Polydopamine-Derivated Hierarchical Nanoplatforms for Efficient Dual

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Biological and Medical Applications of Materials and Interfaces

Polydopamine Derivated Hierarchical Nanoplatform for Efficient Dual-Modal Imaging Guided Combination In Vivo Cancer Therapy Lijiao Ao, Chunlei Wu, Ke Liu, Wei Wang, Lijing Fang, Liang Huang, and Wu Su ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b02973 • Publication Date (Web): 23 Mar 2018 Downloaded from http://pubs.acs.org on March 23, 2018

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ACS Applied Materials & Interfaces

Polydopamine Derivated Hierarchical Nanoplatform for

Efficient

Dual-Modal

Imaging

Guided

Combination In Vivo Cancer Therapy Lijiao Ao,†,§ Chunlei Wu,† Ke Liu,† Wei Wang,† Lijing Fang,† Liang Huang,*,‡ and Wu Su*,† †

Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology,

Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, P.R. China ‡

College of Chemical Engineering, Zhejiang University of Technology, Zhejiang 310014, P.R.

China §

Shenzhen College of Advanced Technology, University of Chinese Academy of Sciences,

Shenzhen 518055, P.R. China KEYWORDS: polydopamine; iron oxide; drug delivery; photothermal therapy; theranostic

ABSTRACT: Exploring multifunctional nanomaterials from biocompatible constituents, with integrated imaging and targeted combination therapeutic modalities of tumors in vivo, provides great prospects for clinical cancer theranostic applications. Here we report a combination strategy for functionalization of polydopamine (PDA) nanohosts with magnetic response and stimuli-controlled drug release capabilities for in vivo cancer theranostic. The high processibility of PDA as nano-templates and surface coating layers as well as its natural affinity to metals,

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facilitated the sandwich of a compact iron oxide nanoparticles (IOs) layer into the PDA matrix, realizing enhanced near infrared (NIR) photothermal conversion and strong superparamagnetic responsiveness. Additionally, the high reactivity of PDA surface allowed facile linkage with reduction-responsive prodrugs and PEG chains for in vivo chemotherapy of cancer. Under the MRI/PAI dual-modal tumor imaging and active magnetic tumor targeting of the nanoagents in vivo, the effective tumor eradication was achieved via synergetic NIR photothermal ablation and anti-cancer drug delivery.

1. INTRODUCTION The bio-inspiration from the strong adhesion feature of invertebrate mussels realized the emergence of polydopamine (PDA) as a robust, facile and universal surface coating material on diverse substrates,1-3 which led to an important breakthrough in materials surface functionalization. For nanoscience and nanotechnology, the striking character of PDA as a novel polymer lies in its advance for multifunctional nanostructure engineering.4-6 From the view point of synthetic scheme, the preparation of colloidal PDA via a Stöber like process is rather facile and well-controlled for both nano-substrates (templates) and encapsulating layers on various nanoscale objects including metals, semiconductors, oxides and polymers, bridging discrete functionalities from different components.7-11 Moreover, as a major pigment of naturally occurring melanin,5 the PDA exhibits superior biocompatibility for potential clinical theranostic applications. Noticeably, the intense and broad absorption spectrum across visible to near infrared (NIR) region enables PDA an excellent photothermal agent to induce highly localized heat for cancer photothermal therapy (PTT).12-14 Simultaneously, the introduction of pulsed NIR laser onto PDA would allow the detection of ultrasonic waves for sensitive and meticulous localization of tumor tissue via photoacoustic imaging (PAI).15


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Superparamagnetic iron oxide nanoparticles (IOs) as a class of biocompatible nanomaterial have drawn great research interests in clinical imaging diagnostic and therapeutic applications.1619

The strong chemical affinity of catechol group to ferrite surfaces have been successfully

employed for creating highly stable hydrophilic IOs using dopamine-derivate ligands.20-24 Inspired by this feature, the incorporation of an IOs layer into PDA matrix to produce magnetic responsive PDA composites seems attractive. The PDA templated magnetic structure shows superiority in particle size and size-distribution controlling, compared with previous single or clustered IOs cored PDA nanocomposites.12,25,26 This strategy may promote new theranostic modalities such as multi-modal imaging diagnosis using both magnetic resonance imaging (MRI) and PAI, as well as magnetic field guided PTT for targeted tumor ablation. Meanwhile, the intrinsic chemical reactivity of PDA facilitates a variety of reactions for functional uses.1,5 For instance, the introduction of therapeutic drugs onto PDA based nanoplatform through cleavable crosslinkers may allow stimuli-response drug release at tumor site,27-29 which could well compensate the limitations of PTT for synergetic in vivo cancer therapy. In this paper, a theranostic nanoplatform derived from biocompatible PDA colloids was designed for multi-modal imaging and magnetic field guided combination cancer therapy. As

Figure 1. Schematic illustration of the synthetic procedure and application of PDA based theranostic nanoplatform.


