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Cu2+-Loaded Polydopamine Nanoparticles for Magnetic Resonance Imaging-Guided pH- and Near-Infrared-Light-Stimulated Thermochemotherapy Rui Ge,† Min Lin,† Xing Li,‡ Shuwei Liu,† Wenjing Wang,† Shuyao Li,† Xue Zhang,† Yi Liu,† Lidi Liu,*,§ Feng Shi,*,∥ Hongchen Sun,*,‡ Hao Zhang,*,† and Bai Yang† †

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, People’s Republic of China ‡ Department of Oral Pathology, School and Hospital of Stomatology, Jilin University, Changchun 130021, People’s Republic of China § Department of Spinal Surgery, The First Hospital of Jilin University, Changchun 130021, People’s Republic of China ∥ Ophthalmology Department, Heilongjiang Provincial Hospital, Harbin 150036, People’s Republic of China S Supporting Information *

ABSTRACT: Cancer multimodal treatment by combining the effects of different theranostics agents can efficiently improve treatment efficacy and reduce side effects. In this work, we demonstrate the theranostics nanodevices on the basis of Cu2+-loaded polydopamine nanoparticles (CuPDA NPs), which are able to offer magnetic resonance imaging (MRI)guided thermochemotherapy (TCT). Systematical studies reveal that after Cu2+ ions loading, the molar extinction coefficient of PDA NPs is greatly enhanced by 4 times, thus improving the performance in photothermal therapy. Despite Cu2+ ions being toxic, the release of Cu2+ is mainly stimulated in acidic environment. Once the NPs deposit in the slightly acidic tumor microenvironment (pH ≈ 6.5−6.8), the release rate boosts ∼30%, which effectively avoids the systematic toxicity during chemotherapy. Meanwhile, due to the increment of the electron−proton dipole−dipole interaction correlation time τC, the spin−lattice relaxation time (T1) for PDA NPs is found to be shortened by Cu2+ loading, which boosts the longitudinal relaxivity (r1). Hence, CuPDA NPs can be used as T1-weighted contrast agent in MRI. In addition, due to the naturally existing DA in the human body with stealth effect, CuPDA NPs have an outstanding tumor retention rate as high as 8.2% ID/g. Further in vitro and in vivo tests indicate that CuPDA NPs possess long blood circulation time, good photothermal and physiological stability, and biocompatibility, which are potential nanodevices for MRI-guided TCT with minimal side effects. KEYWORDS: polydopamine nanoparticles, theranostics agent, magnetic resonance imaging, thermochemotherapy, tumor retention rates

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carbon-based nanomaterials,18 and so forth. Despite their good performance in primary animal experiments, the long-term toxicity also raises concerns due to the accumulation of nonbiodegradable artificial materials in the body, which sheds doubt in further clinical applications.19−21 This obstacle is considered to be solved by using biomimetic materials.22 For example, dopamine (DA) is naturally existing in the human body and can convert into polydopamine (PDA) through self-polymerization under alkaline conditions.23,24 PDA is biodegradable in the presence of hydrogen peroxide, an endogenous molecule produced by reduced nicotinamide

INTRODUCTION Design and construction of nanodevices for tumor theranostics is one of the most important branches of nanoscience and nanotechnology.1 Promoted by the rapid progress in the preparation of nanomaterials, a variety of multifunctional nanodevices with targeting,2 labeling,3,4 drug and gene delivery,5,6 chemotherapy,7 photothermal therapy, and photodynamic therapy8,9 are developed in the past 5 years.10 By embedding the building blocks with specific theranostic functionalities into a single nanocarrier, the nanodevices are capable of accomplishing tumor diagnosis and combined therapies simultaneously.11 To date, the artificial nanocarriers mainly include organic polymer nanoparticles (NPs) and inorganic silica NPs,12,13 while the therapeutic building blocks include noble metal NPs,14,15 copper chalcogenides NPs,16,17 © XXXX American Chemical Society

Received: April 21, 2017 Accepted: May 29, 2017 Published: May 29, 2017 A

DOI: 10.1021/acsami.7b05583 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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ACS Applied Materials & Interfaces

Figure 1. (a−d) TEM images of CuPDA NPs that are prepared with a DA-to-Cu2+ molar feed ratio of 1:0 (a), 1:0.5 (b), 1:1.25 (c), and 1:2 (d). (e) UV−vis absorption spectra of CuPDA NPs with different DA-to-Cu2+ feed ratios. (f) Summary of the absorbance at 808 nm of CuPDA NPs with different DA-to-Cu2+ feed ratios but the same concentration.

MRI images. Guided and monitored by MRI, further combining photothermal therapy with chemotherapy, the synergistic effect of thermochemotherapy (TCT) and imaging will improve tumor treating efficacy. In this work, we demonstrate that Cu2+-loaded PDA (CuPDA) NPs can serve as a novel theranostic agent for simultaneous MRI and TCT. By loading Cu2+, the NIR absorbance and photothermal conversion efficiency of PDA NPs are greatly improved and therefore the photothermal performance is enhanced. Meanwhile, the release of Cu2+ can be stimulated in response to acid pH. Compared to normal healthy tissues (pH ≈ 7.4), the extracellular environment of many sold tumors displays weak acidity (pH ≈ 6.5−6.8), which avoids damage to surrounding tissues. Moreover, CuPDA NPs can also be used as T1-weighted MRI contrast. Last, because of the naturally existing DA in the human body, CuPDA NPs have an excellent stealth effect with a high tumor retention rate and long blood circulation half-life. Both in vitro and in vivo experiments indicate that CuPDA NPs are excellent theranostics nanodevices for performing MRI-guided TCT.

