Cu(II)-Doped Polydopamine-Coated Gold Nanorods for Tumor

Research Article Cite This: ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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Cu(II)-Doped Polydopamine-Coated Gold Nanorods for Tumor Theranostics Shuwei Liu,† Lu Wang,‡ Min Lin,∥ Dandan Wang,‡ Ziqi Song,§ Shuyao Li,† Rui Ge,† Xue Zhang,† Yi Liu,† Zhimin Li,*,§ Hongchen Sun,*,†,‡ Bai Yang,† and Hao Zhang*,† †

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China ‡ Oral Pathology Department and §Radiology Department, Stomatology Hospital of Jilin University, Changchun 130021, P. R. China ∥ School of Materials Science and Engineering, Qingdao University, Qingdao 266071, P. R. China S Supporting Information *

ABSTRACT: Gold nanorods (AuNRs) are potentially useful in tumor theranostics, but the poor stability, high toxicity, and rapid removal by the immune system seriously limit their theranostic applications. In our study, we demonstrate the fabrication of Cu(II)-doped polydopamine-coated AuNR (AuNR@CuPDA), which significantly improves the potentials in tumor theranostics. Besides the improvement of physiological stability and biocompatibility, the PDA shell increases the photothermal performance and prolongs the blood circulation time of AuNRs. The half-life of AuNRs during blood circulation increases from 0.7 to 4.5 h after PDA coating, and the injected dose per gram of tumor tissue is 4.6% ID g−1 for AuNR@CuPDA. In addition to computer tomography imaging, the loading of Cu(II) in PDA shell endows AuNR@ CuPDA with magnetic resonance imaging function. Cu(II) doped in PDA shell also exhibits chemotherapeutic behavior, and the tumor inhibitor rate is 31.2%. Further combining 808 nm laser-driven photothermal therapy, tumors were completely ablated, and no recurrence was observed. Liver and renal functions tests and histological analysis of major organs confirm that AuNR@ CuPDA is in good safety. KEYWORDS: gold nanorods, polydopamine, magnetic resonance imaging, computer tomography imaging, thermo-chemotherapy, tumor theranostics

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INTRODUCTION Gold (Au) nanomaterials are of chemical inertness and exhibit versatile functionalities in recent tumor theranostics,1−8 namely the simultaneous realization of imaging diagnosis and therapy.9 Among the widely tested Au-based nanomaterials, Au nanorods (AuNRs) have attracted great attention because of the excellent functionalities in diagnosis and therapy as well as the facility in achieving functional regulation.10−14 Au processes high X-ray absorption coefficient, which is 5.16 cm−2 kg−1 at 100 keV, much higher than that of the other elements.15 It assures AuNRs as a promising computer tomography (CT) imaging contrast agent for tumor diagnosis.16−18 Precise imaging information can indicate tumor size, location, shape, and theranostic agents distribution in the body.19−24 In addition, AuNRs have strong optical extinction capability in the nearinfrared (NIR) region.25−27 Through the method of adjusting aspect ratio, the longitudinal plasma absorption peak of AuNRs can be tuned to diverse wavelength,28−30 assuring AuNRs as photothermal therapy reagents with relatively high photothermal conversion performance.11,31 Moreover, the anisotropic © XXXX American Chemical Society

morphology of AuNRs may accomplish enhanced tumor uptake rate than spherical nanoparticles (NPs).3,32 The small dimension of AuNRs is close to 10 nm, which provides a strong penetration in tumor tissues, whereas another large dimension benefits tumor retention.33−36 The aforementioned advantages make AuNRs common nanomaterials in tumor diagnosis and therapy.12,14 However, the further theranostic applications of AuNRs are still limited by several disadvantages, such as the toxicity of cetyltrimethylammonium bromide (CTAB) brought during the preparation of AuNRs, poor structural stability, relatively low photothermal conversion efficiency, and the quick clearance after systematic administration.37,38 Many attempts about surface modification and polymer coating have been performed to solve these problems with the aim to expand the theranostic applications of AuNRs.39,40 To Received: September 8, 2017 Accepted: December 5, 2017

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DOI: 10.1021/acsami.7b13643 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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ACS Applied Materials & Interfaces

Figure 1. TEM images of AuNRs (a) and AuNR@CuPDA (b). UV−vis absorption spectra (c) and XRD patterns (d) of AuNRs and AuNR@ CuPDA. The ratio in (c) means the molar ratio of AuNRs and DA. The XPS Au 4f (e), N 1s (f), Cu 2p (g), and Cl 2p (h) spectra.

bring novel functions, a diversity of functional molecules were chosen to modify the surface of as-prepared AuNRs, for

example, the modification with folic acid is capable to enhance active targeting in imaging diagnosis and therapy.41 Besides the B


