-3, and GPB-4) were determined to be 2.52, 2.52, 2.36, and 2.40 eV, respectively, by measuring the x-axis intercept of an extrapolated line from the linear regime of the curve (Figure 2a−d). The change of Eg value of GPB NCs also confirms the variation of Gd3+ ions in the lattice of PB structure. In addition, the Tauc plot curves (Figure 2c,d) of GPB-3 and GPB-4 show an apparent tail between 2.0 and 2.5 eV, which could be helpful for improving the light absorbance and the photocatalytic efficiency.33 More interesting, when the Gd/Fe molar ratio increases from 0.026:1 to 0.84:1, the maximum NIR absorbance of GPB NCs shows a distinct red shift from 710 to 910 nm (Figure 2e). For comparison, the maximum NIR absorbance of pure PB is ∼700 nm, which is mainly ascribed to electronic transition between {Fe I I I [(t 2 g ) 3 (e g ) 2 ]Fe I I [(t 2 g ) 6 ]} and {Fe I I [(t 2 g ) 4 (e g ) 2 ] -

Powder X-ray diffractions (XRD) of all of the GPB NCs with varied Gd3+ contents show high crystallinity (Figure 1f). Therefore, when the Gd/Fe molar ratio is higher than 0.10:1, XRD exhibits a characteristic peak corresponding to the (111) diffraction plane at 15.5° for gadolinium hexacyanoferrate, indicating that Gd3+ ions are covalently attached to the cyanide bonds in the lattice. In addition, as shown in Figure 1g, the spectra of GPB NCs with the Gd/Fe molar ratios lower than 0.10:1 show a peak at 2085 cm−1 corresponding to the FeII− CN−FeIII cyanide stretching vibration, which matches the spectrum obtained for PB, confirming that Gd3+ ions are located in the interstitial sites in PB NC lattices. The FTIR spectra gradually display noticeable peaks at 2140 and 2155 cm−1 with increasing Gd/Fe molar ratios, typical of gadolinium hexacynoferrate, demonstrating that Gd3+ ions are covalently attached to the cyanide bonds in the lattice (Figure 1g). Therefore, the concentrations of H+ and Gd3+ are the main factors to control the sites of Gd3+ in the structure of PB. When the concentration of H+ is large enough or the concentration of Gd3+ is low enough, Gd3+ ions take the place of K+ in the interstitial site of PB (Figure 1h). In the appropriate pH, Gd3+ can first occupy the interstitial site (Figure 1h) and then enter the lattice site to form an Fe−CN−Gd group (Figure 1i−k). The changeable site of Gd3+ in PB has great impact on the performances of PB. 11118


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Figure 3. TEM images of (a) GPB, (b) GPB/PVP, (c) core−shell GPB/PVP, and (d) HGPB as the protected agent was coated on GPB NCs to form GPB/PVP, and then H+ as the etchant was used to dissolve the internal structure at 140 °C. With an increase of etching time, we could obtain the core−shell GPB and finally HGPB NCs. (e, f) TEM images of HGPB NCs. (g−k) Corresponding STEM-EDS elemental mappings of HGPB.

FeIII[(t2g)5]}. The LSPR properties of plasmonic NCs stem from the collective oscillations of free charge carriers.22,34 The free charge carriers in the GPB NCs for a direct band gap material are the vacancy of [Fe(CN)6]. A plausible mechanism involved in this red-shift phenomenon can be ascribed to the LSPRs of GPB NCs principally. When Gd3+ ions located in the interstitial site, there are no impacts on the concentration of [Fe(CN)6] vacancy and the electronic transition between {Fe I I I [(t 2g ) 3 (e g ) 2 ]Fe I I [(t 2g ) 6 ]} and {Fe I I [(t 2g ) 4 (e g ) 2 ] FeIII[(t2g)5]}. With the increased content of Gd3+ ions, the location of Gd3+ ions will occupy the lattice site to form Fe− CN−Gd, leading to the decrease of the [Fe(CN)6] vacancy. The decreasing concentration of the [Fe(CN)6] vacancy results in the red shift of LSPR peak. With more and more Gd3+ ions located in the lattice, the concentration of free charge carriers in the PB become less, inducing the variation of LSPR peaks of PB.34 The absorbance in the wavelength of 810 nm can be ascribed to the LSPR effect and the electronic transition between {FeIII[(t2g)3(eg)2]FeII[(t2g)6]} and {FeII[(t2g)4(eg)2]-