adenine dinucleotide phosphate (NADPH) oxidases, which widely exist in phagocytes and many organs.25 Recent studies reveal that PDA NPs with a diameter bigger than 50 nm are capable to absorb light in the near-infrared (NIR) region and convert into heat energy, showing potential as an agent for performing photothermal therapy.26 Another advantage of PDA NPs is their negative surface charges, which repels most of the protein attachment during blood circulation.27 This stealth effect of PDA NPs prolongs the half-life in blood, thus enhancing the tumor uptake on the basis of enhanced permeability and retention (EPR) effect even without surface modification.28 However, apart from the virtues in biocompatibility, biodegradability, and stealth effect, PDA NPs can merely be used as a photothermal agent. The functionalities of PDA NPs should be further enriched with the motivation of imaging and combined therapies to achieve multifunctional diagnosis and enhanced tumor treating efficacy.29 One of the methods to enrich the functionalities of nanodevices is the introduction of metal ions with theranostics properties, which in return improves the safety of metal ions.30 For example, clinically available Gd complexes are widely used as contrast agents for magnetic resonance imaging (MRI) tests.31 Though Gd3+ is chelated by multidentate organic ligands to depress toxicity caused by free ions, it still introduces nephrotoxicity issues to patients in clinics.32 Hence, it is reasonable to confine metal ions within polymer NPs since polymer envelopment can prevent release of the toxic component.33 Besides Gd3+, some transition metals like Mn2+, Fe3+, and Cu2+ are able to shorten the longitudinal relaxation of protons in magnetic fields, acting as alternative contrast agents for MRI.34 In addition, Cu2+ is also reported for chemotherapy under proper stimulation and controlled release.35 In this context, by loading Cu2+ into PDA NPs, the NPs are considered to lighten up the targeted area in T1-weighted

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RESULTS AND DISCUSSION Preparation and Characterization of CuPDA NPs. CuPDA NPs with various Cu2+-loading ratios are prepared through the oxidation and self-polymerization of DA in a mixture of Tris-buffer solution and ethanol at room temperature.36 In the alkaline solution, DA is oxidized and followed to form 5,6-indolequinone (DHI) via a 1,4 Michael-type addition. DHI and its oxides are capable of forming multiple isomers with different degrees of polymerization, such as dimers and oligomers. These oligomers can assemble into cross-linked polymers through the reverse dismutation reaction. The metal ions, such as Cu2+, Fe3+, Mn2+, etc., can coordinate with the functional groups of PDA including amino, carboxy, imine, oB


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Figure 2. (a−c) TEM images of the CuPDA NPs with average diameters of 51 (a), 119 (b), and 188 nm (c). DA-to-Cu2+ molar feed ratio is 1:1.25. (d) Mass extinction spectra of CuPDA NPs with different diameters. (Inset) Mass extinction spectra of CuPDA NPs with different diameters from 780 to 820 nm. (e) Mass extinction coefficient at 808 nm of CuPDA NPs with different diameters. (f) Molar extinction spectra of PDA and CuPDA NPs with a diameter of 51 nm.

revealed by X-ray diffraction (XRD) measurement. All diffraction peaks belong to tetragonal (NH4)2CuCl4·2H2O (Figure S1a and Table S2), confirming the coordinative interaction between Cu2+ and the amino groups in CuPDA NPs.42 In comparison, pure PDA NPs merely exhibit a syncretic wide peak from 20° to 30°, which means that the crystallization of PDA is greatly influenced by Cu2+ loading. In order to further analyze the amorphous structure in CuPDA NPs, the coordination of Cu2+ with PDA is also confirmed by energy-dispersive X-ray spectroscopy (EDS) (Figure S1b), which shows an average Cu:Cl atom ratio of 6:1. A small amount of chlorine indicates that there are other negative counter groups in the NPs, such as hydroxyl and carboxyl that are produced during the polymerization of DA. The coordination of Cu2+ with these groups is confirmed by X-ray photoelectron spectroscopy (XPS). The XPS survey spectrum of CuPDA NPs presents five peaks at 201.3, 284.8, 399.7, 533.3, and 934.7 eV, corresponding to Cl 2p, C 1s, N 1s, O 1s, and Cu 2p characteristic peaks, Figure S2. The Cu 2p spectrum can be deconvolved into three peaks, correlating to the binding energy of Cu−Cl at 932.3 eV, Cu−O at 934.7 eV, and Cu−N at 942.9 eV (Figure S3a).43 It proves that Cu2+ can coordinate with chloride ion, amino, hydroxyl, and carboxyl. The N 1s spectrum further reveals the presence of N−H (398.4 and 402.3 eV), N−Cu (399.7 eV), and NC (400.5 eV) interactions (Figure S3b), confirming the coordination of Cu2+ with PDA.44 Both peaks at 198 and 199.7 eV in the Cl 2p spectrum result from Cl−Cu interaction (Figure S3c).45 The O 1s spectrum at 531 and 532.3 eV is in good agreement with the O−Cu and O−H linkage (Figure S 3d).46 To further confirm the coordination of Cu2+ with PDA, Fourier transform infrared (FTIR) spectra are measured. As shown in Figure S1c, the peaks of DA at 3352−2959 cm−1 are assigned to the hydroxyl