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ACS Applied Materials & Interfaces Scheme 1. Schematic Illustration of the Synthesis Process and Function Mechanism of AuNR@CuPDA

has many advantages. First, the combination of different building blocks enables the integration of multifunctionalities, such as CT, MRI, photothermal therapy, photodynamic therapy, and chemotherapy.18 Second, the highly biocompatible polymer shell greatly lowers the potential toxicity of metal ions and inorganic NPs.46 Third, the polymer shell can greatly improve the thermal, laser, colloidal, and physiological stability of the encapsulated building blocks.47 These nanomaterials are competitive candidates in multimodal theranostic applications. In this work, AuNRs are coated with Cu(II)-doped PDA shell, which produces Cu(II)-doped PDA-coated AuNR (AuNR@CuPDA), and tested for tumor theranostics. In comparison with AuNRs, AuNR@CuPDA shows improved photothermal performance, represented by the red shift and intensity increment of the absorption spectra. PDA coating also leads to a prolonged half-life of AuNRs from 0.7 to 4.5 h during the blood circulation, resulting in a tumor uptake rate of 4.6% ID g−1. Furthermore, Cu(II) doped in the PDA shell is capable of shortening the T1 of surrounding protons, thus lighting up tumor sites under T1-weighted MRI. By combing CT imaging, a dual model imaging is provided for precise tumor diagnosis. The Cu(II) in PDA shell also exhibits toxicity to tumor tissues, and the tumor inhibitor rate is 31.2%. By further combining NIR photothermal therapy, tumors are completely ablated, and no recurrence is observed. Because AuNRs are coated by PDA, the AuNR@CuPDA presents a good safety for theranostic applications.

improvement of the structural stability and biocompatibility, polymer coating can also introduce additional functionalities.6,18,24 For example, poly(ethylene glycol) (PEG)-coated AuNRs exhibit a prolonged blood circulation half-life after intravenous (i.v.) injection into tumor-bearing mice on the account of steric hindrance.42 The coating of AuNRs with polyaniline, polypyrrole, and polydopamine (PDA) can enhance the photothermal performance.43,44 In this context, dopamine (DA) is a material that inherently exists in the human body, and PDA, the polymerization product of DA spontaneously in alkaline condition, has good stability and biocompatibility in vivo.45,46 After PDA coating, the release of the capping ligands of AuNRs can be effectively suppressed, which greatly lowers the toxicity.47 In addition, PDA is negatively charged and can actively repel the attachment of opsonic proteins, thus decreasing the risk of immune capture and prolonging the blood circulation time.48,49 Hence, the accumulation of AuNRs in the tumor tissues and therefore the theranostic efficiency is considered to be enhanced. Moreover, there are large amounts of amino and hydroxyl groups in PDA shell, and the coordination of these groups with metal ions permits to perform metal doping.50 In this scenario, transition metal ions show tremendous potentials in both tumor diagnosis and therapy. 51 Similar to gadolinium complexes, the commonly used magnetic resonance imaging (MRI) contrast agent in clinical studies,52,53 transition metal ions with unpaired electrons in their atomic orbits are able to shorten the longitudinal relaxation time (T1) of the surrounding protons. As a result, under a T1-weighted MRI, target area can be light up.54 For example, copper (Cu) complexes are potential alternatives as MRI contrast agents.55 In addition, Cu ions also exhibit toxicity to cells, showing the potential as chemotherapeutic agents.56 In the previous works,51,57 we have studied the chemotherapy behavior of Cu(II) doped in polymers in vivo. Under the stimulation of tumor microenvironment, Cu(II) ions can release from the polymers and inhibit the growth of tumor tissues. The strategy of using transition metal-doped polymers to coat inorganic NPs

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RESULTS AND DISCUSSION In this study, AuNRs are fabricated via a seed-mediated method.26 As revealed by transmission electron microscopy (TEM), as-prepared AuNRs are 35 × 9 nm2 in size (Figure 1a). Before PDA coating, the positively charged CTAB on the surface of AuNRs is replaced by the negatively charged sodium dodecylsulfate (SDS), so that DA can be actively absorbed onto the AuNRs by the virtue of electrostatic attraction. By in situ polymerization under alkaline environment, a layer of PDA forms on the surface of AuNRs (Scheme 1). Through control C


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Figure 2. Temperature increment of AuNR@CuPDA aqueous solution by altering the power density at fixed concentration of 50 (a), 100 (b), and 150 μg/mL (c). Temperature increment of AuNR@CuPDA by altering the concentration at the fixed power density of 1 (d), 2 (e), and 3 W/cm2 (f). The photothermal conversion efficiency is measured at the laser power density of 3 W/cm2. 100 μg/mL AuNR@CuPDA is added into 1 × 1 × 4 cm3 quartz pool with tinfoil capped to prevent the vaporization of water. The temperature is determined by an electric thermometer above the light path and recorded at the interval of 15 s. The solution is irradiated for 1320 s until the top temperature gets stable and cooled to room temperature under ambient environment. (g) The real-time temperature. Time constants for heat transfer of AuNRs and AuNR@CuPDA are determined to be τ’s = 404.4 s (h) and 348.5 s (i), respectively, by applying the linear time data from the cooling period (after 1320 s) versus negative natural logarithm of driving force temperature.