FeIII[(t2g)5]}. Additionally, Gd3+ ions located in the lattice will affect the electron density and orbital energies of the cyanide bonds, which will at some extent cause the red shift of the NIR absorbance peak of PB. The NIR absorbance can be assigned to electronic transition by studying the effect of the different solvent media on the absorbance band position, which can also be used to confirm the presence of plasmon resonances.34−36 Therefore, we compared NIR spectra of different GPB NCs (GPB-1, GPB-2, GPB-3, and GPB-4) in three different solvents: ethanol, N,N-dimethylformamide, and N-methyl-2-pyrrolidone with refractive indices of 1.36, 1.43, and 1.46, respectively. When the Gd/Fe molar ratio of GPB is smaller than 0.10:1, there is no significant change for the maximum NIR absorbance observed regardless of the increasing solvent refractive index (Figure 2f). However, by further increasing the Gd/Fe molar ratio of GPB NCs, the remarkable blue-shift in the maximum NIR absorbance with increasing solvent refractive index is found (Figure 2f), which is ascribed to the finding that when the Gd3+ ions are covalently 11119


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Figure 4. Photothermal conversion property of HGPB NCs compared to HMPB NCs. (a) UV−vis−NIR spectra of HMPB and HGPB aqueous solutions. (b) Temperature elevation profiles of the HGPB aqueous dispersions of different concentrations at the same power density of 1.16 W/cm2. (c) Plots of temperature change (ΔT) over a period of 10 min versus the concentrations of HMPB and HGPB NCs. (d) Cell viabilities of HGPB and HMPB NCs of varied concentrations exposed to a 808 nm laser with a power density of 0.58 W/cm2 for 10 min (control group, without treatment; “0” group, without HMPB or HGPB NCs exposed to 808 nm laser).

attached to the cyanide bonds in the lattice Gd3+ ions will have a great impact on the electron density and orbital energies of the cyanide bonds, thus influencing electronic transition in the structure of GPB and chemical interactions between the nanoparticles and the solvent. More importantly, much higher sensitivities of GPB NCs could be obtained at the higher Gd/ Fe molar ratio, indicative of tunable sensitivity of GPB NCs as a chemical probe (Figure 2f). Therefore, this phenomenon convincingly confirms not only the existence of LSPRs in the GPB NCs but also the controllable location of Gd3+ ions in the lattice. The sensitivity of GPB-4 is estimated to be as high as ∼526 nm/RIU, which is higher than those plasmonic sensitivities of gold nanoshells (130 to 360 nm/RIU),37 silver nanoprisms (200 nm/RIU),38 spherical Cu2−xS (350 nm/ RIU),34 and WO2.8 nanowires (280 nm/RIU).35 These results demonstrate that GPB NCs can serve as an excellent chemical probe with tunable sensitivity by changing the Gd3+ site in the lattice of PB. The excellent T1-weighted MRI function of Gd(III) of a high electronic spin (S = 7/2) with a low longitudinal electronic-spin relaxation rate and the excellent biosafety of PB NCs drive us to explore its application in bioimaging. To evaluate the efficacy of GPB NCs as T1-weighted MRI contrast agents, a series of proton T1 relaxation measurements were performed in order to determine their longitudinal relaxivity values r1 at 7 T magnetic field strengths using a Bruker Pharmascan small animal MRI system. The longitudinal relaxivity (r1 value) of the various GPB NCs was derived from a linear fit of R1 versus iron concentration and gadolinium concentration, respectively. The longitudinal relaxivity values of GPB-1, GPB-2, GPB-3, and GPB-4 are calculated to be 3.6, 9.5, 30.4, and 37.9 mM−1 s−1,

respectively, which are higher than those of PB (r1 = 0.14 mM−1 s−1) and the commercial contrast agent ProHance (r1 = 3.00 mM−1 s−1)39 under the same conditions (Figure 2g). The corresponding MR images also confirm the great difference among the various GPB NCs (Figure 2h). In addition, the longitudinal relaxation time of GPB-1, GPB-2, GPB-3, and GPB-4 with the same concentration of Gd3+ ions was different, further confirming that the locations of Gd3+ ions are diverse, from the interstitial site to the lattice site. When Gd3+ ions locate in the interstitial site, though there are no coordinated water molecules onto the Gd3+ paramagnetic centers, some Gd3+ ions still have a chance to contact water molecules because of the existence of [Fe(CN)6] vacancies in the lattice of PB.13,40 Therefore, the T1-weighted MRI property of GPB NCs can be enhanced to some extent. It is consistent with the previously reported gradient gadolinium ironhexacyanoferrate nanoparticles with a higher concentration of gadolinium toward the outer layers as a T1-weighted MRI contrast agent with a longitudinal relaxivity value r1 of 12.3 mM−1 s−1.28 Interestingly, with the increasing content of Gd3+ ions, more Gd3+ ions locate into the lattice sites (Figure 1g−j). When the Gd3+ ions are in the lattice sites of PB, there are two coordinated water molecules onto the Gd 3+ paramagnetic in the inner coordination sphere, which can be efficiently exchanged (Figure S5),39 while the current clinical Gd3+-based MRI contrast agent, including gadoteridol, only contains strictly one coordinated water molecule. Therefore, the r1 value of GPB NCs distinctly increases with the increase of Gd3+ content. Compared to the mononuclear Gd3+ complexes, much larger GPB NCs display minimized molecular tumbling, thus also leading to an increase in longitudinal relaxivity. In addition, the covalent bonding 11120


