Magneto-Plasmonic Nanocapsules for Multimodal-Imaging and

Subscriber access provided by La Trobe University Library

Article

Magneto-Plasmonic Nanocapsules for Multimodal-Imaging and Magnetically Guided Combination Cancer Therapy Liang Huang, Lijiao Ao, Dehong Hu, Wei Wang, Zonghai Sheng, and Wu Su Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.6b02413 • Publication Date (Web): 22 Jul 2016 Downloaded from http://pubs.acs.org on July 24, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

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

Page 1 of 10

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Chemistry of Materials

Magneto-Plasmonic Nanocapsules for Multimodal-Imaging and Magnetically Guided Combination Cancer Therapy Liang Huang†, Lijiao Ao†, Dehong Hu†, Wei Wang, Zonghai Sheng, 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 ABSTRACT: Integrating multiple discrete functionalities into hollow-mesoporous architecture with distinctive electronic/magnetic property, is of particular interest for building multifunctional drug carriers with complementary theranostic modalities. In this paper, the “non-contact” incorporation of gold nanorod (GNR) into porous magnetic nanoshell is achieved via yolk-shell structure, which was intrinsically different from previous direct chemical or heterogeneous conjugation of the two components. The highly preserved plasmonic feature of GNRs enabled photothermal induced photoacoustic imaging and hyperthermia capabilities. The magnetic shell consisted of stacked primary iron oxide nanocrystals yields strong superparamagnetic response with excellent permeability for magnetically targeted drug delivery. Interestingly, the special coordination between doxorubicin and iron species enabled pH/local heating dual-responsive drug release with minor leakage at neutral pH. Under the guidance of magnetic resonance/photoacoustic dual-modal imaging and magnetically tumor targeting using the nanoagents, the photothermal-chemo synergistic therapy was conducted via near-infrared laser for highly efficient tumor eradication.

INTRODUCTION Recent progress in nanotechnology has enabled precise structural controlling and integration of discrete components at the nanoscale.[1-3] The creation of multifunctional hollowmesoporous nanomaterials, for instance, has revealed distinctive prospects in diverse emerging technological fields including biomedical theranostics, heterogeneous catalysis and energy storage.[4-7] These nanostructures with combined magnetic/electronic characters are of particular interest in personalized medicine, such as tumor diagnosis with multiple imaging modalities and combination of complementary therapeutic strategies for synergetic effects.[8-10] Substitution of the welldeveloped silica matrix with superparamagnetic iron oxides for building hollow-mesoporous carriers, would enable magnetically guided enrichment of therapeutic agents at tumor site,[10-12] as well as T2-weighted magnetic resonance imaging (MRI) for whole-body tumor delineation with high spatial resolution.[13-15] Moreover, the iron oxide nanoparticles (IOs) exhibited the superiority of non-toxicity with gradual degradation and metabolization in the organism,[13,16,17] compared with various non-degradable nanomaterials. To break the limitation of MRI in sensitivity[18,19] and achieve synergistic therapeutic effect, the combination of IOs with gold nanostructures bearing tunable localized surface plasmon resonance (LSPR) is desirable. These bi-functional agents would allow photoacoustic imaging (PAI) which particularly favors in vivo diagnosis with excellent tissue penetration, high sensitivity and spatial resolution.[20] Simultaneously, the intense light absorption in near infrared (NIR) region makes such nanocomposites promising photothermal agents to produce highly localized heat for selective cancer photothermal therapy (PTT).[21-23]

Up to date, plenty of efforts have been devoted to build magneto-plasmonic nanostructures for biomedicine.[24-27] Compared with various gold nanoshells,[21,25,28,29] the gold nanorods (GNRs) offer precise control over their LSPR absorption from the shape modulating,[30] enabling highly efficient and customized laser-triggered hyperthermia/imaging applications. Nevertheless, the dynamic binding nature of the surfactants and anisotropic geometry of GNRs,[31,32] rendered them colloidally/optically unstable and tend to attach inhomogeneously with another component.[33,34] Attempts on preparing GNR-IOs nano-conjugates[24,35,36] or heterostructures[37] generally resulted in direct contact of the two contents. This inevitably induced limited attaching and inhomogeneous encapsulation of the magnetic component, accompanied by undesired spectral shifts or LSPR peak broadening, which disturbed the ultimate magneto-plasmonic performances in terms of magnetic response, imaging contrast effects as well as NIR photothermal ability. Fortunately, the yolk-shell architecture isolates the core material from surrounding shell by intermediate voids, allowing special “non-contact” integration of discrete functionalities,[6] which is attractive for incorporating plasmonic materials in a “well-protected” manner. Inspired by the surface derivation capability of silica on diverse metal/metal oxide substrates,[3841] it is interesting to introduce an intermediate silica layer to bridge gold and iron oxide contents. This can not only protect the plasmonic feature of GNRs well, but also facilitate the homogeneous encapsulation of IOs,[42,43] to form successive/permeable shells for MRI and magnetically guided active tumor targeting. Furthermore, the well-controlled and

ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 10

Figure 1. (a) Schematic illustration for the preparation of GNR@IOs-DOX nanocapsules. (b-e) TEM images of GNRs (b), GNR@SiO2 (c), GNR@SiO2@IOs (d) and GNR@IOs nanoparticles (e). (f) STEM and elemental (Fe) mapping of a single GNR@IOs nanocapsule.

removable template favors the formation of various nanocapsules,[44,45] with well-defined internal space and permeability for therapeutic drugs delivery. Herein, we explored a novel combination strategy for magnetic and plasmonic components based on yolk-shell structure. Movable GNRs confined in successive/permeable IOs nanoshells was established through silica templating, in-situ IOs layer deposition and selective template removal, followed by doxorubicin (DOX) loading and adhesion of dopamine modified hyaluronic acid (DA-HA) (Figure 1a). This multifunctional nanocapsule exhibited distinct NIR plasmonic absorption and superior magnetic responsiveness, together with pH/local heating dual-responsive drug release behavior owing to the special coordination between DOX and iron species. Under the guidance of MRI/PAI dual-modal imaging and magnetically tumor homing of the injected nanoagents, the synergistic therapy using PTT and chemical drug was triggered by NIR laser, for highly efficient tumor eradication. The bio-safety of current theranostic nanocapsules for in vivo applications was also evaluated. RESULTS AND DISCUSSION