(Figure 1g). Cu also shows the bonding with O at 935.4 eV, which is attributed to the hydration of water.61 The Cl 2p spectrum exhibits the binding energy at 198.2 and 199.4 eV, confirming the Cu−Cl linkage (Figure 1h).62 Attributed to the PDA shell and Cu(II) doping, the AuNR@ CuPDA shows continuous red shift and intensity increment in the absorption spectra (Figure 1c), which represents the enhancement of NIR extinction capability and photothermal converting performance.57 The molar extinction coefficient at 808 nm increases from 1.7 × 109 to 2.7 × 109 M−1 cm−1 after forming the Cu(II)-doped PDA shell. The photothermal converting performance of AuNRs and AuNR@CuPDA is compared. Under the laser power density of 3 W/cm2, an 808 nm laser is used to heat 2 mL of aqueous solution. By recording the solution temperature variation at the time interval of 15 s, it can be found that AuNR@CuPDA increases over 43 °C in 160 s, whereas the temperature of AuNRs solution is only 33.1 °C (Figure 2g). In addition, the concentration and laser power

of the feeding dose of DA, the thickness of PDA shell can be adjusted. When the DA-to-AuNRs molar ratio is 160 000, the average shell thickness is 8.9 nm and the longitudinal plasmon resonance absorption peak is located in 800 nm (Figure 1b,c). In addition, Cu(II) is introduced into the PDA shell during polymerization through the coordinated interaction with the amino and hydroxyl groups of PDA.51 The as-prepared AuNR@CuPDA is further characterized by X-ray powder diffractometer (XRD) and X-ray photoelectron spectrometer (XPS). Among them, the XRD patterns prove that besides the diffraction peaks of cubic phase AuNRs, other diffraction peaks are consistent with those of copper−ammonia complexes (Figure 1d).58,59 Figure 1e−h presents the XPS Au 4f, N 1s, Cu 2p, and Cl 2p spectra. The binding energy of N exhibits the bonding of N−H, N−Cu, and N−H in ammonium salt at 398.2, 399.5, and 401.8 eV, respectively (Figure 1f).60 As for the element of Cu, the peaks at 934.0 and 939.8 eV represent the linkage of Cu−Cl and Cu−N via coordination interaction D


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Figure 3. (a) KB cells are incubated with different concentration of AuNR@PDA and AuNR@CuPDA, and the cell viabilities are estimated through standard MTT assay. (b) KB cells are incubated with or without 50 μg/mL AuNR@CuPDA for 1 h and then irradiated by an 808 nm laser at the power density of 0, 0.5, 1, 2, and 3 W/cm2 for 5 min. (c−f) Confocal fluorescence images of FDA (green, live cells) and PI (red, dead cells) costaining cells. KB cells are incubated with 50 μg/mL AuNR@CuPDA for 1 h and then irradiated by an 808 nm laser at the power density of 0.33 W/ cm2. Fluorescent images of PI and FDA co-staining cells after combined therapy are taken at 0, 2, 5, and 10 min, respectively. The scale bar is 100 μm. (g−j) The corresponding flow cytometry analysis of figure (c)−(f).

means that the negative surface potential of AuNR@CuPDA is attributed to PDA coating. The AuNR@CuPDA exhibits good stability in a variety of environment, such as water, saline, phosphate buffered solution (PBS), and cell cultures even after 7 days of incubation (Figure S3a,b). AuNR@CuPDA also exhibits good laser stability. At the laser power density of 3.5 W/cm2, the photothermal conversion performance is not affected even after 5 cycles of heating up and cooling down, and there is also no obvious change observed in the absorption spectra (Figure S3c,d). The doping of Cu(II) into AuNR@CuPDA introduces the functionality as a contrast agent in T1-weighted MRI due to the unpaired 3d electron of Cu(II). It endows AuNR@CuPDA with the capability of shortening T1 of the surrounding protons and brightening the targeting area under magnetic field. The performance in MRI test is concentration-dependent and continuous brightening effect is observed with the increase in concentration under a 1.5 T MR clinical scanner (Figure S4a). The T1 is further measured by nuclear magnetic resonance

density dependent temperature increments are also recorded to reveal the photothermal converting capability. As presented in Figure 2a−c, temperature increments increase with the increase in laser power density at fixed concentration of 50, 100, and 150 μg/mL because more energy is applied and converted into heat. Higher concentration also provides higher temperature increments on the account of collective heating effect (Figure 2d−f).63 The heating process is further monitored by a thermal imaging camera (Figure S1). Similar results are observed. Photothermal transduction efficiency (η) is an important evaluation criterion of photothermal performance. The η of AuNR@CuPDA is calculated as 74.4% (Figure 2i), whereas it is only 35.8% for AuNRs without PDA shells (Figure 2h), confirming that AuNR@CuPDA is more efficient in converting NIR irradiation to heat. PDA coating also improves the stability of AuNRs. As shown in Figure S2, the surface potential of AuNR@CuPDA is −36.4 ± 0.6 mV, making it dispersible in aqueous media. Note that the surface potential of pure PDA NPs is −35.2 mV,51 which E