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Figure 5. PA and MRI properties of HGPB NCs compared to HMPB NCs. (a) PA values of HMPB and HGPB NCs at different wavelengths (680−970 nm). (b) Plots of PA values of HMPB and HGPB NCs at varied concentrations (808 nm). Inset: corresponding PA images of HMPB and HGPB NCs at varying concentrations (808 nm). Plots of 1/T1 vs Gd3+ concentrations at a magnetic field strength of 7 T for (c) HMPB and (d) HGPB NCs. Inset: the corresponding T1-weighted MR phantom images of HMPB and HGPB NCs of varied Gd3+ concentrations using a 7 T scanner.

between paramagnetic Gd3+ and Fe3+ metal ions via cyanide bridges in the structure of GPB also benefits the increase of longitudinal relaxivity (r1 value) in contrast to the use of diamagnetic ions.39 The strong absorbance red-shift to the “therapeutic window” will open up practical applications for GPB NCs in bioimaging and PTT for cancer. We then explored the photothermal conversion property of GPB using a laser with a wavelength of 808 nm. Nanoparticles with hollow structures can be used as excellent carriers for biomolecules, drugs, proteins, and so on.41 As shown in Figure 3a−d, we used PVP as a protective agent to protect the surface of GPB-3 and hydrochloric acid as an etching agent to dissolve the interior of GPB-3, forming the hollow mesoporous GPB (HGPB) via the method of “surface protection and interior etching”. The TEM images in the Figure 3e,f show the distinct hollow structure of HGPB, and the corresponding scanning transmission electron microscopyenergy dispersive spectroscopic (STEM-EDS) elemental mapping of HGPB shows that Gd, Fe, C, N, and K elements distribute uniformly in the structure (Figure 3g−k). The similar hollow mesoporous Prussian blue nanoparticles (HMPB, showing in the Figure S6) without Gd3+ incorporation were used as a reference sample, which has been demonstrated to achieve distinct in vivo synergistic chemothermal tumor therapy and synchronous diagnosis and monitoring by US/PA dualmode imaging.16 It is clear that the absorbance band of HGPB is much broader than that of HMPB, and the maximum NIR absorbances of HMPB and HGPB are at 720 and 805 nm, respectively (Figure 4a). The weak blue shift can be ascribed to the slightly increased concentration of [Fe(CN)6] vacancies in HGPB after the formation of hollow structure. Thanks to the

tunable LSPRs, the maximum NIR absorption peak of HGPB NCs can be tunable near the laser wavelength, which is beneficial toward enhancing its photothermal therapeutic efficiency for tumors. Then, the photothermal conversion property of HGPB induced by the strong NIR absorbance under the irradiation of 808 nm laser was studied using HMPB NCs for comparison. Figure 4b and Figure S7 show clearly the photothermal response of the HGPB aqueous dispersion, and the HGPB exhibits concentration-dependent photothermal effects. For comparison, the temperature of pure water shows little change, indicating HGPB could efficiently convert the energy of an 808 nm laser into heat energy, resulting from strong NIR photoabsorbance. Moreover, the temperature increases of HGPB solutions of varied concentrations are higher than those of HMPB under the same conditions (Figure 4c), which confirms that the enhancement of photothermal conversion efficiency of HGPB is superior to that of HMPB. The irradiation time and laser intensity are the two main factors for the extent and mechanism of cell death.2 Herein, the cell viabilities of HGPB and HMPB of varied concentrations were investigated using 808 nm laser with a power density of 0.58 W/cm2 for 10 min. As shown in Figure 4d, the cell viabilities of HGPB at varied concentrations are lower than those of HMPB NCs, further confirming that HGPB has higher photothermal conversion efficiency than HMPB exposed to laser. Therefore, it is believed that incorporation of gadolinium can greatly enhance the photothermal property of HGPB in comparison to those of HMPB, which also implies that a much lower dose and laser flux of HGPB than HMPB is needed to achieve high efficacy in tumor treatment. 11121


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Figure 6. Biocompatibility and biosafety of HGPB NCs. (a) Hydrodynamic diameter of HGPB in various solution at different time points. (b) Concentrations of Gd3+ ions dissolving out from HGPB at different conditions. (c) Cell viabilities of HGPB NCs with various concentrations. (d) Effect of HGPB NCs on hydroxyl radical. (e) HGPB NCs can protect cells from oxidative stress induced by CDDP.