quinone, and phenol groups and accelerate the polymerization by increasing the local concentration of oligomers.37 As revealed by TEM observation, the size and morphology of CuPDA NPs are independent of the DA-to-Cu2+ feed ratio (Figure 1a−d). Figure 1e shows the UV−vis−NIR spectra of CuPDA NPs that are prepared with different DA-to-Cu2+ ratios. Because 808 nm is one of the most frequently used wavelengths for NIR photothermal tumor ablation, the optical absorption of CuPDA NPs with different Cu2+-loading ratios at 808 nm is compared. With the increase of Cu2+ feeding amount, the amount of Cu2+ in CuPDA NPs gradually increases along with the change of absorption spectra (Figure 1f and Table S1). By fixing the concentration of DA, the as-prepared CuPDA NPs exhibit the highest absorbance at 808 nm with a DA-to-Cu2+ feed ratio of 1:1.25. According to our previous study, the increased absorption in the UV−vis−NIR region is attributed to formation of Cu2+ complexes.38 For CuPDA NPs, the Cu2+ interacts with PDA through coordinative interaction, because PDA possesses a large number of amino, hydroxyl, and carboxyl groups.39 At lower Cu2+ ratio, the tetracoordinated structure is dominant, which leads to stronger NIR absorption than other the less coordinated structure.40 With the increase of Cu2+ ratio, the number of tetracoordinated structures also increases, resulting in the observed absorption increment from 1:0 to 1:1.25 DA-to-Cu2+ feed ratio. As the Cu2+ ratio is further increased, the excess Cu2+ prefers to form tertiary-, secondary-, and primary-coordinated structures with PDA, reducing the number of tetracoordinated structures and therefore the absorption intensity.41 The coordination of Cu2+ with PDA NPs was further studied. The Cu2+ in PDA may be in a variety of forms; part of them are in amorphous structures, and others are in crystalline form. The change of the crystalline form of PDA in the presence of Cu2+ is C


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extinction coefficient, another factor to evaluate the photothermal performance is photothermal transduction efficiency (η). The calculated η of 51, 119, and 188 nm NPs is 54.8%, 45.7%, and 25.5%, respectively. The larger CuPDA NPs possessing lower η is attributed to the stronger Rayleigh scattering.29 In addition, the η of pure 51 nm PDA NPs is 37.6%, which is remarkably lower than that of the CuPDA NPs with the same size (54.8%) (Figure S7 and Calculation S2). The higher η of CuPDA NPs results from the coordination between Cu2+ and PDA, which enhances the electron-delivery efficiency like other Cu2+ complexes.35,48 As a result, Cu2+loaded PDA NPs indicate higher η than pure PDA NPs. The good photothermal performance indicates that the CuPDA NPs are potential candidates for photothermal therapy. In further experiments, small CuPDA NPs with a diameter of 51 nm are used, because of the best photothermal performance. There are two reasons that smaller NPs with a diameter less than 51 nm are not chosen. In this context, 21 nm CuPDA NPs are prepared and compared with 51 nm CuPDA NPs (Figure S9). First, the molar extinction coefficient and η of 21 nm CuPDA NPs are 2.1 × 108 M−1 cm−1 and 57.3%, respectively (Figure S9a−c). Compared to the 51 nm CuPDA NPs, although the η of 21 nm ones increases due to the weak Rayleigh scattering, the molar extinction coefficient decreases obviously. The reason is that 21 nm CuPDA NPs have lower Cu2+ content (4.8%) than 51 nm ones (14.5%). Hence, 51 nm CuPDA NPs have better photothermal performance. Second, from the viewpoint of practical applications, 21 nm CuPDA NPs have shorter blood circulation half-life (0.79 ± 0.1 h) and lower tumor retention rate (2.7% ID/g) (Figure S9d). Such small NPs cannot be retained in tumor tissue effectively because they are able to re-enter the bloodstream.27 The as-prepared CuPDA NPs possess good photothermal and physiological stability (Figure S10). After five cycles of heating and cooling, the photothermal performance of CuPDA NPs is unchanged (Figure S10a), while the absorption intensity of CuPDA NPs increases slightly due to the evaporation of a small amount of water (Figure S10b). Figure S10c shows the physiological stability of CuPDA NPs in various environments. CuPDA NPs are well dispersible in water, saline, PBS, and cell culture with and without serum for 7 days. These results confirm that CuPDA NPs are stable enough for further theranostic applications. Apart from photothermal therapy, CuPDA NPs are also potentially useful for chemotherapy due to the existence of toxic Cu2+. The pH-sensitive release of Cu2+ from CuPDA NPs in a variety of physiological environments is evaluated, including pH 6.5−6.8, which is consistent with the tumor microenvironment, pH 5.9, which is consistent with intracellular condition, and pH 7.4, which is consistent with blood.49 Four kinds of phosphate-buffered salines with different pH are mixed with the same concentration of CuPDA NPs. After stirring, the solution is centrifuged and the released Cu2+ in supernatant is determined by ICP. Figure S11a shows that at 4 h the release of Cu2+ is saturated and almost remains constant until 24 h. Within 4 h, less than 10% of Cu2+ ions are released at pH 7.4, but more Cu2+ ions are rapidly released from NPs in acidic environments, discharging 16% at pH 6.8, 39% at pH 6.5, and over 50% at pH 5.9 (Figure S11a). Simultaneously, with the decline of pH from 7.4 to 6.8 to 6.5 to 5.9, CuPDA NPs display the average ζ potential of −15.0, −18.1, −23.4, and −27.0 mV. The average ζ potential of pure PDA NPs is −35.2 mV (Figure S11b). Note that Cu2+ is positively charged. The