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Figure 4. (a−d) Major liver and renal functions indexes in the liver and renal functions tests. No obvious difference is found between healthy and treated mice. The control group is age-matched healthy mice. Blood circulation of AuNR@CuPDA (e) and AuNRs (f). (g) Biodistribution of AuNR@CuPDA in KB tumor bearing mice at 1 day and 7 days after injection. F


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Figure 5. (a−c) T1-weighted MRI of nude mice bearing KB tumor without AuNR@CuPDA treatment. (d−f) T1-weighted MRI of mice 24 h after the injection of 50 μL 50 μg/mL AuNR@CuPDA solution. (g−i) T1-weighted MRI of mice 7 days after the treatment. Organs identified by I−VI in (a−i) represent heart, liver, spleen, lungs, kidneys, and tumor, respectively. The color bar from blue to red represents the MRI signal from low to high, respectively. Cone beam CT images of mice treated with saline (j) and AuNR@CuPDA (k) 24 h after treatment. G


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Figure 6. In vivo photothermal therapy. The mice are divided into four groups, namely, control group (c, g), laser-only group (d, h), AuNR@ CuPDA by i.v. group (e, i), and AuNR@CuPDA by i.v. + laser group (f). Relative tumor volume (a) growing trend, and average body weight (b) for each group. Photographs of typical mouse bearing tumor model (c−f) and tumors (g−i) are taken from them in each group on the 16th day after injection. The average tumor weight is 1.83, 1.65, 0.86, and 0 g for each group, respectively. The scale bar in (g−i) is 1 cm. The dose of injected AuNR@CuPDA is 250 μg in 50 μL saline per mouse. The laser power density is 0.33 W/cm2.

decreases gradually after 5 min of laser irradiation. At a laser power density of 3 W/cm2, the cell viability is lower than 30%. In comparison, the cell viability remains around 98% for the cells without AuNR@CuPDA incubation (Figure 3b). At the fixed laser power density of 0.33 W/cm2, in vitro photothermal ablation from 0 to 10 min is further studied. The laser-treated KB cells are further stained by fluorescein diacetate (FDA) and propidium iodide (PI), where living cells can only be stained into green by FDA and apoptotic cells into red by PI (Figure 3c−f). An obvious decrease in green and increase in red is observed from the dark field fluorescent images with an increase in irradiation duration, indicating that AuNR@CuPDA is a promising agent for photothermal therapy. This consideration is further corroborated by flow cytometry results (Figure 3g−j). The cell apoptosis analysis shows that the percentages of living cells decrease gradually, which are 98.8, 74.4, 14.3, and 0.3% at the time points of 0, 2, 5, and 10 min. The liver and renal functions investigations are treated as an indicator in evaluating the short-term toxicity of AuNR@ CuPDA. 50 μL of 5 mg/mL AuNR@CuPDA is i.v. injected into the mice. 24 h after injection, 1 mL of blood sample is collected to extract serum for the liver and renal functions test. As shown in Figure 4a−d, major liver and renal functions indexes, such as alkaline phosphatase, alanine transferase, albumin, uric acid, and so on, are all within the normal range compared with age-matched healthy mice, indicating that the short-term toxicity of AuNR@CuPDA is not obvious. Moreover, during the blood circulation, the concentration of

(NMR) spectrometer at a variety of concentration, and the longitudinal relaxation rate (r1) of AuNR@CuPDA is stimulated as 1.89 mM−1 s−1 on the basis of the concentration of Cu(II) (Figure S4b). Besides, Au also processes a higher Xray absorption coefficient, which assures AuNR@CuPDA as a promising contrast agent in CT imaging.15−18 With increasing concentration, the CT signal also gradually increases (Figure S4c). The aforementioned results mean that by combining MRI and CT imaging techniques, AuNR@CuPDA shows the potential as a dual-mode contrast agent in imaging diagnosis. To prove the potential in theranostic applications, AuNR@ CuPDA is first tested with human oral epithelia carcinoma (KB) cells in vitro. The cytotoxicity of AuNR@CuPDA is primarily evaluated through a standard methylthiazolyltetrozolium (MTT) assay by incubating AuNR@CuPDA with cells at different concentration for 24 h. As shown in Figure 3a, AuNR@CuPDA possesses a relative low toxicity for KB cells, and the relative cell viability remains over 83% before the concentration rises above 200 μg/mL. But further increasing the concentration to 500 μg/mL, an obvious decrease in relative cell viability is found, which is 67%. As a contrast, the relative cell viability of AuNR@PDA is higher than that of AuNR@CuPDA. The relative cell viability is still above 83% even at 500 μg/mL. This means that the comparatively high toxicity of AuNR@CuPDA is attributed to the toxicity of doped Cu(II).56,57 Subsequently, KB cells are treated by 808 nm laser in vitro for photothermal ablation. As the laser power density is adjusted from 0.5 to 3 W/cm2, the relative cell viability H