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illustrated in Figure 1, the PDA nanospheres were employed as metal-affinity templates for in situ deposition of a compact IOs layer via high temperature thermal decomposition to form PDA@IOs nanospheres. A thin PDA shell was encapsulated onto the IOs surface to form sandwich type PDA@IOs@PDA (PIP) nanocomposites with simultaneous magnetic response, NIR photothermal conversion and high surface reactivity. A redox-sensitive crosslinker containing disulfide bond was employed to bridge the chemotherapy drug (doxorubicin, DOX) and the polyethylene glycol (PEG) spacer which was covalently bonded to PDA surface. With reduction-responsive drug release and PTT therapeutic capabilities of the PIP-DOX nanospheres, the in vivo combination therapy was realized under the MRI/PAI dual-modal imaging and magnetically active tumor targeting. 2. EXPERIMENTAL SECTION 2.1. Materials: Ferric acetylacetonate (Fe(acac)3), dopamine hydrochloride, triethylene glycol (TEG), 3,3’-Dithiodipropionic acid (DTDP), N-(3-dimethylaminopropyl)-N’-ethyl-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were purchased from Sigma-Aldrich. Amine PEG amine (NH2-PEG-NH2, MW~5000) and methoxyl PEG amine (mPEG-NH2, MW~5000) were purchased from Nanocs Inc. Ethanol, ammonia solution (25%-28%) were purchased from Sinopharm Chemical Reagent Co., Ltd. Doxorubicin (DOX) was purchased from Melone Pharmaceutical Co., Ltd. Hoechst, Calcein-AM, and Propidium Iodide (PI) were purchased from Thermo Fisher. DMEM medium, fetal bovine serum, trypsin, EDTA, penicillin and streptomycin were purchased from Hyclone. The ultrapure water with conductivity of 18 MΩ.cm was used throughout the experiments. 2.2. Synthesis of PDA nanospheres: For preparing the PDA nanospheres with average diameter of 120 nm, the ethanol (40 mL), ultrapure water (90 mL) and aqueous ammonia solution (2.2


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mL) were mixed together. Ten milliliter of water containing 0.5 g of dopamine hydrochloride was swiftly added into the above solution, which was subsequently stirred for 30 h. The PDA nanospheres were centrifuged and cleaned several times with water. 2.3. Synthesis of PDA@IOs nanocomposites: In a typical procedure, a wet precipitate of PDA nanospheres (corresponding to 40 mg of dry powder) was dispersed in 1 mL of ethanol. To a 50 mL flask, the Fe(acac)3 (240 mg), TEG (20 mL) and PDA ethanol solution (1 mL) were added successively. The mixed solution was appropriately ultrasonicated and maintained at 70 oC until the ethanol was completely evaporated. After filled with nitrogen, the flask was kept at 210 oC for 2 h with stirring. The solution was then heated to 290 oC and kept with stirring for another 1 h. After cooled to room temperature, the above solution was first diluted with acetone, and the PDA@IOs nanocomposites were purified several times by ethanol, with centrifugation or magnetic separation. 2.4. Synthesis of PIP nanospheres: The dopamine solution was prepared by dissolving dopamine hydrochloride (8 mg) in 20 mL of 10 mM Tris-HCl buffer (pH∼8.5). The PIP nanospheres were prepared by dispersing the PDA@IOs nanospheres (20 mg) into the above dopamine solution and stirred for 24 h. The PIP nanospheres were then purified with water for several times. 2.5. Synthesis of DOX-SS-PEG-NH2 prodrug: The dithiodipropionic anhydride (DTDPA) was first synthesized as following: the DTDP (5 g) was dissolved in acetyl chloride (15 mL) and then refluxed for 2 h at 65 oC. The acetyl chloride was preliminarily distilled by rotary evaporation. The remained solution was added into excess ethyl ether, and the precipitate was collected and dried under vacuum to obtain the DTDPA. To 3 mL of anhydrous DMF, the DOX·HCl (15 mg), TEA (12 µL) and DTDPA (5.4 mg) were added successively. The above solution was reacted for