GNRs with NIR absorption feature were synthesized by seed-mediated growth in the presence of binary surfactants (Figure 1b).[46] A mesoporous silica layer templated by cetyltrimethyl ammonium bromide (CTAB) was primarily deposited onto GNRs (Figure S1) to enhance their colloidal stability in ethanol. A thicker silica shell was achieved via Stöber process, yielding a smooth and clean silica surface (Figure 1c). Subsequently, the magnetic shell consisted of stacked primary IO nanocrystals was in-situ deposited onto silica in polyalcohol, via thermal-decomposition of ferric acetylacetonate at 290 oC, owing to the natural chemical affinity of silica to ferrite.[39,47] As revealed in Figure 1d, the silica surface was occupied by a homogeneous magnetic layer with individual IOs of around 7 nm. This extremely high coverage of IOs benefits not only strong magnetic response of single nanocarrier, but also the formation of intact nanoshell after inner template removal. Before chemical dissolution of silica by weak alkaline solution,[45,48] the nanocomposites were en-

capsulated by another mesoporous silica layer (Figure S2) to prevent possible desorption or disassembly of the IOs. The prepared nanocapsules exhibited intact iron oxide shells with movable GNRs cores (Figure 1e), indicating the complete removal of the template to form yolk-shell architecture. This was further confirmed by STEM imaging (Figure 1f), where the higher atomic numbered gold revealed a brighter rod-shape inside of a darker oval circle of iron oxide. The elemental distribution of Fe also reflected a successive IOs shell with distinct hollow interior (Figure 1f). The crystalline structures of GNR@IOs exhibited characteristic diffraction peaks at 2θ = 30.1, 35.4, 43.2, 53.6, 57.1 and 62.7o (Figure 2a), corresponding well with the typical diffractions of cubic Fe3O4 (JCPDS 19-0629). And the well-defined peaks centered at 2θ = 38.1, 44.4, 64.5 and 77.6o could be assigned to the diffractions of cubic structured Au (JCPDS 040784). The porosity analysis of the nanocapsule (Figure 2b) reflected a type IV gas sorption isotherm, where the hysteresis loop was indicative of a mesoporous system. The BrunauerEmmett-Teller (BET) surface area was determined as 147 m2 g-1, and the pore size distribution according to Barrett-JoynerHalenda (BJH) method was mainly located within 2~6 nm range. Such a mesoporous feature allows small molecular drugs to diffuse readily through the IOs shell for drug delivery applications. As a secondary structure of individual IOs, the whole magnetic shell revealed zero remanence/coercivity (Figure 2c) as expected. The high saturation magnetization (42.5 emug-1) enabled strong magnetic response of single nanocapsule, which is desirable for in vivo magnetically tumor targeting while maintaining good dispersion state of the drug carriers.[13,49] The plasmonic feature of the nanocapsules was subsequently studied. The plain GNRs possessed a distinct LSPR absorption peak, which retained almost unchanged in the NIR region (650~1100 nm) after silica growth and IOs layer deposition, compared with the increased absorbance in UV-Vis region owing to the absorption of IOs (Figure 2d). This highly preserved plasmonic property may arise from the remaining of gold surface chemistry and monodispersity by silica protection in the thermal decomposition process. After template etching,


Page 3 of 10

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 2. (a) XRD pattern of GNR@IOs. (b) Nitrogen sorption isotherm and pore size distribution (inset) of GNR@IOs. (c) Magnetic hysteresis curve of GNR@IOs at 300 K and photographs of GNR@IOs aqueous dispersion in the absence and presence of a magnet (inset). (d) UV-Vis absorption spectra of GNR, GNR@SiO2@IOs and GNR@IOs. (e) Temperature changes of water and various concentrated GNR@IOs aqueous dispersions during laser irradiation (808 nm, 1 W/cm2, 5 min). (f) Temperature changes of GNR@IOs aqueous dispersion (50 µg/mL) with laser irradiation (808 nm, 1 W/cm2) for 8 circles.

the hollow-mesoporous GNR@IOs showed a LSPR peak at 807 nm with the original NIR absorption character. Within a wide concentration range, the GNR@IOs solution underwent a distinct temperature rise along with the 808 nm laser irradiation (Figure 2e). With a concentration of 50 µg/mL, the solution temperature rose up to 58.2 oC which was sufficient for hyperthermia ablation of malignant cells.[50,51] Previously, it was indicated that bare gold nanostructures including GNRs were unstable against NIR laser irradiation.[52-54] While in our experiment, the GNR@IOs solution after irradiated with 808 nm laser for 8 successive circles all reached a final temperature around 58 oC with a similar heating rate of the solution (Figure 2f), confirming the high photothermal stability of IOs shell isolated GNRs. The plasmonic and hollow/permeable nanostructure motivated us to explore combination cancer therapeutic strategy using both PTT and stimuli-responsive drug release (Figure 3a). DOX as a model anti-cancer drug was loaded into GNR@IOs nanocapsules with a loading content of 15.6%. To maintain good colloidal stability of the drug carriers in biological systems, dopamine (DA) molecules were grafted onto hyaluronic acid (HA) to achieve a biocompatible DA-HA polymer,[55,56] which was subsequently adhered to IOs surface owning to the strong chemical affinity of catechol groups to iron oxides.[57-59] The hydrodynamic diameter of the surface encapsulated drug carriers was 241 nm by DLS (Figure S3) with a polydispersity index (PDI) of 0.093, indicating a good dispersion state of the nanocapsules in solution. The zeta potential of the polymer encapsulated drug carrier was determined as -24.3 mV (Figure S4) and such a strong negative charge facilitated the dispersion of individual nanoparticle. Interestingly, the GNR@IOs-DOX revealed a typical acid responsive release profile at 37 oC (Figure 3b), in which the cumulative release of DOX exceeded 70% under pH~5.5 after