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Figure 7. Infrared thermal images of the mice treated with saline (a) and AuNR@CuPDA (b) under the irradiation of 808 nm laser at the power density of 0.33 W/cm2.

organs, in which the AuNR@CuPDA clearly labels the organs into red and yellow (Figure 5d−f). However, 7 days after i.v. injection, the MRI signal of vital organs shows a dramatic decrease on the account of normal metabolism (Figure 5g−i). The prolonged circulation benefits the accumulation of AuNR@CuPDA in the tumor sites as the result of enhanced permeability and retention (EPR) effect.35 In KB tumor, the retention of AuNR@CuPDA is determined as 4.6 ± 0.2% ID g−1 (Figure 4g), whereas it is only 1.4% ID g−1 for bare AuNRs without PDA modification. As shown in Figure 5a−c, tumor without AuNR@CuPDA treatment is observed with low MRI signal in green. In contrast, 24 h after the i.v. injection, tumor area is brightened into red and yellow clearly (Figure 5d−f), indicating the significant retention of AuNR@CuPDA in tumor on the basis of the EPR effect. Furthermore, under a Planmeca cone beam CT, the tumor area has a strong absorption with Xray, proving the accumulation of AuNR@CuPDA once again (Figure 5j,k). These evidences firmly prove that AuNR@ CuPDA is an effective and promising agent for dual-mode tumor diagnosis. In addition to tumor diagnosis, AuNR@CuPDA can also perform tumor therapies by combining photothermal therapy and chemotherapy. The in vivo tumor therapies are tested in KB tumor model planted in nude mice, and experiment starts when the average tumor volume is over 60 mm3. In the control group, tumors are only treated with saline. The tumor growing

AuNR@CuPDA in blood is monitored for the in vivo pharmacokinetic study by determining the content of Au in blood samples. Based on the laboratory finding from inductively coupled plasma atomic emission spectroscopy (ICP-AES), the half-life time for AuNR@CuPDA in blood is calculated as 4.5 ± 0.3 h, which is about 6-fold longer than that of AuNRs without the PDA coating (Figure 4e,f). The prolonged circulation time in blood contributes to the enhanced stealth effect of PDA modification.51 The negatively charged surface of PDA-coated AuNRs can actively repel the attachment of most negatively charged proteins, thus avoiding the fast clearance by phagocytes.49 The distribution profiles of AuNR@CuPDA in major organs are also evaluated. The Au levels are found to be as high as 7.3 ± 0.2% ID g−1 in the heart, 20.0 ± 0.3% ID g−1 in the liver, 18.9 ± 0.3% ID g−1 in the spleen, 5.4 ± 0.9% ID g−1 in the lungs, and 13.6 ± 1.7% ID g−1 in the kidneys at 24 h after injection. Seven days after injection, the content of Au in these organs shows a significant decrease to 2.6 ± 0.1, 5.9 ± 0.4, 9.9 ± 0.3, 2.4 ± 0.2, and 0.6 ± 0.1% ID g−1 for heart, liver, spleen, lungs, and kidneys, respectively, indicating that AuNR@CuPDA can be slowly metabolized out of the living body (Figure 4g). The biodistribution of AuNR@CuPDA is further revealed by MRI tests. As shown in Figure 5a−c, vital organs exhibit a low MRI signal in green or blue in blanket control. In contrast, 24 h after the i.v. injection, enhanced MRI signal is observed in vital I


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Figure 8. H&E stained splanchnic slices 30 days after the injection of AuNR@CuPDA. The control group is age-matched healthy mice. The thermochemotherapy group is AuNR@CuPDA by i.v. + laser group in our experiments. The scale bar is 50 μm.

50 °C (Figure 7b), and a large area of damage is caused in the tumors (Figure S5b). The synergetic effect of photothermal therapy and chemotherapy achieves complete tumor ablation 5 days after laser treatment (Figure 6f). In comparison, the mice without AuNR@CuPDA injection show negligible temperature change under the same dose of laser irradiation (Figure 7a). It should be mentioned that the tumors ablated by thermochemotherapy do not appear to recrudesce in the following observation for 2 months. These evidences indicate that AuNR@CuPDA is a promising agent for tumor theranostics. The biosecurity of AuNR@CuPDA is also evaluated by monitoring the weight changes and H&E stained vital organs. The AuNR@CuPDA and laser-treated mice exhibit a stable growth in body weight (Figure 6b), indicating a little influence in metabolism. In addition, there is no inflammatory cell infiltration or hydroncus observed in H&E stained histopathological slices of heart, liver, spleen, lungs, and kidneys. And, all of the cells in the above-mentioned organs are basically at the same status compared with healthy mice of the same age (Figure 8). This information confirms that AuNR@CuPDA is of good safety for tumor theranostics.