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12 h in the dark at room temperature, for the preparation of DOX-dithiodipropionic anhydride derivative (DOX-DTDPA). The above solution was subsequently added with 19.8 mg of EDC and 11.9 mg of NHS and stirred at room temperature for 4 h. In order to obtain the DOX-SSPEG-NH2 prodrug, the above DOX-DTDPA solution was added into DMF (8 mL) containing NH2-PEG-NH2 (104 mg). After stirred for 12 h in dark, the reaction solution was subsequently dialyzed in ultrapure water for three days for purification. The yields for DTDPA, DOX-DTDPA and DOX-SS-PEG-NH2 were measured to be 40%, 71%, and 76%, respectively. 2.6 Synthesis of PIP-DOX nanospheres: The obtained DOX-SS-PEG-NH2 solution was added dropwise into 10 mL of Tris-HCl buffer (pH∼8.0) containing PIP nanospheres (2 mg mL-1). After stirring for 12 h, the solution was mixed with 4 mL of water containing 52 mg of mPEGNH2 and stirred for another 12 h. The final product was retrieved by centrifugation and washed with ultrapure water for several times. 2.7 Characterization: Transmission electron microscopy (TEM) was performed on FEI-F20 electron microscopy with accelerating voltage of 200 kV. Dynamic light scattering (DLS) were measured using a Malvern Zetasizer Instrument. The magnetic hysteresis curve was determined by the MPMS-7 (Quantum Design) superconducting quantum interference device (SQUID) magnetometer. The 1H nuclear magnetic resonance (1H NMR) spectra were acquired with AVANCE 400 spectrometer at 400 MHz using CF3COOD as the solvent. The T2 relaxivity and MRI imaging were obtained using a Siemens 3.0 T clinical MR scanner at room temperature. The PA imaging was performed on a photoacoustic computerized tomography scanner (Endra Nexus 128, Ann Arbor, MI). The UV-Vis absorption spectra were measured with a Perkin-Elmer spectrometer (Lambda 750). The Fe content was analyzed on an inductively coupled plasma optical emission spectrometry (ICP-OES, Perkin-Elmer/OPTIMA 7000DV). The drug loading


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content (DLC) was measured by fluorescence spectroscopy (480 nm excitation) and calculated as following: DLC (wt%) = [weight of loaded drug/(weight of loaded drug+ weight of nanoparticle)]× 100%. 2.8 In vitro drug release: The drug release process was evaluated as followed: the PIP-DOX (0.5 mL) was suspended in 10 mL of PBS (pH~7.4) or PBS with different concentrated GSH. At desired time of intervals, 0.8 ml of the incubation solution was taken and centrifuged, the release amount of DOX was determined by testing the fluorescence intensity of supernatant using fluorescence spectrometer (LS55, PerkinElmer) with excitation wavelength of 480 nm and emission wavelength of 556 nm. 2.9. Cellular experiments: 2.9.1. Cellular uptake: The murine breast cancer cells (4T1) was supplied by Shanghai cell bank and cultured regularly in DMEM culture medium with 10% heat-inactivated FBS, 1% penicillin and streptomycin under 37 °C within 5% CO2. For cell uptake, 2×104 cells were seeded in 8-well chambered plate in 200 µL medium. After culturing for 24 h, the medium was removed by new medium containing free DOX, PIP-DOX or PIP-DOX with a magnet at the bottom of the plate (all DOX were equivalent to 5 µg/mL). After 2 h incubation, the medium was discarded and the cells were washed three times with PBS and fixed with 10% formalin for 10 min (0.5 mL/well). After washing with PBS, Hoechest was added to stain the nuclei for 10 min. The cells after PBS washing were applied for fluorescent imaging with confocal microscopy. The cell uptake was further quantitatively evaluated by flow cytometry. The 4T1 cells were seeded into 24-well plate in 0.5 mL of medium with 1×105 cells per well. After culturing for 24 h, the medium was removed by new medium with free DOX, PIP-DOX or PIP-DOX with a magnet at the bottom of the plate (all DOX were equivalent to 5 µg/mL). After 2 h incubation,