asymmetric stretching vibration. The peaks at about 2719− 2427 cm−1 result from the amino stretching vibration. Compared to DA, the peaks of PDA NPs at 3352−2959 and 2719−2427 cm−1 disappear into a broad peak, indicating that the hydroxyl and amino are consumed during DA polymerization. Similarly, the peak intensity of these two positions decreases in the FTIR of CuPDA NPs. It also proves that during polymerization the coordination of Cu2+ with PDA NPs consumes the hydroxyl and amino. The peaks of DA at about 1617−556 cm−1 correspond to the characteristic absorption peaks of the DA benzene ring. PDA and CuPDA NPs give broad peaks at the same positions, resulting from stretching and deformation of aromatic rings.47 The change of infrared peaks are all consistent with the previous literature.26 Compared to DA, 1H NMR analysis shows that most of the peaks disappear in PDA and CuPDA NPs. The peak at 2.5 ppm is the proton from carbon of the benzene ring branched chain (δ 3.33, water peak; δ 0, TMS peak). In addition, other protons are all involved in the polymerization. Because the polymerization of DA is very complicated, involving amino, hydroxyl, and carboxyl, it is still difficult to determine the specific groups that Cu2+ coordinates with. Hence, combined with elemental analysis and inductively coupled plasma optical emission spectrometry (ICP-OES), the formula of CuPDA NPs is speculated as [C8NH8O2Cu0.41Cl0.08]n. The molecular weight of CuPDA NPs is determined as 7.5 × 107. Theranostics Potential of CuPDA NPs. To tune the size of CuPDA NPs, the amount of DA monomer is altered from 2.6 to 5.2 to 7.8 mM by fixing the DA-to-Cu2+ ratio at 1:1.25. With the increase of DA amount, the diameter of as-prepared CuPDA NPs increases from 51 to 119 to 188 nm (Figure 2a− c). On the basis of UV−vis−NIR absorption spectra (Figure S4), the mass extinction spectra of differently sized CuPDA NPs are compared in Figure 2d. Although the maximum absorbance appears at 600 nm, the reason we choose 808 nm NIR is that compared to the 600 nm visible light, 808 nm NIR light can penetrate the tissue to reach the deep position and it is safer. Under the same concentration, 51 nm CuPDA NPs exhibit the highest absorption at 808 nm, with a mass extinction coefficient of 0.06 cm−1 mg−1, which is higher than 119 (0.02 cm−1 mg−1) and 188 nm (0.01 cm−1 mg−1) CuPDA NPs (Figure 2e and Calculation S1). A comparison of the molar extinction coefficient of PDA and CuPDA NPs with the same diameter is also performed. The molar extinction coefficient of CuPDA NPs is almost 4-fold (6.1 × 108 M−1 cm−1) that of PDA NPs (1.5 × 108 M−1 cm−1) (Figure 2f and Calculation S1). It means that CuPDA NPs possess better photothermal performance than pure PDA NPs. Under 3.5 W/cm2 808 nm NIR laser irradiation, 75 μg/mL 51 nm CuPDA and PDA NPs, respectively, show a temperature increment of 42.2 and 21.5 °C (Figure S5a). The influence of other factors on the temperature increment, such as the concentration of CuPDA NPs and the power intensity of incident laser, is also shown (Figure S5b,c). To reveal the size effect of CuPDA NPs on the photothermal performance, the aqueous suspensions of 51, 119, and 188 nm CuPDA NPs are exposed to 808 nm laser for 1200 s with an output of 3.5 W/cm2 (Figure S5d). With an increase of NPs size, the temperature increment declines from 42.2 to 20.3 °C, which is consistent with the variation of the mass extinction coefficient (Figure 2d). The size effect is also studied by an IR thermal camera. At the same mass concentration, the temperature increment of 51 nm CuPDA NPs is much higher than 119 and 188 nm NPs (Figure S6). Besides the mass D


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Figure 3. TCT of cells in vitro. (a) KB and 293 cells are incubated with different concentrations of PDA or CuPDA NPs for 24 h, and cell viabilities are estimated through standard MTT assay. (b) KB cells are incubated with or without 50 μg/mL CuPDA NPs for 2 h, and then they are irradiated by an 808 nm laser with a power density of 1, 1.5, 2, and 3 W/cm2 for 10 min. (c) Schematic illustration of the photothermal therapy. (d−f) Confocal fluorescence images of FDA (green, live cells) and PI (red, dead cells) costained cells after photothermal ablation with the images taken at three different locations in the culture dish: (d) far from the irradiation, (e) close to the irradiation, and (f) under the irradiation. Scale bar is 200 μm. Diameter of CuPDA NPs is 51 nm.

loading of Cu2+ in PDA NPs will lower the ζ potential. In our experiment, with the decrease of pH, the NPs become more negative. It means more positively charged Cu2+ ions are released.50 This result is consistent with the Cu2+ released percentage in various physiological environments, namely, the release of loaded Cu2+ ions in CuPDA NPs is promoted under acidic pH environment. CuPDA NPs are also capable of shortening the T1 of protons in water as an effective T1 contrast agent in MR imaging. It possesses a longitudinal relaxivity (r1) of 5.39 mM−1 s−1 at pH 7.4, superior to the commercially used Gd-based contrast agent, Magnevist (4.25 mM−1 s−1) (Figure S12a).51 Although the r1 decreases to 3.66 mM−1 s−1 at pH 6.5 because of the release of Cu2+ from CuPDA NPs in acidic environments, it is still higher than CuCl2 (0.21 mM−1 s−1) and PDA NPs (0.76 mM−1 s−1). According to the previous reports,52 the observed longitudinal water proton relaxation rate (R1obs) in a solution containing a paramagnetic complex is given by two terms R1obs =