trend is revealed in Figure 6a. Sixteen days after saline treatment, the average volume of tumors reaches 688 mm3 and weights 1.83 g (Figure 6a,c,g). Similar results are also observed in the laser-only group. Slight difference is observed compared to the tumors in the control group after saline and 0.33 W/cm2 laser treatment. The tumors also grow quickly, and the average volume and weight reach 633 mm3 and 1.65 g, respectively (Figure 6a,d,h). In contrast, tumors with i.v. injection exhibit an obviously depressed growth trend in the first 10 days (Figure 6a). Besides, on fourth day, locally damaged cancerous cells can be found in the hematoxylin-eosin (H&E) stained tumor slice (Figure S5a) as a result of the chemotherapeutic behavior of Cu(II) in AuNR@CuPDA. The release of doped Cu(II) from AuNR@CuPDA can be stimulated by the glutathione (GSH) in the tumor area. This is a coordination competition induced ion-release process. The foremost interaction force in Cu(II)doped PDA shell is the Cu−N coordination interaction. However, the coordination interaction between −SH and Cu(II) is much stronger than the Cu−N coordination.57 Besides −SH, GSH possesses −NH2, −NH−, and −COOH groups, which can also coordinate with Cu(II). As a result, GSH is capable of stimulating the release of doped Cu(II) in PDA. To confirm this, the released content of Cu(II) is tested and determined by adding GSH into the aqueous solution of AuNR@CuPDA. During the period of 24 h of continuous stirring under the environment of 10 mM GSH, released Cu(II) is determined by ICP-AES. As revealed in Figure S5c, Cu(II) has a fast release rate, and more than 10.5% of Cu(II) doped in PDA shell is released in the first hour. Furthermore, after 24 h incubation, the percentage of released Cu(II) is up to 71.8. However, tumor growth cannot be fully depressed by chemotherapy alone. Ten days after the i.v. injection of AuNR@CuPDA, the tumors exhibit a faster growth rate than in the first 10 days (Figure 6a,e,i). The tumor growth inhibition rate of chemotherapy is calculated as 31.2% on the 16th day after injection (Figure 6a). Hence, to realize the complete ablation of tumors, photothermal therapy combined chemotherapy is performed with a 808 nm laser. After irradiation under 0.33 W/cm2 for 12 min, tumor area shows a fast temperature increment over 43 °C. Upon continuous irradiation for another 6 min, the local temperature reaches

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CONCLUSIONS In conclusion, we show the fabrication of AuNR@CuPDA with good theranostic performance. Besides the improvement of biocompatibility and physiological stability, the PDA shell increases the photothermal performance and prolongs blood circulation time of AuNRs. The half-life of AuNRs during blood circulation increases from 0.7 to 4.5 h after PDA coating, and the tumor uptake rate is 4.6% ID g−1 for AuNR@CuPDA. The loading of Cu(II) in PDA shell endows AuNR@CuPDA with the function of MRI. Further combining the CT imaging from AuNRs, a dual-model tumor-imaging diagnosis is achieved. Moreover, Cu(II) in the PDA shell exhibits chemotherapeutic behavior, and the tumor inhibitor rate is 31.2%. By combining NIR photothermal therapy, tumors are completely ablated, and no recurrence is observed. Safety tests prove that AuNR@ CuPDA is safe and reliable. Because of the easy preparation, high tumor retention, excellent theranostic performance, and good safety of AuNR@CuPDA, the current strategy of using transition metal-doped polymer to coat AuNRs gives a J