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the medium was discarded and the cells were washed with PBS and harvested by 0.05% trypsin EDTA. The FL was determined by Accuri C6 flow cytometry. 2.9.2. In vitro therapeutic treatments: The in vitro cytotoxicity of the drug and nanoagents were evaluated by MTT viability assay. The 4T1 cells with a seeding density of 5×103 cell/well were cultured in 96-well plates in 100 µL DMEM medium supplemented with 10% FBS at 37 °C for 24 h. After discarding the medium, the cells were treated with fresh medium with 808 nm laser, free DOX, PIP-DOX or PIP-DOX with 808 nm laser, respectively, at various DOX concentrations. The laser irradiation (1 W/cm2, 5 min) was conducted after 2 h of cells treatments. After incubated for 48 h, the cells in each well were treated with 10 µL of MTT solution (5 mg/mL in PBS) and further incubated for 4 h. After replacing the medium and the addition of DMSO (100 µL), the optical absorbance of each well at 490 nm was determined by a microplate reader. 2.10. In vivo experiments: Balb/c mice were used under protocols approved by Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences Animal Care and Use Committee. A suspension of 4T1 cells (2×106) in 100 µL of PBS were injected subcutaneously onto the right flank of the mouse. The mice were applied for experiments after 10 days of cells injection. To determine the biodistribution of the nanoagents, the PIP-DOX (200 µL, 1 mg/mL) were injected intravenously into the tumor-bearing mice (n=5). The mice were sacrificed after 24 h with the heart, liver, spleen, lung, kidney and tumor collected. After weighting and digesting of the organs, the Fe contents were determined by ICP-OES with the background Fe signals from organs of controlled mice subtracted. For in vivo imaging study, the PIP-DOX solution (100 µL, 1 mg/mL) was injected intravenously into the 4T1 tumor mice (three per group), and the tumors were treated with or without a small magnet attachment. The MR imaging of the mice was


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acquired at 0 h and 24 h after PIP-DOX injection on the MR scanner equipped with a special coil designed for small animal imaging. The PA imaging of the mice was performed at 0 h, 6 h, 12 h and 24 h after PIP-DOX injection using a photoacoustic computerized tomography scanner with 810 nm excitation. The 4T1 tumor mice that were divided into four groups (five per group) were injected with 100 µL of PBS or PIP-DOX (1 mg/mL in PBS) intravenously, for in vivo combination therapy study. The tumors were treated with or without a small magnet attachment. The tumors were treated with or without 808 nm laser (1 W/cm2) for 5 min at 24 h post injection. Tumor volume was calculated as A × B2/2, where A and B correspond to the max and minor axes of the tumor. For histology examinations, the tumors from mice (three per group) were collected at 12 h after therapeutic treatments, fixed with 10% formalin and sectioned into 8 µm slices. The controlled mice and PIP-DOX (100 µL, 1 mg/mL) injected mice (three per group) were sacrificed at 30 d post-administration. The organs including heart, liver, spleen, lung, and kidney were collected, fixed with 10% formalin and sectioned at 8 µm. After washing, the sections were stained with hematoxylin for 3 min, washed with water and stained with eosin for another 1 min. The observation was performed on a Nikon Eclipse 90i microscope. 3. RESULTS AND DISCUSSION The PDA nanospheres were synthesized in alkaline solution by self-polymerization of dopamine monomer, via a facile Stöber like process.30 The TEM image in Figure 2a shows these PDA spheres were almost monodisperse with an average diameter approaching 120 nm. By the assistance of PDA as metal-affinity template,31 a dense layer of IOs was deposited around the PDA spheres (Figure 2b), through thermo decomposition of ferric acetylacetonate in polyalcohol. As revealed in the HRTEM image (Figure 2c), the IOs with average particle size of 7 nm and good crystallinity could be observed. The superior binding ability of iron atoms to catechol


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Figure 2. TEM images of the PDA (a), PDA@IOs (b-c) and PIP (d) nanospheres. Inset shows the enlarged image of a PIP nanosphere. groups leading to an ultrahigh coverage of IOs on PDA surface compared with previous reports using other conventional nano-templates,32,33 which may greatly benefit the magnetic response and MRI contrast effect. Furthermore, in order to enhance the colloidal stability and endow convenient surface functionalization to the nanocomposites, a successive layer of PDA was encapsulated around PDA@IOs to form a sandwich type PDA@IOs@PDA (PIP) architecture (Figure 2d), allowing their facile covalent conjugation with amino-terminated molecules.1,2 Compared with our previously established gold nanorod incorporated magnetic nanocomposite,24 the current PDA based magnetic structure shows superiorities of improved biocompatibility and biodegradability of the organic component, easy functionalization such as direct deposition of inorganic particles as well as the natural surface reactivity for further derivation.5 The absorption spectra of the IOs and PDA-based nanocomposites were depicted in Figure 3a. The IOs without PDA templating were observed in nanoparticle or nanoparticle cluster form (Figure S1) and showed an absorption mainly across the visible region. While the PDA spheres