48 h incubation, compared with the less than 10% of DOX release under pH~7.4. Such a stimuli-responsive release could be attributed to the formation or breakage of metal-ligand coordination bonding under external pH variations.[60-62] As illustrated in Figure 3a, under a neutral condition, the DOX molecules filling in the mesopores of IOs shell served as lewis base to coordinate with Fe atoms, which blocked the free difussion of loaded DOX. While in acidic environment, the protons competitively binded with DOX as a lewis acid against Fe species, rendering protonated DOX detached from IOs to leave the nano-channels clean for diffusion of internal drug. The release could be further stimulated by NIR (808 nm) laser as indicated in Figure 3c. During the irradiation, the drug release was dramatically increased in either neutral or acidic environment, likely owing to the local heating enhanced free diffusion of loaded small molecules. Noticeably, the NIR laser induced drug release enhancement was more prominent in acidic environment (pH~5.5). Such a pH/NIR laser dualresponsive release character may not only minimize the undesirable leakage of drugs during vascular delivery, but also favor the tumor tissue (acidic environment) specific as well as precisely manipulated on-demand chemotherapy. The cellular uptake of the drug carriers was verified using confocal laser scanning microscopy (CLSM) and flow cytometry. The 4T1 cells incubated with GNR@IOs-DOX showed strong fluorescence in the cytoplasm after 4 h incubation, compared with the relative weak fluorescence observed in cells treated with the same contentrated free DOX (Figure S5). The flow cytometric result quantitatively illustrated the internalization of drugs (Figure S6), where the fluorescent intensity of cells incubated with the nanocapsules was approximately 1.5 times to that with free DOX treatment. Such an enhanced uptake of loaded drug may ascribe to the receptor-mediated endocytosis of hyaluronic acid encapsulated



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 10

Figure 3. (a) Schematic illustration of the combination therapy strategy using GNR@IOs-DOX nanocapsule based on PTT and pH/NIR laser dual-responsive drug release. (b) Release profiles of DOX from GNR@IOs-DOX under different pH values at 37 oC. (c) Release profiles of DOX from GNR@IOs-DOX at different pH values under periodic laser irradiation (808 nm, 1 W/cm2). (d) Viabilities of 4T1 cells after various therapeutic treatments as indicated. *p< 0.05, **p< 0.01.

nanoparticles.[55,56,63] When irradiated with NIR laser, the DOX probably released from the nanocarriers and stained the cell nucleus with red fluorescence as free DOX (Figure S7), indicating the successful laser trigered drug release. The plain nanocapsules (GNR@IOs) exhibited a satisfactory biocompatibility on cellular level, since the 4T1 cells incubated with GNR@IOs (from 12.5 to 400 µg/mL) revealed a viability above 90% (Figure S8). To access the combination therapy feasibility of the drug carriers, different therapeutic modalities using the nanocapsules were studied (Figure 3d). The GNR@IOs-DOX showed a comparable cells killing efficiency to that of free DOX, implying their potentials for anti-cancer drug delivery. Impressively, the GNR@IOs-DOX with laser (L) irradiation exhibited the best therapeutic ability, confirming the effectiveness of combining individual drug delivery with PTT. The calcein-AM and propidium iodide co-stained

Figure 4. Biodistributions of GNR@IOs-DOX determined by Au concentrations in various organs of 4T1 tumor-bearing mice at 24 h after intravenous injection, without or with magnetic targeting at tumor sites. Error bars represent the standard deviation of three mice per group. *p< 0.05, **p< 0.01.

cells visually demonstrated the synergism of individual therapies (Figure S9). The single therapeutic modality using chemical drug or PTT all induced considerable but still partially cell death. Yet, the intense and homogeneous red fluorescence illustrated the effectiveness of the combination therapy for

Figure 5. (a) T2-weighted MR images of GNR@IOs-DOX (upper) and plot of inverse transverse relaxation times versus Fe concentrations. (b) PA images (upper) and linear relationship of PA signal intensities with different GNR@IOs-DOX concentrations.


Page 5 of 10

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 6. (a,c) In vivo T2-weighted MR images of 4T1 tumor-bearing mice at various time points post-injection of GNR@IOs-DOX without (a) or with (c) magnetic tumor targeting. White circles indicate the positions of tumors. (b,d) In vivo PA images of the tumor sites at different time points post-injection of GNR@IOs-DOX without (b) or with (d) magnetic targeting.

cancer cells elimination. The in vivo biodistribution of the nanocapsules in 4T1 tumor-bearing mice was assessed by intravenous administration and detection of Au content via ICP-OES. As indicated in Figure 4, a considerable amount of nanocapsules were accumulated in tumors at 24 h post-injection, likely owing to the enhanced permeability and retention (EPR) effect.[51,64] Additionally, the nanocapsules were mainly distributed in liver and spleen, which were reticuloendothelial organs and responsible for the clearance of foreign nanoparticles.[13] With the assistance of magnetic targeting, the amount of GNR@IOs-DOX in tumors was considerably enhanced (12.4% of injection dose compared with that of 5.6% from non-targeted tumors), which could be ascribed to the magnetic field promoted EPR effect.[10] This efficient accumulation of the nanoagents at tumor site may facilitate the increase of local drug concentration as well as local photothermal heating for synergetic in vivo cancer therapy. The combination of MRI with PAI shows the potential for accurate localization of the tumor sites by simultaneous whole-body diagnosis and fine tumor region detection. The PA imaging ability of GNR@IOs-DOX was investigated by irradiation with 810 nm pulsed laser. As revealed in Figure 5a, the PA signal enhancement was linear with the nanocapsule concentration increase, revealing an excellent PA contrast effect. The performance of the nanocapsule as MRI contrast agents was measured with a 3T clinical MR scanner (Figure 5b). The darkening of the MRI along with the increment of Fe concentration indicated a good T2-weighted MRI contrast effect, with the T2 relaxation rate (r2) estimated to be 177 mM-1s1 , demonstrating the potential of current nanocapsules in T2weighted MR imaging. The in vivo dual-modal imaging was carried out on 4T1 tumor-bearing mice intravenously injected with the nanocapsules. For T2-weighted MRI, the tumor exhibited an obvious darkening effect at 24 h post injection compared with that of 0 h (Figure 6a), indicating the enrichment of the nanoagents at tumor region probably by EPR effect. While with the magnetic field guidance for 24 h, the MRI contrast effect at tumor site was significantly improved (Figure 6c), owing to the strong magnetic response of the nanocapsules. The PAI was subsequently acquired using 810 nm pulsed laser as exci-