combining with water molecules, which can contribute to the enhancement of the r1 value. The above results indicate that HGPB NC is essentially an excellent T1-weighted MRI contrast agent which displays the great enhancement in the MR relaxivity, compared to the commercial one. The corresponding MR images further confirm the great difference between HGPB and HMPB (the inset of Figure 5c,d). Thus, for this constructed multifunctional HGPB NCs, the suitable amount incorporation of Gd3+ enables both the synergistic combination and enhancement of MRI and PA imaging, providing an ingenious solution for concurrently optimizing multiple factors such as sensitivity, resolution, tissue penetration, which is much useful for the accurate early tumor diagnosis and real-time imaging during tumor therapy. It is well-known that the stability and biocompatibility of nanoagents are vital in further medical applications.42,43 The physicochemical properties of HGPB NCs are investigated herein. HGPB NCs can be stable for at least 4 days in various solutions including water, phosphate buffer solution (PBS), DMEM, and serum by investigating their hydration diameter and absorbance at a wavelength of 808 nm (Figure 6a and Figure S8). The zeta potential of HGPB NCs is about −32 mV (Figure S9). In addition, the content of Gd3+ ions dissolving out from HGPB NCs is lower than 0.7% in all four kinds of solution (PBS, DMEM, serum, and solution of pH 5.0) over 48 h, which is in the safe dose without side effects (Figure 6b). Furthermore, three kinds of cells (PC12, 4T1, Hela) were used to investigate its biocompatibility via the Cell Counting Kit-8. As shown in Figure 6c, all of the cell viabilities are higher than 90% even at the 200 ppm concentration of HGPB NCs, which demonstrates that HGPB NCs have good biocompatibility at our tested concentrations. It is reported that the cytotoxicity is related to the generation of ROS induced by nanoparticles.26 Many reported nanomaterials,26,44,45 including quantum dots, silica nanoparticles, nano-ZnO, single-walled carbon nanotubes, nanoiron oxide, and MnO2, can induce toxicity mediated by ROS in many biological systems such as skin fibroblasts and human erythrocytes, which will hinder their clinical application to some extent. Nanomaterial-induced ROS can lead to oxidative stress, causing DNA damage, mitochondrial damage, and lipid peroxidation.26 The low redox potential of PB46 drives

Encouraged by the enhancement of the photothermal conversion properties of HGPB, the PA property of HGPB was also investigated. As shown in Figure 5a, the PA values of HGPB at the wavelengths from 750 to 970 nm are higher than those of HMPB under the same concentration, which is consistent with their UV−vis−NIR absorbance. Both HGPB and HMPB NCs exhibit concentration-dependent PA signal intensity at 808 nm, as shown in Figure 5b, and the PA values of HGPB at varied concentrations are higher than those of HMPB under the same conditions. In addition, the corresponding PA images of HGPB are brighter than those of HMPB, as shown in the inset of Figure 5b. The enhanced PA signals of HGPB NCs can be ascribed to the increasing absorbance at 808 nm compared to HMPB NCs. All of the above results convincingly confirm that the Gd3+ doping can greatly enhance the PA property of HGPB over than that of HMPB, indicating that HGPB NCs could be used as an excellent PA contrast agent for cancer diagnosis. It is well-known that PA imaging displays high sensitivity, real-time imaging, and spatial resolution but poor tissue penetration, while MRI possesses poor sensitivity but high spatial resolution and tissue penetration. Therefore, it is of great significance to combine MRI and PA imaging into a single system, which can provide an optimized solution to address the multiple issue of sensitivity, resolution, and tissue penetration in tumor diagnosis. The longitudinal relaxivity (r1 value) of HMPB and HGPB is derived from the linear fitting of R1 versus iron concentration and gadolinium concentration, respectively (Figure 5c,d). Very interestingly, the relaxivity measurements of HGPB give an extraordinarily high r1 value of as high as 32.8 mM−1 s−1, which is remarkably higher than that of HMPB (r1 = 0.14 mM−1 s−1) and is about 11 times that of the commercial gadoteridol contrast agent (r1 = 3.00 mM−1 s−1). It is noted that longitudinal relaxivity value of HGPB is also higher than that of GPB-3, which is mainly owing to the hollow mesoporous structure. The surface location of most paramagnetic centers (Gd3+) and fast diffusion of water molecules in the core provide greatly favor water molecule exchange, resulting in a much enhanced water-exchange rate constant.39 Simultaneously, owing to the hollow mesoporous structure, there are more [Fe(CN)6] vacancies of HGPB, leading to more Gd3+ ions 11122