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exhibited a broad and intense absorption from visible to NIR spectrum.13 After IOs growth, the PDA@IOs nanocomposites displayed a remarkably enhanced NIR absorption, which may be attributed to the combination of clustered IOs layer with PDA host.34-35 Moreover, the outer PDA layer also favored the enhancement of NIR absorption, giving rise to distinguished PAI and PTT performances of the final nanocomposites. The photographs of the nanospheres during the processing also confirms the darkening of the aqueous dispersions as indicated in Figure 3b. The PIP water dispersions with different concentrations were subsequently irradiated with a 808 nm NIR laser (1 W/cm2) and monitored with the temperature change. As expected, the PIP exhibited a remarkable concentration dependent photothermal conversion effect, and reached final temperatures of 40.9 °C, 47.5 °C, 55 °C and 60.2 °C (corresponding to 25 ug/ml, 50 ug/ml, 100 ug/ml and 250 ug/ml, respectively) within 5 min (Figure 3c), allowing sufficient photothermal

Figure 3. (a) Absorption spectra of IOs, PDA, PDA@IOs and PIP nanospheres. (b) Photographs of the water dispersions of IOs, PDA, PDA@IOs and PIP nanospheres. (c) Temperature changes of water and aqueous dispersions of PIP with 808 nm laser irradiation (1 W/cm2). (d) Magnetic hysteresis curves of PDA@IOs and PIP nanospheres at 300 K and photographs of PIP aqueous dispersion treated without and with a magnet (inset). (e-f) Release profiles of DOX from PIPDOX in physiological buffer (e) and with different concentrated GSH (f) at 37oC.


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ablation of malignant cells. The photothermal conversion efficiency of PIP at 808 nm was calculated to be 33.4% according to previous method,36 which is higher than that of 21% for gold nanorods, as effective PTT agents for cancers. Meanwhile, the successive laser irradiation of 6 circles all induced a similar heating up of the PIP dispersion, with temperatures rose up to around 55 °C (Figure S2). Accordingly, the PIP nanospheres showed no obvious change in dimension or morphology after successive laser irradiation (Figure S3), illustrating the high photothermal stability of current nanoagents in aqueous dispersion state. The room-temperature magnetic hysteresis curve (Figure 3d) indicates the zero remanence/coercivity of both PDA@IOs and PIP nanospheres, probably owing to the formation of secondary nanostructure from individual small IO nanocrystals, which is similar to previously reported magnetic supraparticles.37,38 The encapsulation of a thin PDA shell around IOs layer caused minor influence on the superparamagnetism, and the final saturation magnetization value reaches 32.5 emu/g, enabling rapid and complete separation of the PIP from water dispersion. This superparamagnetic feature with strong magnetic response promotes both good dispersion state of single nanosphere and efficient magnetic guided accumulation of theranostic agents at tumor sites.17,39 The combination of photothermal ablation with chemotherapy holds great promise in sufficient eradication of cancers in vivo.40,41 The facile amine-catechol adduct formation on PDA surface was employed for the introduction of pro-anticancer-drug, which contains doxorubicin (DOX), reduction-responsive disulfide linker and amino-terminated PEG chain (Figure 1). The pro-drug (DOX-SS-PEG-NH2) was synthesized by coupling both DOX and amino-terminated homo-bifunctional PEG to dithiodipropionic anhydride (DTDPA) as the reduction-responsive linker.42-44 The as synthesized DOX-DTDPA and DOX-SS-PEG-NH2 were characterized by 1H NMR. As indicated in Figure S4, the DOX-DTDPA exhibits characteristic peaks at 7.34-7.88