tation source (Figure 6b and d). Before intravenous injection, only weak PA signal was visualized in tumor blood vessels owing to the endogenous contrast effect of hemoglobin.[20] At 6 h, 12 h and 24 h post injection, the PA signals increased gradually and considerably, implying the certain accumulation of the nanocapsules by passive tumor targeting. The magnetic field was applied at the tumor site for different time durations to realize the active targeting of GNR@IOs-DOX. Encouragingly, at time points of 6 h, 12 h and 24 h post injection, remarkbly enhanced PA signals at tumor site were observed compared with those for non-targeted mice, consistent with the MRI results. The current dual-modal imaging provided complementary informations for in vivo cancer diagnosis, followed by active tumor homing of the therapeutic agents via external magnetic guidance. To access the anti-tumor capability of GNR@IOs-DOX, the in vivo combination therapy was conducted. The NIR laser induced temperature rise at tumor region was monitored at 24 h post administration of the nanoagents (Figure 7a). The mice treated with PBS revealed a minor tumor temperature rise of ca. 4 oC after 808 nm laser irradiation (1 W/cm2, 7 min). For the nanocapsules injected mice, the tumor temperature gradually increased to 47 oC during the irradiation. In remarkable contrast, the magnetic targeting induced a significant temperature rise up to 57 oC at the tumor site, which was sufficient to ablate the malignant cells by hyperthermia. The 4T1 tumor bearing mice subjected to different therapeutic treatments were monitored with tumor growing status every 3 d after treatments. As shown in Figure 7b, the mice treated with free DOX or GNR@IOs-DOX exhibited only slight or gentle suppression to tumor growth during the observation, and showed mean survival times of ca. 20 and 22 days, respectively (Figure 7e). Despite the apparent restraining of tumor volume induced by GNR@IOs plus laser at 6 d after treatment, the tumor regrowth occurred rapidly (Figure 7c), which led to a survival rate of only 40% at 30 days post-treatment, implying the incomplete eradication of tumor tissue by only PTT. As expected, the combination therapy using GNR@IOs-DOX exposed to laser gained much improved antitumor effect than either single PTT or chemotherapy, accompanied by a survival rate of 100% over a course of 30 days. Noticeably, with the assistance of magnetic field targeting, the tumor was



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 10

Figure 7. (a) Infrared thermal images of 4T1 tumor-bearing mice with different treatments exposed to 808 nm laser (1 W/cm2) for various times. (b) Growth profiles of 4T1 tumors from mice after different treatments. *p < 0.05, **p < 0.01. (c) Photographs of 4T1 tumor-bearing mice on day 18 after different treatments. (d) H&E stained tumor sections from mice with different treatments. Scale bars: 100 µm. (e) Survival rates of 4T1 tumor-bearing mice after different treatments. (f) Body weights of 4T1 tumor-bearing mice after different treatments.

completely eliminated at much earlier stage, probably by the enhanced accumulation of the nanoagents and synergism of PTT with anticancer drug delivery. Hematoxylin and eosin (H&E) stained tumor slices (Figure 7d) confirmed the most prominent tissue necrosis induced by GNR@IOs-DOX with both magnetic targeting and laser irradiation, followed by the combination therapy and PTT treatments. These results consistently illustrated the superior tumor ablation ability using active targeting and complementary therapeutic modalities of the nanocapsules. The potential side-effects of the therapeutic treatments using the nanomedicine were subsequently evaluated. The bodyweights of the treated mice showed a similarly steady increment during the 18 d post administration, and no evident body weight variation was observed (Figure 7f), suggesting the therapeutic treatments were well-tolerated. The major organs were collected from the mice at 30 days post injection of GNR@IOs-DOX for in vivo cytotoxicity study. The H&E stained images showed no obvious tissue damage nor inflammation compared with the controlled ones (Figure S10), indicating the negligible side effects of the theranostic agents. The in vivo hemocompatibility was further investigated via hematology analysis of the mice treated with the nanoagents. The routine blood parameters of the treated group fell well in the normal range with no significant difference from those in controlled group (Table S1), suggesting the function of blood was not disrupted by the administration of the nanomaterial. These preliminary data demonstrated a satisfactory in vivo safety of the nanocapsules for biomedical applications, which was consistent with previously reported nanoagents consisted of gold and ferrite.[10,26] CONCLUSION In summary, a rational-designed hollow-mesoporous nanocapsule with magneto-plasmonic property and stimuli-responsive drug release behavior was synthesized. The “non-contact”

incorporation of GNR into IOs shell via yolk-shell architecture, realized highly preserved plasmonic cores and successive/permeable magnetic shells, allowing MRI/PAI dualmodal tumor diagnosis, photothermal therapy and DOX delivery. The coordination between DOX and iron species enabled pH/local heating dual-responsive drug release with minor leakage at neutral pH. With magnetically guided tumor homing of the nanoagents and synergism of PTT with anticancer drug delivery, the tumor was completely eradicated with no recurrence. This stimuli-triggered chemotherapy and NIR laser controlled PTT reveal great prospects in precise cancer therapy, based on pre-treatment diagnosis and therapeutic process tracking using multiple imaging modalities. EXPERIMENTAL SECTION

Materials. Ferric acetylacetonate (Fe(acac)3), triethylene glycol (TEG), cetyltrimethyl ammonium bromide (CTAB), tetraethyl orthosilicate (TEOS), dopamine hydrochloride, sodium borohydride (NaBH4), N-(3-Dimethylaminopropyl)-N′ethylcarbodiimide hydrochloride (EDC) and NHydroxysuccinimide (NHS) were purchased from SigmaAldrich. Gold(III) chloride trihydrate (HAuCl4·4H2O), silver nitrate (AgNO3), ascorbic acid, hydrochloric acid (HCl, 37%), sodium hydroxide (NaOH), ethanol, ammonia aqueous solution (25%~28%) and sodium carbonate were purchased from Sinopharm Chemical Reagent Co., Ltd. Sodium oleate was purchased from Tokyo Chemical Industry Co., Ltd. Sodium hyaluronan (MW~50 kD) was purchased from Liuzhou Sheng Qiang Biotech Co., Ltd. Doxorubicin hydrochloride (DOX) was purchased from Melone Pharmaceutical Co., Ltd. Ultrapure water with a conductivity of 18 MΩ.cm was produced by a Millipore Milli-Q system. Synthesis of GNR@SiO2 nanocomposite. The GNRs were synthesized according to previous literature.46 The freshly prepared GNRs solution (300 mL) were centrifuged at 9000 rpm for 15 min. After discarding the supernatant, the