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Figure 7. Simutaneously enhanced dual-mode imaging and tumor photothermal therapy in vivo. (a) Temperature curves of tumor before and after PBS, HMPB, and HGPB NCs solution via intratumor injection. (b) Corresponding thermal images of tumor before and after injection of PBS, HMPB, and HGPB NC solution. (c) PA values at different wavelengths (680−970 nm) before and after HMPB and HGPB NCs injected subcutaneously. (d) PA values at 808 nm before and after HMPB and HGPB NCs injected subcutaneously. (e) MRI signal intensity and (f) MRI images of tumor before and after injection of PBS, HMPB, and HGPB NC solutions. (g) Relative tumor volumes of mice in different groups. (h) Body weight of mice in different groups. (i) H&E staining of heart, live, spleen, lung, and kidney of mice after treatment for 14 days.

us to explore its performance of scavenging ROS, which can protect cell against oxidative stress. As shown in reactions 1 and 2, HGPB can be oxidized into hollow mesoporous Gdcontaining Berlin green (HGBG) or hollow mesoporous Gdcontaining Prussian yellow (HGPY). First, a TiO2/UV system producing •OH was used as a reference to study the effect of HGPB on hydroxyl radicals. It is found that the signal intensity of BMPO/•OH decreased dramatically with an increase of the concentration of HGPB (Figure 6d), demonstrating that HGPB has an excellent capability of scavenging •OH directly. The redox potential of HGPB/HGBG and HGBG/HGPY are about 0.9 and 1.4 V, respectively,46 while the redox potential of •OH/ H2O is 2.9 V. Therefore, the scavenging of •OH by HGPB can be represented in reaction 3. (K x − 3Gd)(Gd mFe(III)y − 1)[Fe(II)(CN)6 ]z

(HGPB)

(K x − 3Gd)(Gd mFe(III)y − 1)[Fe(III)(CN)6 ]n [Fe(II)(CN)6 ]z − n

(Kx − 3Gd)(GdmFe(III )y − 1)[Fe(III )(CN )6 ]z

after mixing HGPB NCs with H2O2, demonstrating that HGPB NCs could scavenge ROS (the detailed mechanism can be seen in Supporting Information). The above results demonstrate that HGPB NCs do not induce oxidative stress; instead, they can scavenge ROS. Afterward, cis-dichlorodiamineplatinum(II) (CDDP) was selected as a drug model to study the protective actions of HGPB NCs against damage. As shown in Figure 6e, there is a remarkable cytotoxicity of CDDP after 24 h in vitro mediated by ROS generation. Nevertheless, HGPB NCs with the concentration of 100 ppm can obviously inhibit the generation of ROS via CDDP, protecting the cell effectively. The results demonstrate that HGPB NCs do not only show good biocompatibilities, but also have great potential as antioxidases applied in the field of Alzheimer’s disease, anti-inflammation, and even diabetes. Encouraged by the above results in vitro, we further validate in vivo if the addition of Gd3+ ions can simultaneously optimize the properties of HGPB NCs in diagnosis (MRI and PA) and therapy (PTT). As shown in Figure 7a,b, the increased temperature of a tumor in the group of HGPB NCs with a concentration of 75 ppm exposed to a 808 nm laser with a power density of 0.58 W/cm2 for 10 min is higher than that of HMPB NCs. Additionally, by further reducing the concentration of HGPB NCs from 75 to 50 ppm, the increased temperature of tumors is still higher than that of HMPB with a concentration of 75 ppm. The above results in vivo clearly demonstrated that Gd3+ can optimize the photothermal conversion property of PB. In order to better compare the

(HGBG)

(HGPY)

HGPB → HGBG + ne−

(1)

HGBG → HGPY + (z − n)e−

(2)

HGPB + H + + HO• → HGPY + H 2O

(3)

Furthermore, the interaction between HGPB NCs and H2O2 was investigated, since H2O2 is another kind of ROS existing in the tumor or inflammation. As shown in Figure S10, the generation of bubbles is clearly observed, and verified to be O2,8 11123


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ACS Nano

The discovery of tunable NIR LSPRs of GPB NCs with low cost and good biocompatibility will open up another regime in plasmonics like gold nanoparticles. Nevertheless, some issues, such as smaller particle size and targeted functionalization of HGPB NCs, etc., need to be addressed for more nanoparticles accumulating in the tumor site.