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and annexin-V-FITC double staining. Briefly, after laser treating, the cells from each group were collected and washed by annexin-binding buffer and PBS. Afterward, 5 μL of PI and 5 μL of annexin-V-FITC solution were added in cell suspension, respectively. After being cultured for 15 min at room temperature, 500 μL of annexin-binding buffer was added. All of these co-stained cells were analyzed with flow cytometry at 530 and 575 nm under 488 nm excitation. Pharmacokinetic and Safety in Vivo. To study the detailed pharmacokinetics of AuNR@CuPDA, the blood circulation profiles were determined. 50 μL of 5 mg/mL AuNR@CuPDA aqueous solution was i.v. injected into the mice. Then, 8 μL blood of mice was quantitatively drew from the caudal vein of the mice at different time points 0, 1, 2, 4, 6, 12, and 24 h after injection. Later on, aqua regia was used to dissolve the blood samples, and deionized water was used in the dilution of 10 mL. To show the effect of PDA coating, the blood circulation of AuNRs without coating was also studied in the same way as described above. The Au levels in blood samples were determined through ICP-AES measurement. As for in vivo safety research, 50 μL of 5 mg/mL AuNR@CuPDA was i.v. injected into five healthy balb/c mice. Then, 24 h after injection, 1 mL blood samples were collected before the mice were euthanized. There were also another five healthy mice in the control group. All of the blood samples were used for liver and kidney functions tests. Then, to study the biodistribution of AuNR@CuPDA in vivo, major organs of the above-mentioned mice were dissected and dissolved with aqua regia for ICP-AES. The group without treatment was used as control. The group treated with AuNR@CuPDA was named as 1 day group. Another five balb/c mice i.v. injected with AuNR@CuPDA were euthanatized after 7 days and their major organs were also harvested. The group was called 7 days group. For biodistribution study, Au levels in major organs were determined by ICP-AES after hearts, livers, spleens, lungs, and kidneys from all of these mice were disolved by aqua regia. The tumor uptake of AuNR@ CuPDA was also studied. 50 μL of 5 mg/mL AuNR@CuPDA aqueous solution was i.v. injected into the KB-bearing mice, tumors of those mice were harvested after 24 h and dissolved by aqua regia to determine the Au levels in the tumors using ICP-AES. Animal Experiments. Twenty eight of balb/c nude mice bought from Beijing Vital River Laboratory Animal Technology Co. Ltd. were 4 weeks old. Our experiment was conducted under the regulations of Animal Experiment Center of Life Science Institute, Jilin University. After feeding 1 week, 150 μL cell suspension containing 2 000 000 KB cells was subcutaneously injected to build tumor model in the right hind leg of the mice. A digital caliper was used to monitor the tumor size every other day. When the average tumor volume grew to 60 mm3, the KB-bearing mice were grouped into 4 groups randomly, named control group, laser control group, i.v. injection group, and i.v. injection + laser group. As for the i.v. injection group and i.v. injection + laser group, the mice were i.v. injected with 50 μL of 5 mg/mL AuNR@CuPDA aqueous solution. 24 h after injection, an 808 nm laser was used to treat the mice in laser control group and i.v. injection + laser group for 18 min at 0.33 W/cm2. In the days that followed, the tumor volumes and weights of the mice were recorded on a separate day. In this process, tumor volumes were calculated by an estimation formula: V = D2L/2 (V: tumor volume, mm3; D: short axis length of tumor, mm; L: long axis length of tumor, mm). Sixteen days after AuNR@CuPDA injection, tumors from every group were weighted and photographed after complete tumor excision. Afterward, the resected tumor specimens of each group were fixed with 10% formalin and stained by H&E dye for further pathological examination. In the i.v. injection group, one tumor was taken on fourth day to study the chemotherapeutic behavior. As for the i.v. injection + laser group, one tumor was excised at once after laser irradiation for subsequent histopathological examination by H&E staining to observe the cellular morphology. Lastly, the chemotherapeutic activity of Cu(II) was studied. 10 mg of AuNR@CuPDA was added into 10 mL of 10 mM GSH aqueous solution. Then, at different time points of 0, 1, 2, 4, 8, 12, and 24 h, 1 mL of the mixture was centrifuged and the supernatant was used to determine the dose of released copper ions by ICP-AES.

competitive approach for designing and fabricating multimodal theranostic nanodevices.