Page 7 of 10

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


precipitate was dissolved by 200 mL of CTAB solution (3 mM) and added with 2 mL of NaOH solution (0.1 M). The GNRs solution was added with 600 µL of TEOS solution (20% in methanol) in every 30 min duration for three times, followed by stirring at room temperature for two days. The mesoporous silica coated GNRs were centrifuged and washed by methanol and water for several times and then dispersed into a mixture consisted of 34 mL of water, 160 mL of ethanol and 6 mL of ammonia aqueous solution. The above mixture was added with 200 µL of TEOS dropwise and stirred at room temperature for 6 h. The GNR@SiO2 nanocomposite was centrifuged, washed with ethanol and water for several times and finally dispersed into 4 mL of ethanol. Synthesis of GNR@IOs nanocapsule. The GNR@SiO2 ethanol dispersion (4 mL) was added into a 150 mL two-neck flask containing 320 mg of Fe(acac)3 and 60 mL of TEG. The flask was kept under vacuum at 70 oC for 15 min to evaporate the organic solvant. The flask was then filled with argon and heated to 210 oC and kept for 2 h with vigorous stirring. The temperature was further raised to 290 oC and kept for another 1 h under stirring. After cooling to room temperature, the solution was mixed with acetone and the GNR@SiO2@IOs were seperated by a magnet and washed with ethanol several times and then dispered into 20 mL of water. The GNR@SiO2@IOs solution (10 mL) was added into a glass bottle containing 390 mL of CTAB solution (3 mM) and 4 mL of NaOH solution (0.1 M). The mixture was added with 1.2 mL of TEOS solution (20% in methanol) in every 30 min duration for three times, followed by stirring at room temperature for two days. The mesoporous silica coated GNR@SiO2@IOs were centrifuged and then dispersed into 200 mL of Na2CO3 solution (0.2 M). The mixture was stirred at 50 oC for 12 h for etching of the silica components. The as prepared GNR@IOs nanocapsules were magnetically seperated and washed with water. Drug loading and surface modification of GNR@IOs. GNR@IOs nanocapsules (5 mg) was dispersed into 10 mL of methanol containing 3 mg of DOX. The mixture was shaken for 12 h in dark at room temperature, and the DOX loaded GNR@IOs was magnetically seperated, washed with methanol and water and then dispersed into 1 mL of water. The dopamine modified hyaluronic acid (DA-HA) was synthesized according to previous report,56 with minor modification. Briefly, 100 mg of sodium hyaluronan was dissolved by 50 mL of phosphate buffered saline (PBS, pH~5.0). EDC (50 mg) and NHS (30 mg) was successively added into the solution, followed by the introduction of dopamine hydrochloride (50 mg). The pH of the solution was monitored and maintained at 5.0 for 12 h. The mixture was dialyzed (MWCO=10000) for 48 h for purification and then lyophilized into powder. The DA-HA (10 mg) was dissolved in 10 mL of water, followed by the addition of as prepared DOX loaded GNR@IOs (1 mL). After 30 min of stirring, the DA-HA encapsulated GNR@IOs-DOX nanocapsules were harvested by a magnetic and washed with water. Characterizations. Transmission electron microscopy (TEM) was carried out on FEI-F20 electron microscopy operated at 200 kV. The X-ray diffraction (XRD) patterns were recorded by a Bruker D8 ADVANCE diffractometer with Cu-Kα radiation (λ = 1.54 Å). The room temperature magnetic hysteresis curve was determined by a

superconducting quantum interference device (SQUID) magnetometer (MPMS-7, Quantum Design) with magnetic field up to 20 kOe. The nitrogen sorption isotherm was measured at 77 K with an Autosorb-iQ surface area and pore size analyzer (Quantachrome Instruments). Dynamic light scattering (DLS) was acquired with a Malvern Zetasizer NanoZS Instrument. The T2 relaxivity was measured using a 3.0 T clinical MR scanner (Siemens) at room temperature. The UV-Vis absorption spectra were recorded by a Perkin-Elmer Lambda 750 spectrometer. The Fe content was determined by a Perkin-Elmer/OPTIMA 7000DV inductively coupled plasma optical emission spectrometry (ICP-OES). 4T1 tumor-bearing mouse model. The 4T1 cells were cultured in DMEM supplemented with 10% heat-inactivated FBS, and 1% penicillin and streptomycin at 37 °C and 5% CO2. Balb/c mice were used under protocols approved by Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences Animal Care and Use Committee. To setup 4T1 tumors, the 4T1 cells (1×106) suspended in serumfree cell medium were subcutaneously injected into the right flank of each mouse. Experiments were carried out about 10 days after the cells injection. In vitro cellular uptake. 4T1 cells were seeded in a 8well plate in DMEM containing FBS and incubated for 24 h at 37 °C. The medium was discarded and the cells were incubated with fresh medium containing GNR@IOs-DOX or free DOX with the same DOX concentration (5 µg/ml). After incubated for another 4h, the medium was removed and the cells were washed with PBS and fixed with 10% formalin. After washing the cells with PBS, hoechst was added to stain the nucleus. The cells were washed with PBS followed by confocal microscopy fluorescent imaging using a Leica DMI6000 inverted microscope. To determine the cellular uptake by flow cytometry, the cells were seeded in a 24-well plate (2×105/well) in DMEM supplemented with 10% FBS overnight at 37 °C. The medium was removed and then added with fresh medium containing GNR@IOs-DOX or free DOX with the same DOX concentration (5 µg/ml). The cells were incubated for 4 h and then washed with PBS, trypsinized, centrifugated and resuspended in PBS. The uptake of DOX was measured using a BD Accuri C6 flow cytometer. Biodistribution study. The 4T1 tumor-bearing mice were intravenously injected with 150 µL of GNR@IOs-DOX (2 mg/mL). The mice were treated with or without a small magnet attaching to the tumor site. After 24 h, the mice were sacrificed and the heart, liver, spleen, lung, kidney and tumor were collected. The organs were weighted and digested for the measurement of Au content by ICP-OES. In vivo tumor imaging. The tumor-bearing mice were injected intravenously with GNR@IOs-DOX (1 mg/mL, 200 µL). The mice were treated with or without a small magnet attaching to the tumor site. The MR imaging was performed on the mice at 0 h and 24 h post injection on a 3.0 T clinical MR scanner (Siemens) using the following parameters: TR = 2000 ms, TE = 47 ms, slice thickness = 1.0 mm, matrix = 128 × 256. The PA imaging was acquired on the mice at 0 h, 6 h, 12 h and 24 h post injection on a photoacoustic computerized tomography scanner (Endra Nexus 128, Ann Arbor, MI), with 810 nm as the excitation laser wavelength. In vivo combination therapy. 4T1 tumor-bearing mice were divided into six groups (n = 5 per group). The mice were



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

injected intravenously with 200 µL of PBS, free DOX (0.16 mg/mL), GNR@IOs (0.84 mg/mL) or GNR@IOs-DOX (1 mg/mL), respectively. The mice were treated with or without a small magnet attaching to the tumor site. At 24 h post injection, the tumors were irradiated with or without NIR laser (808 nm, 1 W/cm2) for 7 min. The tumor sizes were measured by a digital caliper every 3 days for 18 days and the tumor volume was calculated as (tumor length) × (tumor width)2/2.