PA property of HMPB and HGPB NCs, PLGA is chosen as a carrier to fix the nanoparticles in situ with the same concentration, since the phase change from liquid to solid will happen when PLGA is in contact with water. After subcutaneous injection, the PA values from 680 to 970 nm of HGPB and HMPB with the same concentration are much higher than that of the control group under the same test conditions (Figure 7c), indicating that HGPB and HMPB NCs are both good PA contrast agents. Furthermore, the PA intensities of HGPB are stronger than that of HMPB under the laser of wavelengths from 730 to 970 nm, confirming the enhancement of PA property after introduction Gd3+ into PB. The PA images at the wavelength of 808 nm also confirm the enhancement of PA intensity (Figure 7d). In addition, the solutions of HMPB and HGPB NCs with the same concentrations were injected directly into tumor. The PA intensity of tumor injected with HGPB is stronger than that of HMPB (Figure S11). The MRI properties of HMPB and HGPB NCs with the same concentration were studied by using a 7.0 T BrukerBiospec small animal MRI system (Bruker, Inc., Billerica, MA). As shown in Figure 7e,f, the signal intensity of HGPB NCs is much higher than that of HMPB with the same dose under same conditions, which is consistent with the results in vitro. Finally, HGPB NCs with a concentration of 50 ppm were chosen to explore the PTT efficacy. There are three groups in the animal test, including the control group (treated with PBS), the HGPB group (treated with HGPB NCs without irradiation), and the HGPB + NIR group (treated with HGPB NCs exposed to irradiation). As shown in Figure 7g, tumors of mice in the HGPB + NIR group can be completely eliminated after treatment for 2 days, while the other two groups had no significant inhibitions of tumor, showing good PTT performance of HGPB NCs for tumors. There are no apparant changes in their body weights (Figure 7h), and H&E staining of different organs including heart, liver, spleen, lung, and kidney (Figure 7i) showed no changes. According to the above in vivo results, HGPB NCs show great potential as good multifunctional theranostic agents for tumors.

EXPERIMENTAL METHODS Chemicals. All chemicals were of analytical grade and used directly without further purification. Polyvinylpyrrolidone (PVP, K30), potassium ferricyanide (K3[Fe(CN)6]), hydrochloric acid (HCl, 36.0% ∼38.0%), and gadolinium nitrate hexahydrate [Gd(NO3)3· 6H2O] were purchased from Adamas-beta. Preparation of Gd-Containing Prussian Blue with Various Sizes and Gd Content. PVP (1.0 g), K3[Fe(CN)6] (32 mg), and HCl solution (10 mL; , 0.1, 0.01, and 0.001 M) were mixed under magnetic stirring (400 rpm/min) to obtain a clear solution (solution A), and PVP (1.0 g), Gd(NO3)3·6H2O (45 mg), and HCl (10 mL) solution (1, 0.1, 0.01, and 0.001 M) were mixed under magnetic stirring (400 rpm/min) to obtain a clear solution (solution B). Then solution A was slowly dropped into solution B under magnetic stirring (400 rpm/min) for 3 h. After a clear solution was obtained, the mixed solution was placed in an electric oven (80 °C for 24 h). After centrifugation and washing in distilled water several times, GPBs were obtained. Preparation of Gd-Cntaining Prussian Blue with Various Gd Contents and Similar Sizes. PVP (1.0 g), K3[Fe(CN)6] (32 mg), and HCl solution (10 mL, 0.01 M) were mixed under magnetic stirring (400 rpm/min) to obtain a clear solution (solution A), and PVP (1.0 g), Gd(NO3)3·6H2O (0, 15, 30, 45, and 60 mg), and HCl solution (10 mL, 0.01 M) were mixed under magnetic stirring (400 rpm/min) to obtain a clear solution (solution B). Then, solution A was slowly dropped into solution B under magnetic stirring (400 rpm/ min) for 3 h. After a clear solution was obtained, the vial was placed in an electric oven (80 °C for 24 h). The Gd-containing mesoporous GPBs were obtained after centrifugation and washing in distilled water for several times. Preparation of HMPB. HPMB can be prepared according to the reported method.16 Typically, PVP (1.0 g), K3[Fe(CN)6] (32 mg), and HCl solution (20 mL, 0.01 M) were mixed under magnetic stirring (400 rpm/min) to obtain a clear solution (solution A). After a clear solution was obtained, the vial was put into an electric oven at 80 °C for 24 h. Then, after centrifugation and washing in distilled water several times, mesoporous Prussian blue nanoparticles (MPBs) were obtained. PVP (5 mg mL−1) was added to the solution of MPBs (1 mg mL−1) in a Teflon vessel under magnetic stirring. The mixed solution was transferred into a stainless autoclave after 3 h. Then the autoclave was put in an electric oven (140 °C for 4 h). After centrifugation, the precipitations were washed in distilled water several times. HMPBs were obtained after freeze-drying. Preparation of HGPB. The prepared process of HGPB is similar to that of HMPB. Typically, PVP (5 mg mL−1) was added to the solution of GPB-3 (1 mg mL−1) in a Teflon vessel under magnetic stirring. After 3 h, the solution was placed into a stainless autoclave at 140 °C for 3 h in an electric oven. After centrifugation, the precipitations were washed in distilled water several times. HGPB were obtained after freeze-drying. T1-Weighted MRI Properties of HGPB and HMPB NCs. HMPB and HGPB solutions with different concentrations were used for T1 relaxivity measurements at 25 °C using a 7.0 T BrukerBiospec small animal MRI system (Bruker, Inc., Billerica, MA). An inversion recovery gradient echo sequence with TE = 4 ms was used for T1 relaxivity measurements. Photothermal Performance of HGPB and HMPB NCs. The temperature trends of HGPB and HMPB NCs solution with different concentrations were monitored by exposure to a 808 nm laser (Connet Fiber Optics Co., Ltd.). Pure water was chosen as the control. An FLIR thermal camera (FLIR ThermalCAM E40) and FLIR Examiner software were used to record the real-time thermal imaging.