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and 2.57-2.89 ppm, which could be attributed to protons of benzene ring from DOX and methylene protons from DTDPA moieties, respectively, as previously reported.43,44 While the DOX-SS-PEG-NH2 shows newly appeared peak at 3.10-4.30 ppm, which was ascribed to the protons from repeated units (−OCH2CH2−) of the PEG chain, thus certifying the formation of the prodrug. As revealed in Figure S5, the PIP nanospheres exhibited a hydrodynamic diameter (HD) of 238 nm, with a zeta-potential of −41.3 mV, which may result from the deprotonation of catechol groups on particle surface.7 After been grafted with DOX-SS-PEG-NH2 and further blocked with amino-terminated PEG monomethyl ether, the PIP-DOX nanospheres displayed an increased HD of 267 nm and a partially neutralized zeta-potential of −15.6 mV (Figure S5), which could be attributed to the introduction of the prodrugs as well as PEG chains to the PDA surface. The drug loading content (DLC) of DOX in PIP was calculated to be 2.2%. The colloidal stabilities of the as prepared PIP-DOX nanospheres in PBS and DMEM were evaluated by dynamic light scattering (Figure S6). The nanoagents exhibited relatively stable hydrodynamic diameters in both mediums during 24 h of incubation, verifying the robustness of these PEG grafted nanocomposites in biological system. The stimuli-responsive drug release capability of the drug carriers was further investigated. The PIP-DOX after incubation at 37 oC in physiological buffer (PBS, pH~7.4) revealed a minor DOX release of 16% over a period as long as 30 h (Figure 3e), suggesting these nanocarriers were fairly stable under physiological conditions. Whereas in the presence of 5 mM glutathione (GSH), a prompt release of DOX exceeding 50% was observed immediately (within 90 min), as shown in Figure 3f. And the accumulative drug release reached 84% under free GSH concentration up to 10 mM, probably owing to the breakage of disulfide bonds to release DOX molecules. Such a reduction-responsive


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release may largely benefit the reduction environment specific chemotherapy in tumor,29 while minimizing the undesired drugs leakage in vascular delivery. The cellular uptake of the PIP-DOX nanoagents was visualized by confocal laser scanning microscopy (CLSM) as depicted in Figure 4. After 2 h of incubation, the PIP-DOX treated 4T1 cells revealed obvious red fluorescence in cytoplasm, which could be attributed to the endocytosis of the nanoparticles by cells, compared with the free DOX that was mainly observed in the cellular nucleis probably dominated by the passive diffusion of small molecules. Notably, when subjected to magnetic field, the cells exhibited remarkably enhanced fluorescence (Figure 4c). This could be attributed to the high magnetic responsiveness of single PIP nanosphere for enhanced cellular uptake, enabling efficient active drug delivery under magnetic guidance. The flow cytometric analysis was performed to further confirm the cellular uptake of PIP-DOX nanocarriers as indicated in Figure S7, which reveals a considerable cellular uptake of the PIP-

Figure 4. CLSM images of 4T1 cells after incubation with free DOX (a), PIP-DOX (b) and PIP-DOX with magnetic field (c) for 2 h, respectively.


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DOX nanocarriers after 2 h incubation. While the fluorescent intensity of cells incubated with PIP-DOX showed a remarkable increment of more than 50% with magnetic attraction, approaching that of cells treated with DOX of the same concentration. These results illustrated the effective cell internalization of the magnetic-responsible nanocarriers for guided drugs delivery applications. To access the biocompatibility of the nanocarriers on cellular level, the PEG grafted PIP nanospheres without DOX loading were incubated with 4T1 cells. As indicated in Figure S8, the cells incubated with the nanospheres (from 10 to 500 µg/mL) all exhibited a viability approaching 90%, confirming the satisfactory biocompatibility of the plain nanocarriers consisted of ferrite and polydopamine as theranostic agents. Nevertheless, the incorporation of anti-cancer drug into the PIP nanospheres induced a typical concentration dependent cytotoxicity on malignant cells, which was similar with the trend for free DOX treated cells (Figure 5), revealing their prospects for drug delivery application. Noticeably, the NIR laser irradiation on PIP-DOX treated 4T1 cell caused a remarkable increment in the killing efficiency of malignant cells, exceeding that of free DOX with same drug concentrations, thus confirms the synergism of

Figure 5. 4T1 cells viabilities under different treatments for 48 h as indicated.