ASSOCIATED CONTENT Supporting Information. The Supporting Information material is available free of charge via the Internet at http://pubs.acs.org. The supporting data includes TEM, DLS and zeta potential characterizations of the nanocapsules, cellular uptake by CLSM and flow cytometry, in vitro cytotoxicity results as well as biosafety evaluations of the nanoagent.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Author Contributions †

L. Huang, L. Ao and D. Hu contributed equally.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We gratefully acknowledge the financial support from National Natural Science Foundation of China (21501191), Shenzhen Sciences & Technology Innovation Council (JCYJ20150630114942307) and “Hundred Talents Program” of Chinese Academy of Sciences.

REFERENCES (1) Lou, X. W.; Archer, L. A.; Yang, Z. Hollow Micro/Nanostructures: Synthesis and Applications. Adv. Mater. 2008, 20, 3987–4019. (2) Jin, Y.; Gao, X. Plasmonic Fluorescent Quantum Dots. Nat. Nanotechnol. 2009, 4, 571–576. (3) Lu, Z.; Yin, Y. Colloidal Nanoparticle Clusters: Functional Materials by Design. Chem. Soc. Rev. 2012, 41, 6874–6887. (4) Tang, F.; Li, L.; Chen, D. Mesoporous Silica Nanoparticles: Synthesis, Biocompatibility and Drug Delivery. Adv. Mater. 2012, 24, 1504–1534. (5) Pérez-Lorenzo, M.; Vaz, B.; Salgueiriño, V.; Correa-Duarte, M. A. Hollow-Shelled Nanoreactors Endowed with High Catalytic Activity. Chem. Eur. J. 2013, 19, 12196–12211. (6) Liu, J.; Qiao, S. Z.; Chen, J. S.; Lou, X. W.; Xing, X.; Lu, G. Q. Yolk/Shell Nanoparticles: New Platforms for Nanoreactors, Drug Delivery and Lithium-Ion Batteries. Chem. Commun. 2011, 47, 12578–12591. (7) Lai, X.; Halpert, J. E.; Wang, D. Recent Advances in Micro/Nano-Structured Hollow Spheres for Energy Applications: From Simple to Complex Systems. Energy Environ. Sci. 2012, 5, 5604– 5618. (8) He, Q.; Guo, S.; Qian, Z.; Chen, X. Development of Individualized Anti-Metastasis Strategies by Engineering Nanomedicines. Chem. Soc. Rev. 2015, 44, 6258–6286. (9) Fan, W.; Shen, B.; Bu, W.; Chen, F.; Zhao, K.; Zhang, S.; Zhou, L.; Peng, W.; Xiao, Q.; Xing, H.; Liu, J.; Ni, D.; He, Q.; Shi, J. Rattle-Structured Multifunctional Nanotheranostics for Synergetic

Page 8 of 10

Chemo-/Radiotherapy and Simultaneous Magnetic/Luminescent Dual-Mode Imaging. J. Am. Chem. Soc. 2013, 135, 6494–6503. (10) Li, Z.; Yi, S.; Cheng, L.; Yang, K.; Li, Y.; Liu, Z. Magnetic Targeting Enhanced Theranostic Strategy Based on Multimodal Imaging for Selective Ablation of Cancer. Adv. Funct. Mater. 2014, 24, 2312–2321. (11) Zhang, F.; Braun, G. B.; Pallaoro, A.; Zhang, Y.; Shi, Y.; Cui, D.; Moskovits, M.; Zhao, D.; Stucky, G. D. Mesoporous Multifunctional Upconversion Luminescent and Magnetic “Nanorattle” Materials for Targeted Chemotherapy. Nano Lett. 2012, 12, 61–67. (12) Wang, Y.; Huang, R.; Liang, G.; Zhang, Z.; Zhang, P.; Yu, S.; Kong, J. MRI-Visualized, Dual-Targeting, Combined Tumor Therapy Using Magnetic Graphene-Based Mesoporous Silica. Small 2014, 10, 109–116. (13) Colombo, M.; Carregal-Romero, S.; Casula, M. F.; Gutiérrez, L.; Morales, M. P.; Böhm, I. B.; Heverhagen, J. T.; Prosperi, D.; Parak, W. J. Biological Applications of Magnetic Nanoparticles. Chem. Soc. Rev. 2012, 41, 4306–4334. (14) Hu, F.; Wei, L.; Zhou, Z.; Ran, Y.; Li, Z.; Gao, M. Preparation of Biocompatible Magnetite Nanocrystals for In Vivo Magnetic Resonance Detection of Cancer. Adv. Mater. 2006, 18, 2553–2556. (15) Ho, D.; Sun, X.; Sun, S. Monodisperse Magnetic Nanoparticles for Theranostic Applications. Acc. Chem. Res. 2011, 44, 875–882. (16) Arami, H.; Khandhar, A.; Liggitt, D.; Krishnan, K. M. In Vivo Delivery, Pharmacokinetics, Biodistribution and Toxicity of Iron Oxide Nanoparticles. Chem. Soc. Rev. 2015, 44, 8576–8607. (17) Kolosnjaj-Tabi, J.; Javed, Y.; Lartigue, L.; Volatron, J.; Elgrabli, D.; Marangon, I.; Pugliese, G.; Caron, B.; Figuerola, A.; Luciani, N.; Pellegrino, T.; Alloyeau, D.; Gazeau, F. The One Year Fate of Iron Oxide Coated Gold Nanoparticles in Mice. ACS Nano 2015, 9, 7925– 7939. (18) Baker, M. Whole-Animal Imaging: The Whole Picture. Nature 2010, 463, 977–980. (19) Kunjachan, S.; Ehling, J.; Storm, G.; Kiessling, F.; Lammers, T. Noninvasive Imaging of Nanomedicines and Nanotheranostics: Principles, Progress, and Prospects. Chem. Rev. 2015, 115, 10907–10937. (20) Kim, C.; Favazza, C.; Wang, L. V. In Vivo Photoacoustic Tomography of Chemicals: High-Resolution Functional and Molecular Optical Imaging at New Depths. Chem.Rev. 2010, 110, 2756–2782. (21) Liu, H.; Chen, D.; Li, L.; Liu, T.; Tan, L.; Wu, X.; Tang, F. Multifunctional Gold Nanoshells on Silica Nanorattles: A Platform for the Combination of Photothermal Therapy and Chemotherapy with Low Systemic Toxicity. Angew. Chem. Int. Ed. 2011, 50, 891–895. (22) Park, J.-H.; Maltzahn, G.; Xu, M. J.; Fogal, V.; Kotamraju, V. R.; Ruoslahti, E.; Bhatia, S. N.; Sailor, M. J. Cooperative Nanomaterial System to Sensitize, Target, and Treat Tumors. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 981–986. (23) Zhang, Z.; Wang, L.; Wang, J.; Jiang, X.; Li, X.; Hu, Z.; Ji, Y.; Wu, X.; Chen, C. Mesoporous Silica-Coated Gold Nanorods as a Light-Mediated Multifunctional Theranostic Platform for Cancer Treatment. Adv. Mater. 2012, 24, 1418–1423. (24) Wang, C.; Chen, J.; Talavage, T.; Irudayaraj, J. Gold Nanorod/Fe3O4 Nanoparticle “Nano-Pearl-Necklaces” for Simultaneous Targeting, Dual-Mode Imaging, and Photothermal Ablation of Cancer Cells. Angew. Chem. Int. Ed. 2009, 48, 2759–2763. (25) Jin, Y.; Jia, C.; Huang, S. W.; O′Donnell, M.; Gao, X. Multifunctional Nanoparticles as Coupled Contrast Agents. Nat. Commun. 2010, 1, 41. (26) Dong, W.; Li, Y.; Niu, D.; Ma, Z.; Gu, J.; Chen, Y.; Zhao, W.; Liu, X.; Liu, C.; Shi, J. Facile Synthesis of Monodisperse Superparamagnetic Fe3O4Core@Hybrid@Au Shell Nanocomposite for Bimodal Imaging and Photothermal Therapy. Adv. Mater. 2011, 23, 5392– 5397. (27) Wu, C.-H.; Cook, J.; Emelianov, S.; Sokolov, K. Multimodal Magneto-Plasmonic Nanoclusters for Biomedical Applications. Adv. Funct. Mater. 2014, 24, 6862–6871.