CONCLUSIONS In summary, we have found an efficient strategy to enable PB with tunable LSPRs, enhancing the efficiency of PTT and PA imaging for tumors with lower dose and laser flux by controlling the Gd3+ site in the framework structure of PB. The emerging tunable LSPR effect can be ascribed to the change of the electronic transition, the electron density, and orbital energies of the cyanide bonds, as well as the variation of charge carriers in the PB NCs after the incorporated Gd3+ ions. Concurrently, the MRI performance of PB NCs heightens substantially, with the longitudinal relaxivity values increasing from 0.14 to 37.9 mM−1 s−1, which is ascribed to the coordination of two water molecules onto the incorporated Gd3+ (S = 7/2), high water exchange rate constant, and the covalent linkage of Fe3+ to Gd3+. These integrated effects and substantial performance enhancements in GPB NCs provide effective tools for more precise diagnosis and much higher therapeutic efficiency for tumors. In addition, these incorporated Gd3+ ions endow PB NCs with great potential in chemical probes with the tunable sensitivity of optical response to their immediate surrounding environment. Importantly, unlike other nanomaterials generating ROS to induce damage to cells, GPB NCs could serve as an efficient ROS scavenger to protect cells far from oxidative stress, indicating excellent biosafety of PB. 11124


Article

ACS Nano In Vitro Antitumor Activity. Murine breast cancer cells (4T1) were seeded into 96-well plates at a density of 105 cells per well and incubated in 5% CO2 at 37 °C for 12 h. The culture medium was changed, and cells were incubated with complete medium containing PBS (control), HMPB, and HGPB. After 4 h of incubation, excess unbound materials were removed by rinsing three times with PBS. Fresh complete medium was then added to the wells. The cells of the groups PBS (control), HMPB, and HGPB were exposed to an 808 nm laser at a power density of 0.58 W cm−2 for 10 min for PTT treatment and then added to the culture oven with 5% CO2 at 37 °C for 24 h. Relative cell viabilities were determined by the standard CCK-8 assay. In Vitro PA Imaging. HMPB and HGPB NCs with different concentrations in the prepared agarose hydrogel and then PA imaging were obtained by a Vevo LAZR photoacoustic imaging system. Experiment parameters: frequency, 21 MHz; PA gain, 40 dB; 2D gain, 18 dB. In Vivo Infrared Thermal Imaging. First, the balb/c mice with tumor in the lateral thigh were anesthetized while maintaining a normal body temperature. They were divided into four groups (control, HGPB-50 ppm, HGPB-75 ppm, and HMPB-75 ppm) and injected with PBS buffer, HGPB with concentrations of 50 and 75 ppm, and HMPB with a concentration of 75 ppm through intratumor injection (30 μL), respectively. The spatial temperature distribution of the tumor was monitored and recorded by thermography under 808 nm laser irradiation with a power density of 0.58 W cm−2 for 10 min. In Vivo Ultrasound (US) and PA of HMPB and HGPB NCs. HMPB (50 μg) and HGPB were dissolved in 1 mL of NMP/PLGA (80 wt %/20 wt %), respectively. Then 30 μL of each the above solutions was injected into the animal by subcutaneous injection. US and PA imaging were obtained after subcutaneous injection. In addition, HMPB and HGPB with concentrations of 50 ppm (30 μL) were injected into the tumor. US and PA imaging were obtained before and after intratumor injection. All of the PA imaging was obtained using a Vevo LAZR photoacoustic imaging system. Experiment parameter: frequency, 21 MHz; PA gain, 40 dB; 2D gain, 18 dB. In Vivo MRI Properties of HMPB and HGPB NCs. balb/c mice with a tumor in the lateral thigh were anaesthetized. The mice were injected with PBS buffer, HGPB with a concentration of 50 ppm, and HMPB with a concentration of 50 ppm through intratumor injection (30 μL), respectively. The MRI images and their intensity were obtained by using a 7.0 T BrukerBiospec small animal MRI system (Bruker, Inc., Billerica, MA). An inversion recovery gradient echo sequence with TE = 4 ms was used for T1 relaxivity measurements. In Vivo PTT. The tumor-bearing female balb/c nude mice were randomly allocated into three groups (control, HGPB, and HGPBs +NIR, n = 6 for each group). The mice of the control group were injected with PBS (30 μL) by intratumor injection, and the other two groups were injected with HGPB NCs with a concentration of 50 ppm (30 μL). Then one of the group injected with HGPB NCs was irradiated with 808 nm laser (0.58 W cm−2) for 10 min. The tumor dimensions were measured with a caliper, and the tumor volume was calculated according to the equation: volume = (tumor lenghth) × (tumor width)2/2. All of the animals received care in accordance with the Guidance Suggestions for the Care and Use of Laboratory Animals. The procedures were approved by the Second Affiliated Hospital of Chongqing Medical University. Characterization. Transmission electron microscopy (TEM)/ scanning transmission electron microscopy (STEM) images were acquired on a JEM-2100F electron on a field emission Magellan 400 microscope (FEI Company). Dynamic light scattering measurements were conducted on a ZetasizerNanosize (Nnao ZS90). UV−vis−NIR spectra were recorded on a UV-3101PC shimadzu spectroscope. Realtime thermal imaging of samples was recorded using a FLIR thermal camera (FLIR ThermalCAM E40). PA imaging was obtained by a Vevo LAZR photoacoustic imaging system.