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EXPERIMENTAL SECTION

Materials. In this work, all of the reagents used were analytically pure. Cetyltrimethylammonium bromide (CTAB) and sodium dodecylsulfate (SDS) were purchased from Aladdin. L-Ascorbic acid (AA), glutathione (GSH), 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), tris(hydroxymethyl) aminomethans (Tris), and Dopamine·HCl (DA) were bought from Sigma-Aldrich. Chloroauric acid (HAuCl4·4H2O), sodium borohydride (NaBH4), and silver nitrate (AgNO3) were purchased from the Sinopharm Chemical Reagent Co. Ltd. Fluorescein diacetate (FDA), propidium iodide (PI), annexin-binding buffer, and Annexin-V-FITC were purchased from Nanjing Keygen Biotech Company. Copper chloride dehydrate (CuCl2·2H2O), saline, phosphate buffered solution (PBS), and cell culture were all ordinary commercial products. We used deionized water in all of our experiments. Preparation of AuNR@CuPDA. AuNRs were prepared from chloroauric acid via a seed-medium method.26 In brief, 36.5 mg CTAB and 0.25 mL HAuCl4 (10 mM) were foremost dissolved in 9.75 mL H2O, and 0.6 mL of ice-cold NaBH4 (10 mM) was added quickly. The obtained brownish solution was stirred for about 1 min and then kept at 25 °C for 2.5 h to get the seed solution. To prepare AuNRs, 2.9160 g CTAB was foremost dispersed in 80 mL H2O, then 1.28 mL AgNO3 (10 mM), 8 mL HAuCl4 (10 mM), as well as 0.88 mL AA (100 mM), were added in the order. Afterward, 0.6 mL of as-prepared seed solution was added and the mixture was stored in 28 °C water bath over night. The mixed solution was centrifuged at 10 000 rpm for 15 min to separate the products. Then, excess reactants were removed by washing twice using deionized water. Finally, the collected AuNRs were dispersed in 20 mL deionized water for subsequent experiments, which were stable for weeks without obvious precipitation. To prepare AuNR@CuPDA, 0.3 mL SDS aqueous solution (10 mM) was added into AuNR solution to perform a surface ligand exchange. Then, CTAB and excess SDS were removed by centrifugation. Supernatant was discarded, and the precipitate was redispersed in 20 mL of Tris buffer solution. Lastly, 3.03 mg DA and 0.91 g CuCl2·2H2O dissolved in 1.6 mL deionized water were added. After stirring overnight at room temperature, AuNR@CuPDA was obtained after centrifugation and washing twice. The preparation process of AuNR@CuPDA is also illustrated in Scheme 1. Afterward, AuNR@CuPDA was dispersed in H2O, saline, PBS, and RPMI 1640 cell culture medium containing 10% fetal bovine serum to demonstrate the physiological stability in various environments. Cytotoxicity Tests and Photothermal Therapy in Vitro. KB cells were incubated with AuNR@CuPDA in dissimilar concentrations for 24 h in standard cell media, and followed by standard MTT assay. The optical density value at 490 nm could reveal the relative cell viability for each sample. Each experiment was repeated five times. As for in vitro photothermal therapy study, the KB cells were cultured with AuNR@CuPDA solution for 1 h at the concentration of 50 μg/ mL, and subsequently irradiated by 808 nm NIR laser for 5 min at different power densities. In the control group, the KB cells were irradiated by laser at the same power density for the same time. The only difference was the lack of AuNR@CuPDA. Then, the relative cell viability was learned by MTT assay. Each experiment was also repeated for five times. FDA and PI Co-Stain Assay, and Flow Cytometry Analysis. 30 000 KB cells were incubated in a 6-well cell culture plate, and 50 μg of AuNR@CuPDA dissolved in 1 mL cell culture medium was used to replace the intrinsic cell culture medium and incubated for 1 h. After the laser irradiation of 0.33 W/cm2 for 0, 2, 5, and 10 min, FDA and PI co-stain assay method was used to evaluate the treating efficacy in each well. FDA and PI of 1 μg/mL were used to stain the live and apoptosis cells, and the staining times were 15 s and 15 min, respectively. A fluorescence microscope was used to take the fluorescent photographs of cells. For flow cytometry analysis, the aforementioned KB cells from different groups were used to perform the apoptosis analysis using PI K



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Characterization. Shimadzu 3600 UV−vis−NIR spectrophotometer was used to perform UV−vis−NIR absorption spectra. Hitachi H800 electron microscope and a charge-coupled device camera were used to perform the transmission electron microscopy (TEM) investigation. Rigaku X-ray diffractometer with Cu Kα radiation (λ = 1.5418 Å) was used to perform the X-ray powder diffraction (XRD) analysis. VG ESCALAB MKII spectrometer with an Mg Kα excitation (1253.6 eV) was used to perform the X-ray photoelectron spectroscopy (XPS) investigation. ζ-Potential was performed using a Malvern Zetasizer NanoZS. T1 relaxation time was measured by a BRUKER AVABCEIII500 NMR spectroscope. CT images were acquired using a clinical use Planmeca cone beam CT. GE Signa 1.5 T clinical use MRI unit was used to recorded the T1-weighted MRI images. LEO diode laser (808 nm) was employed in photothermal effect study. Olympus IX71 inverted fluorescence microscope was used to acquire fluorescent images of KB cells. BD FACSCalibur was used to perform the flow cytometry analysis. The Au and Cu concentrations were measured by ICP-AES measurements with a PerkinElmer Optima 3300DV. Infrared thermal images were monitored by a FLUKE infrared (IR) thermal camera.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.7b13643. Additional IR thermal photos, surface potential, colloidal stability, photothermal stability, MRI, and CT of AuNR@CuPDA, as well as tumor slices and Cu(II) release from AuNR@CuPDA (PDF)

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Research Article

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (Z.L.). *E-mail: [email protected] (H.S.). *E-mail: [email protected]. Fax: +86 431 85193423 (H.Z.). ORCID

Yi Liu: 0000-0003-0548-6073 Hongchen Sun: 0000-0002-5572-508X Bai Yang: 0000-0002-3873-075X Hao Zhang: 0000-0002-2373-1100 Author Contributions

H.Z. supervised and proposed the project. H.Z., S.W.L., M.L., Y.L., Z.M.L., H.C.S., and B.Y. designed and performed the experiments and co-wrote the paper. L.W, D.D.W., Z.Q.S., S.Y.L., R.G., and X.Z. participated in most experiments. All of the 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 work was partially supported by National Natural Science Foundation (NSFC) of China (51603084, 51425303, 21374042); JLU Science and Technology Innovative Research Team 2017TD-06; and the Special Project from MOST of China. The authors would like to thank Prof. Deli Wang and Animal Experiment Center of Life Science Institute, Jilin University for the help in animal experiments. L


Research Article

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Cu(II)-Doped Polydopamine-Coated Gold Nanorods for Tumor

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