Page 9 of 10

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(28) Levin, C. S.; Hofmann, C.; Ali, T. A.; Kelly, A. T.; Morosan, E.; Nordlander, P.; Whitmire, K. H.; Halas, N. J. Magnetic-Plasmonic Core-Shell Nanoparticles. ACS Nano 2009, 3, 1379–1388. (29) Zhou, H.; Kim, J.-P.; Bahng, J. H.; Kotov, N. A.; Lee, J. SelfAssembly Mechanism of Spiky Magnetoplasmonic Supraparticles. Adv. Funct. Mater. 2014, 24, 1439–1448. (30) Chen, H.; Shao, L.; Li, Q.; Wang, J. Gold Nanorods and Their Plasmonic Properties. Chem. Soc. Rev. 2013, 42, 2679–2724. (31) Pastoriza-Santos, I.; Pérez-Juste, J.; Liz-Marzán, L. M. SilicaCoating and Hydrophobation of CTAB-Stabilized Gold Nanorods. Chem. Mater. 2006, 18, 2465–2467. (32) Vigderman, L.; Khanal, B. P.; Zubarev, E. R. Functional Gold Nanorods: Synthesis, Self-Assembly, and Sensing Applications. Adv. Mater. 2012, 24, 4811–4841. (33) Wang, C.; Irudayaraj, J. Multifunctional Magnetic–Optical Nanoparticle Probes for Simultaneous Detection, Separation, and Thermal Ablation of Multiple Pathogens. Small 2010, 6, 283–289. (34) Wang, F.; Cheng, S.; Bao, Z.; Wang, J. Anisotropic Overgrowth of Metal Heterostructures Induced by a Site-Selective Silica Coating. Angew. Chem. Int. Ed. 2013, 52, 10344–10348. (35) Gole, A.; Stone, J. W.; Gemmill, W. R.; Loye, H.-C.; Murphy, C. J. Iron Oxide Coated Gold Nanorods: Synthesis, Characterization, and Magnetic Manipulation. Langmuir 2008, 24, 6232–6237. (36) Yang, H.-W.; Liu, H.-L.; Li, M.-L.; His, I-W.; Fan, C.-T.; Huang, C.-Y.; Lu, Y.-J.; Hua, M.-Y.; Chou, H.-Y.; Liaw, J.-W.; Ma, C.-C. M.; Wei, K.-C. Magnetic Gold-Nanorod/ PNIPAAmMA Nanoparticles for Dual Magnetic Resonance and Photoacoustic Imaging and Targeted Photothermal Therapy. Biomaterials 2013, 34, 5651–5660. (37) Bao, Z.; Sun, Z.; Li, Z.; Tian, L.; Ngai, T.; Wang, J. Plasmonic Gold-Superparamagnetic Hematite Heterostructures. Langmuir 2011, 27, 5071–5075. (38) Graf, C.; Vossen, D. L. J.; Imhof, A.; Blaaderen, A. A General Method to Coat Colloidal Particles with Silica. Langmuir 2003, 19, 6693–6700. (39) Lu, Y.; Yin, Y.; Mayers, B. T.; Xia, Y. Modifying the Surface Properties of Superparamagnetic Iron Oxide Nanoparticles through A Sol-Gel Approach. Nano Lett. 2002, 2, 183–186. (40) Gorelikov, I.; Matsuura, N. Single-Step Coating of Mesoporous Silica on Cetyltrimethyl Ammonium Bromide-Capped Nanoparticles. Nano Lett. 2008, 8, 369–373. (41) Guerrero-Martínez, A.; Pérez-Juste, J.; Liz-Marzán, L. M. Recent Progress on Silica Coating of Nanoparticles and Related Nanomaterials. Adv. Mater. 2010, 22, 1182–1195. (42) Qu, H.; Tong, S.; Song, K.; Ma, H.; Bao, G.; Pincus, S.; Zhou, W.; O’Connor, C. Controllable in Situ Synthesis of Magnetite Coated Silica-Core Water-Dispersible Hybrid Nanomaterials. Langmuir 2013, 29, 10573–10578. (43) Huang, L.; Ao, L.; Wang, W.; Hu, D.; Sheng, Z.; Su, W. Multifunctional Magnetic Silica Nanotubes for MR Imaging and Targeted Drug Delivery. Chem. Commun. 2015, 51, 3923–3926. (44) Chen, D.; Li, L.; Tang, F.; Qi, S. Facile and Scalable Synthesis of Tailored Silica “Nanorattle” Structures. Adv. Mater. 2009, 21, 3804– 3807. (45) Chen, Y.; Chen, H.; Guo, L.; He, Q.; Chen, F.; Zhou, J.; Feng, J.; Shi, J. Hollow/Rattle-Type Mesoporous Nanostructures by a Structural Difference-Based Selective Etching Strategy. ACS Nano 2010, 4, 529–539. (46) Ye, X.; Zheng, C.; Chen, J.; Gao, Y.; Murray, C. B. Using Binary Surfactant Mixtures to Simultaneously Improve the Dimensional Tunability and Monodispersity in the Seeded Growth of Gold Nanorods. Nano Lett 2013, 13, 765–771. (47) Ding, H.; Zhang, Y.; Wang, S.; Xu, J.; Xu, S.; Li, G. Fe3O4@SiO2 Core/Shell Nanoparticles: The Silica Coating Regulations with a Single Core for Different Core Sizes and Shell Thicknesses. Chem. Mater. 2012, 24, 4572–4580. (48) Fang, Y.; Zheng, G.; Yang, J.; Tang, H.; Zhang, Y.; Kong, B.; Lv, Y.; Xu, C.; Asiri, A. M.; Zi, J.; Zhang, F.; Zhao, D. Dual-Pore Mesoporous Carbon@Silica Composite Core–Shell Nanospheres for