ASSOCIATED CONTENT S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsnano.6b05990. Detailed characterization of GPB NCs and HGPB NCs, photothermal property of HGPB NCs, and the effect between HGPB NCs and H2O2 (PDF)

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Hangrong Chen: 0000-0003-0827-1270 Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS This work was supported by China National Funds for Distinguished Young Scientists (51225202), the National Natural Science Foundation of China (Grant Nos. 51132009 and 51402329), and the Shanghai Excellent Academic Leaders Program (Grant No. 14XD1403800) REFERENCES (1) Cheng, L.; Wang, C.; Feng, L. Z.; Yang, K.; Liu, Z. Functional Nanomaterials for Phototherapies of Cancer. Chem. Rev. 2014, 114, 10869−10939. (2) Perez-Hernandez, M.; del Pino, P.; Mitchell, S. G.; Moros, M.; Stepien, G.; Pelaz, B.; Parak, W. J.; Galvez, E. M.; Pardo, J.; de la Fuente, J. M. Dissecting the Molecular Mechanism of Apoptosis during Photothermal Therapy Using Gold Nanoprisms. ACS Nano 2015, 9, 52−61. (3) Yang, Y.; Brownell, C.; Sadrieh, N.; May, J.; Del Grosso, A.; Place, D.; Leutzinger, E.; Duffy, E.; He, R.; Houn, F.; et al. Quantitative Measurement of Cyanide Released from Prussian Blue. Clin. Toxicol. 2007, 45, 776−781. (4) Yang, Y.; Faustino, P. J.; Progar, J. J.; Brownell, C. R.; Sadrieh, N.; May, J. C.; Leutzinger, E.; Place, D. A.; Duffy, E. P.; Yu, L. X.; et al. Quantitative Determination of Thallium Binding to Ferric Hexacyanoferrate: Prussian Blue. Int. J. Pharm. 2008, 353, 187−194. (5) Mohammad, A.; Faustino, P. J.; Khan, M. A.; Yang, Y. Long-Term Stability Study of Prussian Blue: A Quality Assessment of Water Content and Thallium Binding. Int. J. Pharm. 2014, 477, 122−127. (6) Mohammad, A.; Yang, Y.; Khan, M. A.; Faustino, P. J. A LongTerm Stability Study of Prussian Blue: A Quality Assessment of Water Content and Cesium Binding. J. Pharm. Biomed. Anal. 2015, 103, 85− 90. (7) Karyakin, A. A. Prussian Blue and Its Analogues: Electrochemistry and Analytical Applications. Electroanalysis 2001, 13, 813− 819. (8) Yang, F.; Hu, S. L.; Zhang, Y.; Cai, X. W.; Huang, Y.; Wang, F.; Wen, S.; Teng, G. J.; Gu, N. A Hydrogen Peroxide-Responsive O2 Nanogenerator for Ultrasound and Magnetic Resonance Dual Modality Imaging. Adv. Mater. 2012, 24, 5205−5211. (9) Kong, B.; Selomulya, C.; Zheng, G.; Zhao, D. New Faces of Porous Prussian Blue: Interfacial Assembly of Integrated HeteroStructures for Sensing Applications. Chem. Soc. Rev. 2015, 44, 7997− 8018. (10) Patra, C. R. Prussian Blue Nanoparticles and Their Analogues for Application to Cancer Theranostics. Nanomedicine 2016, 11, 569− 572. (11) Cheng, L.; Gong, H.; Zhu, W.; Liu, J.; Wang, X.; Liu, G.; Liu, Z. PEGylated Prussian Blue Nanocubes as a Theranostic Agent for Simultaneous Cancer Imaging and Photothermal Therapy. Biomaterials 2014, 35, 9844−9852. 11125


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Enabling Prussian Blue with Tunable Localized Surface Plasmon

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