1 1 1 = w + p obs T1 T1 T1

these factors is the Solomon−Bloembergen−Morgan equation53 2 2 2 7τC ⎞ 1 2 s(s + 1)γ g β ⎛ 3τC ⎟ ⎜ = + p 2 2 6 T1 15 1 + ωs2τC2 ⎠ r ⎝ 1 + ω1 τC

+

⎞ τC 2s(s + 1) ⎛ A ⎞2 ⎛ ⎜ ⎟ ⎜ ⎟ 2 2 ⎝ ℏ ⎠ ⎝ 1 + ωs τe ⎠ 3

(2)

where s represents the electron spin quantum number, γ is the nuclear gyromagnetic ratio, g is the Landau factor of an electron, β is the Bohr magneton, r is the distance between the paramagnetic ions and the protons, τC is the electron−proton dipole−dipole interaction correlation time, ω1 is the Larmor frequency of the proton spin magnetic moment, ωs is the Larmor frequency of the electron spin magnetic moment, A/ℏ is the hyperfine or scalar coupling constant between the electron spins of the paramagnetic ions and the proton spins of the coordinated water molecule, and τe is the scalar interaction correlation time.53 Among them, in our system, the dipole−dipole interaction correlation time τC and the distance r between the paramagnetic ions and the protons are the two key variables.52 The value of 1/T1obs increases with the increment of τC. It is influenced by molecular rotation, spin state change, and proton exchange.54 They can be expressed as follows

(1)

where T1obs is the observed longitudinal water proton relaxation time, T1w is the water proton relaxation time in the absence of the paramagnetic complex, and T1p represents the increment of proton relaxation time due to the effect of the paramagnetic complex. Hence, 1/T1p plays the key function in eq 1 and relates to the following parameters: electron spin magnetic moment, the distance between paramagnetic ions and protons, the magnetic resonance frequency, and the relevant time of paramagnetic ion movement.52 The theoretical formula for expressing the proton relaxation rate (R = 1/T) determined by

1 1 1 1 = + + τC τR τS τm

(3)

where τR is the rotational correlation time of paramagnetic ions and their hydrated molecules, τS is the longitudinal electron E


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Figure 4. KB-tumor-bearing mice are injected with CuPDA NPs by intravenous administration. Biodistribution of CuPDA NPs in mice at 24 h p.i. by (a) determining the content of Cu2+ with ICP and (b) MRI signal intensity. T1-weighted MR images of mice without (c) and with (d) i.v. injection. Organs identified by i, ii, iii, iv, and vi in c and d represent heart, liver, spleen, lungs, kidneys, and tumor, respectively. Inset color bar from blue to red represents the MRI signal from low to high.

spin relaxation time, and τm is the proton exchange time. In water, τm is usually too long to ignore 1/τm. For the paramagnetic ions, such as Cu2+, Mn2+, and Gd3+, τS is fixed. Therefore, the method to enhance the relaxation rate is to form covalently or noncovalently bound complexes with macromolecules, which can efficiently retard the rotational motion of the complexes and increase τR. For the distance r, although chelated macromolecules increase the distance between paramagnetic ions and protons, weakening the effect of shortening relaxation time, in most cases, the relaxation effect is enhanced by the increase of τR due to the chelation of paramagnetic ions with macromolecules, which, to a large extent, counteracts the adverse effect of r increment in the chelates.55−58 In our system, for CuPDA NPs, PDA strongly constrains paramagnetic Cu2+ ions to its interior, so that the movement of Cu2+ is limited. The rotation rate of Cu2+ is slowed. As a result, with the increase of rotational correlation time τR, the electron−proton dipole−dipole interaction correlation time τC increases. Thereby, the relaxation effect is effectively enhanced by shortening the relaxation time T1obs. Figure S12b compares the T1-weighted MR images of Cu2+, PDA NPs, and CuPDA NPs. With the increase of concentration, CuPDA NPs exhibit better contrast enhancement and therefore a brighter image than Cu2+ and PDA NPs. This is the prerequisite for in vivo application as MRI contrast media. In Vitro TCT. Before culturing the cells, the pH of all culture medium is tuned to an optimum value in order to accommodate the growth of different cells. The optimum culture pH values for KB and 293 cells are 6.8−7.0 and 7.2−7.4,