Multidrug Delivery. Angew. Chem. Int. Ed. 2014, 53, 5366–5370. (49) Guo, J.; Yang, W.; Wang, C. Magnetic Colloidal Supraparticles: Design, Fabrication and Biomedical Applications. Adv. Mater. 2013, 25, 5196–5214. (50) Zheng, M.; Yue, C.; Ma, Y.; Gong, P.; Zhao, P.; Zheng, C.; Sheng, Z.; Zhang, P.; Wang, Z.; Cai, L. Single-Step Assembly of DOX/ICG Loaded Lipid-Polymer Nanoparticles for Highly Effective Chemo-Photothermal Combination Therapy. ACS Nano 2013, 7, 2056–2067. (51) Liu, T.; Shi, S.; Liang, C.; Shen, S.; Cheng, L.; Wang, C.; Song, X.; Goel, S.; Barnhart, T. E.; Cai, W.; Liu, Z. Iron Oxide Decorated MoS2 Nanosheets with Double PEGylation for Chelator-Free Radiolabeling and Multimodal Imaging Guided Photothermal Therapy. ACS Nano 2015, 9, 950–960. (52) Hu, X.; Gao, X. Multilayer Coating of Gold Nanorods for Combined Stability and Biocompatibility. Phys. Chem. Chem. Phys. 2011, 13, 10028–10035. (53) Liu, Y.; Ai, K.; Liu, J.; Deng, M.; He, Y.; Lu, L. DopamineMelanin Colloidal Nanospheres: an Efficient Near-Infrared Photothermal Therapeutic Agent for in Vivo Cancer Therapy. Adv. Mater. 2013, 25, 1353–1359. (54) Jin, Y.; Gao, X. Spectrally Tunable Leakage-Free Gold Nanocontainers. J. Am. Chem. Soc. 2009, 131, 17774–17776. (55) Lee, Y.; Lee, H.; Kim, Y. B.; Kim, J.; Hyeon, T.; Park, H. W.; Messersmith, P. B.; Park, T. G. Bioinspired Surface Immobilization of Hyaluronic Acid on Monodisperse Magnetite Nanocrystals for Targeted Cancer Imaging. Adv. Mater. 2008, 20, 4154–4157. (56) Wang, Z.; Chen, Z.; Liu, Z.; Shi, P.; Dong, K.; Ju, E.; Ren, J.; Qu, X. A Multi-Stimuli Responsive Gold Nanocage-Hyaluronic Platform for Targeted Photothermal and Chemotherapy. Biomaterials 2014, 35, 9678–9688. (57) Xu, C.; Xu, K.; Gu, H.; Zheng, R.; Liu, H.; Zhang, X.; Guo, Z.; Xu, B. Dopamine as A Robust Anchor to Immobilize Functional Molecules on the Iron Oxide Shell of Magnetic Nanoparticles. J. Am. Chem. Soc. 2004, 126, 9938–9939. (58) Xie, J.; Chen, K.; Lee, H.-Y.; Xu, C.; Hsu, A. R.; Peng, S.; Chen, X.; Sun, S. Ultrasmall c(RGDyK)-Coated Fe3O4 Nanoparticles and Their Specific Targeting to Integrin αvβ3-Rich Tumor Cells. J. Am. Chem. Soc. 2008, 130, 7542–7543. (59) Wei, H.; Insin, N.; Lee, J.; Han, H.-S.; Cordero, J. M.; Liu, W.; Bawendi, M. G. Compact Zwitterion-Coated Iron Oxide Nanoparticles for Biological Applications. Nano Lett. 2012, 12, 22–25. (60) Barick, K. C.; Nigam, S.; Bahadur, D. Nanoscale Assembly of Mesoporous ZnO: A Potential Drug Carrier. J. Mater. Chem. 2010, 20, 6446–6452. (61) Zheng, H.; Wang, Y.; Che, S. Coordination Bonding-Based Mesoporous Silica for pH-Responsive Anticancer Drug Doxorubicin Delivery. J. Phys. Chem. C 2011, 115, 16803–16813. (62) Wu, M.; Meng, Q.; Chen, Y.; Xu, P.; Zhang, S.; Li, Y.; Zhang, L.; Wang, M.; Yao, H.; Shi, J. Ultrasmall Confined Iron Oxide Nanoparticle MSNs as a pH-Responsive Theranostic Platform. Adv. Funct. Mater. 2014, 24, 4273–4283. (63) Swierczewska, M.; Choi, K. Y.; Mertz, E. L.; Huang, X.; Zhang, F.; Zhu, L.; Yoon, H. Y.; Park, J. H.; Bhirde, A.; Lee, S.; Chen, X. A Facile, One-Step Nanocarbon Functionalization for Biomedical Applications. Nano Lett. 2012, 12, 3613–3620. (64) Sheng, Z.; Hu, D.; Zheng, M.; Zhao, P.; Liu, H.; Gao, D.; Gong, P.; Gao, G.; Zhang, P.; Ma, Y.; Cai, L. Smart Human Serum Albumin-Indocyanine Green Nanoparticles Generated by Programmed Assembly for Dual-Modal Imaging-Guided Cancer Synergistic Phototherapy. ACS Nano 2014, 8, 12310–12322.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

SYNOPSIS TOC


Page 10 of 10

Magneto-Plasmonic Nanocapsules for Multimodal-Imaging and

Recommend Documents