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chemotherapy combined with PTT on cellular level. The co-staining of cells using calcein-AM and propidium iodide was further performed to visualize the therapeutic effect (Figure S9). Compared with the controlled live cells with only NIR laser irradiation, the PIP-DOX induced chemotherapy lead to extensive but still incomplete cell death. While the combination of drug delivery with PTT generated thorough cancer cells elimination reflected by the homogeneous red fluorescence (Figure S9c), which implied the potential of the synergism with individual therapeutic modalities. The MCF-10A cells were subsequently employed for evaluating the cytotoxicity of the PIP-DOX nanoagents against normal cells. As illustrated in Figure S10, the MCF-10A cells after incubation with PIP-DOX nanospheres with various DOX concentrations all exhibited visibly higher viabilities than those treated with same concentrated free DOX. The preliminary results revealed the effectiveness of PIP-DOX nanocarriers for reduction-responsive drug delivery against malignant cells while reducing the cytotoxicity to normal cells. For elucidating the feasibility of current nanoagents for in vivo theranostic applications, the biodistribution of PIP-DOX nanospheres in 4T1 tumor-bearing mice was investigated by ICPOES after intravenous administration. As indicated in Figure S11, the majority of the nanospheres was found to distribute in liver and spleen. And this could be explained by the clearance of external particles by these reticuloendothelial organs.17 Simultaneously, a considerable amount of the nanospheres (approaching 5% ID/g) was observed in tumor, at 24 h post administration. This accumulation could be attributed to the enhanced permeability and retention (EPR) effect of PIP-DOX.45 The integration of IOs layer into PDA host facilitates the dual-modal imaging capability using both MRI and PAI for complementary diagnostic information. The potential of current nanospheres in MR imaging was investigated using a 3T clinical MR scanner (Figure 6a). The


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Figure 6. (a) T2-weighted MR images of PIP-DOX (upper) and linear relationship of inverse transverse relaxation times with Fe concentrations. (b) PA images of different concentrated PIPDOX dispersions (upper) and plot of corresponding PA intensities versus PIP-DOX concentrations. (c-d) In vivo T2-weighted MR images of 4T1 tumor mice with various time durations after PIP-DOX injection without (c) and with (d) magnetic targeting at tumor site. Red circles indicate the tumor locations. (e-f) In vivo PA images of the tumor sites with various time durations after PIP-DOX injection without (e) and with (f) magnetic tumor targeting. signal intensity of MR decreased proportionally with the increase of Fe concentration. The T2 relaxation rate (1/T2) could be fitted linearly with the Fe concentration, giving a T2 relaxation rate (r2) of 128 mM-1s-1, confirming the PIP-DOX as a potential T2-weighted MRI contrast agent. The PA imaging capacity of the PDA based nanospheres was evaluated by the photoacoustic tomography scanner. As revealed in Figure 6b, with the excitation of 810 nm pulsed laser, the PA signal intensity enhanced linearly with the PIP-DOX concentration increment, illustrating a satisfactory PA contrast effect of the nanoagents based on the photothermal conversion feature of the PDA constituent. The PIP-DOX was subsequently injected intravenously into 4T1 tumorbearing mice for evaluating the in vivo dual-modal imaging ability. As indicated in Figure 6c, the apparent negative MRI contrast effect at the tumor region could be attributed to the nanoagents


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accumulated at tumor site probably originated from the EPR effect. After magnetic targeting at tumor site for 24 h, remarkably enhanced darkening effect was observed, owing to the good magnetic response of the nanoagents (Figure 6d). The PAI of PIP-DOX treated mice revealed a gradually increased PA signals at tumor site at various time points post-injection, compared with the weak PA background signal in tumor blood vessels by endogenous hemoglobin before injection (Figure 6e).15,46 With magnetic field targeting for different time durations (Figure 6f), considerable PA signal enhancement was observed at tumor site, reflecting the effective tumor active targeting under exogenous stimulus against the passive accumulation of the nanoagents. Such dual-modal tumor imaging using PIP-DOX nanoagents provided the opportunity for comparative in vivo cancer diagnosis using complementary imaging information, for guiding subsequent precise tumor targeting and therapy. The photothermal-chemo combination in vivo cancer therapy was conducted on 4T1 tumorbearing mice intravenously injected with PIP-DOX nanospheres. The thermal imaging on mice was acquired to demonstrate the temperature rise at tumor sites induced by NIR laser irradiation after 24 h of the nanoagents injection. As revealed in Figure 7a, the PBS treated mice showed only a slight temperature rise (within 4 oC) under laser irradiation (808 nm, 1 W/cm2) up to 5 min. Yet the PIP-DOX injection generated a considerable heating effect on the tumor region reaching a final temperature of 46 oC upon NIR laser, implying the passive accumulation of the nanoagents in tumors. Encouragingly, the magnetic attraction remarkably increased the local temperature at tumor up to 54 oC which was sufficient to kill the malignant cells by thermal ablation,40 confirming the excellent magnetic response of these nanoagents in vivo. For investigating the anti-cancer efficiency of PIP-DOX in tumor bearing mice, the tumors growth was evaluated every 3 days after different treatments. Both the mice photographs and the tumor