respectively. Deliberate control of the pH of the culture medium makes it possible to simulate the pH of the tumor microenvironment. Twenty-four hour cytotoxicity of PDA and CuPDA NPs are tested for KB cells (Figure 3a). Quantitative evaluation results show that compared to PDA NPs, the viability of KB cell incubated with CuPDA NPs is lower due to the chemotherapy of released Cu2+. However, more than 70% of the cells remain alive with a concentration as high as 400 μg/ mL. It means that chemotherapy alone is not enough to eliminate tumor cells; it must be combined with photothermal therapy. Meanwhile, the potential cytotoxicity of CuPDA NPs incubated with KB tumor cells and 293 normal cells is investigated. The viability of 293 cells is a little higher than KB cells. It confirms the pH-stimulated chemotherapy property of CuPDA NPs, namely, release of Cu2+ is promoted in acidic tumor microenvironment. During the photothermal ablation in vitro (Figure 3b), KB cells are cultured with or without CuPDA NPs and then irradiated with an 808 nm laser at different power densities. The standard methyl thiazolyl tetrazolium (MTT) assay is carried out to evaluate the cell viability. When the laser power density reaches 3 W/cm2, the cell viability is lower than 20%, while the viability is almost 100% for the control group. These results demonstrate that CuPDA NPs hold great promise as photothermal agents for in vivo tumor treatment. Subsequently, the cells are stained with both propidium iodide (PI) and fluorescein diacetate (FDA) after photothermal ablation treatment (Figure 3c). The fluorescent images of cells show a clear demarcation line between the region of live cells (green) and apoptotic cells (red) (Figure 3e). As expected, F


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Figure 5. TCT of KB tumors in vivo. Relative tumor volume (a) growing trend and average body weight (b) for each group. Photographs of typical mouse bearing tumor model (c−f), H&E staining of tumor slices (g−j), and tumors (k−m) taken from each group in the 16th day. Scale bar in g−j represents 50 μm. Mice are divided into four groups: control group (c, g, k), laser-only group (d, h, l), CuPDA NPs i.v. injection group (e, i, m), and TCT i.v. injection group (f, j).

the cells within irradiation range are completely ablated to apoptosis, while the cells out of irradiation remain alive (Figure 3d and 3f). These results suggest that CuPDA NPs can effectively kill the KB cells through TCT effect induced by NIR irradiation. In Vivo MRI-Guided TCT. Prior to the in vivo imaging experiment, it is important to know the blood circulation kinetics of CuPDA NPs. Blood samples are collected at different time points after intravenous (i.v.) injection of CuPDA NPs into KB tumor-bearing BALB/C-nude mice and then decomposed in aqua regia solution (HCl:HNO3 = 3:1 volume ratio) to determine the Cu2+ concentration by ICP. As shown in Figure S13 and Figure 4a, CuPDA NPs exhibit a relatively long blood circulation with a half-life of 3.1 ± 0.2 h and high tumor retention rate with 8.2 of injected dose per gram tissue (% ID/g) at 24 h p.i. (post injection). Meanwhile, major organs are harvested to determine the Cu2+ content. As presented in Figure 4a, CuPDA NPs are mainly distributed in reticuloendothelial organs such as the liver, spleen, and kidneys. In the following MR imaging, CuPDA NPs are i.v. injected into KB tumor-bearing BALB/C-nude mice, and then a set of MR images are acquired before and after injection at 24 h (Figure 4c and 4d). The results clearly demonstrate that only a weak MRI signal in the tumor and five vital organs region can be detected before injection of CuPDA NPs, and the signal gradually increases with the circulation of NPs after i.v. injection. Detailed quantitative MRI signal intensities are analyzed in Figure 4b, which is basically similar to the biodistribution determined by ICP. Two reasons lead to the

efficient tumor tissue retention. On one hand, for the tumor itself, compared to the small drug molecules with rapid metabolism, the leaky tumor vasculature and poor lymphatic drainage of tumors allow NPs to accumulate in the tumor much more than that in normal tissues based on the enhanced permeability and retention (EPR) effect.27 On the other hand, for the CuPDA NPs, since DA naturally exists in the body, CuPDA NPs have good biocompatibility and high stability. The negative charge, suitable size, and stealth effect of NPs may hinder NP−cell interactions during the blood circulation.26 These features make NPs have a long blood circulation half-life. Hence, during the same blood circulation time, more NPs can accumulate effectively into tumor tissue. Motivated by the excellent in vitro TCT efficacy of CuPDA NPs and its high tumor retention rate, the in vivo tests are further performed. First, the KB cells are subcutaneously implanted in nude mice. When the average size of tumors reaches ∼60 mm3, the tumor-bearing mice are randomized into four groups: control group, laser-only group, CuPDA NPs i.v. injection group, and TCT i.v. injection group. Then the tumor volumes in different groups are monitored every other day (Figure 5a). It is found that the tumors in the control and laseronly groups show the rapid growth. Meanwhile, the tumors stimulated by NPs in i.v. injection are depressed in the first 4 days but expand even faster in the following days. The reason is probably that the chemotherapy of CuPDA NPs can partially inhibit tumor growth but not eliminate it.29 The tumors who receive NPs stimulation but not be completely eliminated will show explosive growth when they reoccurth in the secondary G


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these functionalities, CuPDA NPs are employed to perform MRI-guided TCT in the mouse tumor model, which indicate a remarkable synergistic effect in eliminating tumors. Due to the high tumor retention rate, excellent theranostic efficacy, good safety, low cost, and easy preparation, the current transition metal-loaded strategy gives a competitive alternative for designing and fabricating multimodal theranostic nanodevices for noninvasive tumor treatment.

relapse. In contrast, the tumors in the TCT group are totally eliminated after 4 days of being treated by 808 nm laser irradiation at a power density of 0.33 W/cm2 for 20 min. No recrudesce is observed even after 16 days. Moreover, the body weight of the mice after injection and treatment is maintained normally without a noticeable decrease (Figure 5b). The temperature of the tumor area under NIR irradiation is monitored by an IR thermal camera. As shown in Figure 6, the

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EXPERIMENTAL SECTION

Materials. Dopamine hydrochloride (DA, 99.0%), tris(hydroxymethyl) aminomethans (Tris) (99.0%), fluorescein diacetate (FDA), and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) are purchased from Sigma-Aldrich. Dulbecco’s modified Eagle’s medium with high glucose and fetal bovine serum are purchased from Gibco. Cooper chloride dihydrate (CuCl2·2H2O) and PBS are all commercially available products and used as received without further purification. Propidium iodide (PI) is purchased from Invitrogen. Absolute ethanol and deionized water are used in all experiments. Preparation of CuPDA NPs. The preparation of CuPDA NPs is carried out in a water−ethanol mixed solution.36 Briefly, the Trisbuffer solution (10 mM, based on deionized water, pH 8.5) is mixed with ethanol with a ratio of 5:1. A 0.16 mmol amount of DA is added to 60 mL of a mixed solution and stirring for 15 min. Then 0.2 mmol of CuCl2·2H2O is quickly added into the mixed solution. After vigorous stirring for 3 h, the product is centrifuged and washed with deionized water three times. For the preparation of CuPDA NPs with different diameters and Cu2+-loading ratio, the amounts of DA and CuCl2·2H2O are adjusted with specific feed ratios. Photothermal Tests of CuPDA NPs. A 2 mL aqueous suspension of CuPDA NPs with a specific concentration is injected in a 1 × 1 × 4 cm quartz cuvette cell and irradiated with an 808 nm NIR laser at a specific power density. A digital thermometer with a thermocouple probe is inserted into the suspension perpendicular to the path of the laser. The temperature is recorded every 15 s. Cytotoxicity Assay in Vitro. Typically, 293, KB, and Hela cells are incubated with different concentrations of CuPDA NPs in the culture medium at 37 °C at an atmosphere of 5% CO2 and 95% air for 24 h. The viabilities of these cells are evaluated by a well-known methyl thiazolyl tetrazolium (MTT) assay. Photothermal Effect and Costain Assay in Vitro. To quantitatively evaluate the photothermal therapy in vitro, KB cells are cultured in 96-well plates with 50 μg/mL CuPDA NPs for 2 h and then irradiated with an 808 nm laser at different power densities for 10 min. For the control group, the cells are irradiated at different power densities but without CuPDA NPs. The viabilities of KB cells are evaluated by an MTT assay. For the costain assay, KB cells are first incubated with 50 μg/mL CuPDA NPs for 2 h at a quantity of 3.0 × 104 cells per well on 6-well plates and then exposed to an 808 nm laser at a power density of 1.0 W/cm2 for 10 min. Thereafter, the cells are stained with both PI and FDA. Photos of cells are taken by a fluorescence microscope after they are stained. Animal Experiments. Animal care and handing procedures are in agreement with the guidelines of Jilin University Laboratory Animal Center. KB cells are incubated in the culture medium at 37 °C at an atmosphere of 5% CO2 and 95% air. The 2.0 × 106 KB cells suspended in 150 μL of serum-free cell medium are inoculated subcutaneously in Balb/c-nu mice. When the tumors have grown to ∼60 mm3, the tumor-bearing mice are randomized into four groups: control group, laser-only group, CuPDA NPs i.v. injection group, and TCT i.v. injection group. The former two groups are intratumorally injected with 9% saline, while the latter two groups are intravenously injected with 50 μL of 250 μg/mL CuPDA NPs in 9% saline. Two days after injection, the tumors except the control group are exposed to the 808 nm NIR laser at a power density of 0.33 W/cm2 for 20 min. The tumor sizes are measured by a digital caliper every other day for 16

Figure 6. IR thermal images of KB tumor-bearing mice recorded by an IR camera. Laser irradiation is conducted by using an 808 nm laser (0.33 W/cm2) for 600 s on the tumors.

temperature of the tumor on a mouse 24 h after i.v. injection with CuPDA NPs rises from 35 to 62 °C under NIR irradiation at 0.33 W/cm2, which is sufficient to ablate the cancer cells and eradicate their malignant proliferation. In huge contrast, the tumor temperature of mice injected with PBS solution only increases ∼6 °C. Hematoxylin and eosin (H&E) staining of tumor slices after treatment is further carried out to reveal the therapeutic efficacy (Figure 5g−j). No obvious malignant necrosis is observed in the mice from the control group, laseronly group, and CuPDA NPs i.v. injection group, while apparent extensive karyopyknosis and necrosis are found in the mice of the TCT group, which demonstrates the excellent therapeutic efficacy of CuPDA NPs. Meanwhile, the short-term safety of CuPDA NPs is evaluated by the liver and renal functions 24 h post i.v. injection. As shown in Figure S14, the accumulation of CuPDA NPs in liver and renal does not affect their normal functions. To further determine that there is no recurrence of tumors or metastasis of the cancer, the major viscera such as heart, liver, kidneys, lungs, and spleen are harvested at day 30 after treatment and stained with H&E (Figure S15). Compared to the age-matched healthy mice, no evident inflammation or damage is observed in any of the major viscera treated with NIR irradiation after injection of CuPDA NPs, further confirming that there are almost no side effects or toxicity associated with CuPDA NPs on the basis of our observation.