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Figure 7. (a) Infrared thermal images of 4T1 tumor-bearing mice under various treatments after irradiated with 808 nm laser (1 W/cm2) for different times. (b) Photographs of 4T1 tumorbearing mice before and 20 days after different treatments. (c) Tumor growth curves from the mice after various treatments. The data are shown as mean ± SD of 5 mice. *p < 0.05, **p < 0.01. growth curves (Figure 7b-c) reflected a rapid tumor size increment for the controlled (PBS treated with NIR irradiation) group. And the PIP-DOX treated mice showed partially suppressed but still rapid tumor occurrence during the whole observation. When NIR laser was conducted after accumulation of the nanoagents for 24 h, the tumor growth was prominently restrained over the course of 18 d, probably benefited from the combination of PTT with anti-cancer drug delivery. Impressively, the combination therapy with magnetic guidance induced a complete eradication of the tumor at much earlier stage (a few days after NIR irradiation) without reoccurrence. The hematoxylin and eosin (H&E) stained tumor slice (Figure 8a) indicated a significant cell damage induced by PIP-DOX with magnetic targeting and laser irradiation, compared with the normal cell morphology in controlled tumor tissue. This may be attributed to the enhanced accumulation of the nanoagents by active tumor targeting and the highly efficient synergism of complementary therapeutic modalities. The major organs from mice at 30 days post-injection of PIP-DOX were collected and examined by H&E staining. As illustrated in


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Figure 8b, the tissue images showed no appreciable damage nor inflammation after PIP-DOX injection compared with the controlled ones, indicating the nanoagents were not noticeably toxic preliminarily.

Figure 8. H&E stained tissue sections of (a) the tumors from control mice and those injected with PIP-DOX after 12 h of therapeutic treatment and (b) the major organs from control mice and those injected with PIP-DOX after 30 d of treatment. 4. CONCLUSIONS In summary, the biocompatible colloidal PDA nanospheres were successfully employed as processible and versatile nanohosts for developing novel cancer theranostic nanoagents with complementary imaging and therapeutic modalities in vivo. Favored by the facile controlling over the self-polymerization of dopamine in Stöber like system as well as the natural affinity of catechol groups to iron atoms, a sandwich structure incorporating compact IOs layer in PDA matrix was established, via thermal decomposition and surface encapsulation with thin PDA shell. The strong magnetic responsiveness and photothermal conversion of these multifunctional nanocomposites enable MRI/PAI dual-modal tumor imaging and magnetic targeted PTT. Moreover, the high reactivity of PDA allowed facile linkage of surface catechol groups with amino-terminated prodrug and PEG chain for the reduction-responsive anticancer drug release. The current theranostic nanoplatform reveals great prospects in precise in vivo cancer therapy, based on multi-modal tumor imaging diagnosis, magnetically guided active tumor targeting and combination of PTT with chemotherapy for highly efficient tumor eradication.


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ASSOCIATED CONTENT Supporting Information Available. Figure S1-Figure S11. This information is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Authors *E-mail address: [email protected]. *E-mail address: [email protected]. ACKNOWLEDGMENT We gratefully acknowledge the financial support from National Natural Science Foundation of China (21501191 and 21672254), Shenzhen Sciences & Technology Innovation Council (JCYJ20150630114942307) and SIAT Innovation Program for Excellent Young Researchers (201513). REFERENCES (1) Lee, H.; Dellatore, S. M.; Miller, W. M.; Messersmith, P. B. Mussel-Inspired Surface Chemistry for Multifunctional Coatings. Science 2007, 318, 426−430. (2) Ye, Q.; Zhou, F.; Liu, W. Bioinspired Catecholic Chemistry for Surface Modification. Chem. Soc. Rev. 2011, 40, 4244–4258. (3) Sedo, J.; Saiz-Poseu, J.; Busque, F.; Ruiz-Molina, D. Catechol-Based Biomimetic Functional Materials. Adv. Mater. 2013, 25, 653–701. (4) Yan, J.; Yang, L.; Lin, M.-F.; Ma, J.; Lu, X.; Lee, P. S. Polydopamine Spheres as Active Templates for Convenient Synthesis of Various Nanostructures. Small 2013, 9, 596–603.


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SYNOPSIS TOC


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Polydopamine-Derivated Hierarchical Nanoplatforms for Efficient Dual

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