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CONCLUSIONS In summary, we demonstrate the preparation of multifunctional nanodevices of Cu2+-loaded PDA NPs for MRI-guided TCT. The as-prepared CuPDA NPs exhibit enhanced photothermal performance and pH-stimulated chemotherapy. In addition, the loading of Cu2+ endows the NPs with the functionality of MR imaging. Because of the excellent stealth effect of DA, CuPDA NPs also show outstanding tumor retention rate. By combining H



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days and calculated as the volume. The tumor volume is calculated by the formula35 V=

Research Article

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.7b05583. UV−vis absorption spectra, EDS, XRD, XPS, photothermal tests, IR thermal images, stability and MRI of PDA and CuPDA NPs, and additional blood circulation, liver and renal functions, and H&E stained splanchnic slices tests (PDF)

1 L × D2 2

where L and D (mm) represent the lengths of the long and short axes, respectively. Relative tumor volumes are calculated as V/V0 (V0 is the tumor volume when the treatment is initiated). To examine the histological changes of the viscera and tumors, some tumor-bearing mice are killed, and the viscera including heart, liver, lungs, kidneys, spleen, and tumor are removed and stained with Hematoxylin and Eosin (H&E) for histopathology analysis. To quantitatively evaluate the distribution of Cu PDA NPs in the viscera and tumor, they are digested in aqua regia for 12 h for dissolution of the tissues. The concentrations of Cu in these organs are quantified by ICP. For blood analysis, both healthy mice and tumor-bearing mice are intravenously administered with a single dose of CuPDA NPs. Several mice without injection are used as the control group. One month after, the mice are anesthetized and the blood is collected for blood biochemistry assay. The viscera are also removed and preserved in a 10% formalin solution and used for histological analysis. In Vivo MRI. The KB tumor bearing mouse is first anesthetized by intraperitoneal injection of chloral hydrate solution (5 wt %), and then 50 μL of 5 mg/mL CuPDA NPs is administrated intravenously into the mouse. The T1-weighted images are acquired using a 1.5 T human clinical scanner. Characterization. UV−vis absorption spectra are measured with a Shimadzu 3600 UV−vis−near-IR spectrophotometer at room temperature under ambient conditions. Transmission electron microscopy (TEM) is performed using a Hitachi H-800 electron microscope at an acceleration voltage of 200 kV with a CCD camera. An energydispersive X-ray spectroscopy (EDS) detector (Bruker Co.) equipped on SEM (SU8020 Scanning Electron Microscope, HITACHI Co.) is used for composition analysis. X-ray powder diffraction (XRD) investigation is performed on an Empyrean diffractometer, PANalytical B.V. using Cu Kα radiation (λ = 1.5418 Å). X-ray photoelectron spectroscopy (XPS) is carried out by a PREVAC XPS/UPS System with Al Kα excitation (1486.7 eV). Fourier-transform infrared (FTIR) spectra were obtained on a Bruker IFS66 V instrument. 1H NMR spectra and T1 relaxation time are measured by a BRUKER AVABCEIII500 NMR spectroscope (Acquisition parameters: PL12, f2 channel-power level for CPD decoupling; PCPD2, f2 channel-90° pulse for decoupling sequence; CPD2, WALTZ16-CPD decoupling sequence, defined by cpdprg2; D1, 60 s relaxation delay; D11, 30 ms delay for disk I/O; D12, 20 usec delay for power switching; TD, 32 K; SW, 200 ppm; O2, middle of the 1H NMR spectrum; NS, 8; DS, 4; VD, variable delay, taken from VD-LIST; L4, number of experiments = number of delays in VD-LIST; TD1, 8-number of experiments define VD-LIST; Parmod, 2D; RG, receiver gain for correct ADC input. Processing parameters: au-program, splitser; SI, 16 K; WDW, EM; LB, 2 Hz; XF2, transformation is only performed in the F2 direction; phase correction, to adjust phase, read spectrum number 8, in which all signals have positive phase and transfer this phase correction to all other spectra). T1-weighted MRI images are acquired using a GE Signa 1.5-T (General Electric, Milwaukee, WI) unit (slice thickness, 2 nm; TR/TE, 2000/81.9 ms; FOV, 6 × 6 cm; matrix, 256 × 160). The MRI signal intensities are determined by software (The Codonics Clarity Viewer) used in MR imaging. The measuring tool in the software can be used to calibrate the MRI signal intensities. In the study of the photothermal effect, an 808 nm diode laser (LEO photonics Co. Ltd.) is employed with an output power tunable from 0 to 10 W/cm2. The Cu concentration is measured by inductively coupled plasma optical emission spectrometer (ICP-OES) measurements with a PerkinElmer Optima 3300DV. Fluorescent images of KB cells are obtained by an Olympus IX71 inverted fluorescence microscope. Infrared thermal images are monitored by a FLUKE infrared (IR) thermal camera.

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AUTHOR INFORMATION

Corresponding Authors

*Fax: *Fax: *Fax: *Fax:

+86 +86 +86 +86

431 431 431 431

85193423. 85193423. 85193423. 85193423.

E-mail: E-mail: E-mail: E-mail:

[email protected]. infl[email protected]. [email protected]. [email protected].

ORCID

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

H.Z. proposed and supervised the project. H.Z., R.G., Y.L., L.D.L., F.S., H.C.S., and B.Y. designed and performed the experiments and cowrote the paper. M.L., X.L., S.W.L., W.J.W., X.Z., and S.Y.L. participated in most experiments. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the NSFC (21374042, 51425303, 51603084, 81320108011), the National Key Research and Development Program of China (2016YFC1102800), the Special Project from MOST of China, and the Fundamental Research Funds for the Central Universities.

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