Inorganic Nanoshell-Stabilized Liquid Metal for Targeted

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Inorganic Nanoshell-Stabilized Liquid Metal for Targeted Photo-Nanomedicine in NIR-II Biowindow Piao Zhu, Shanshan Gao, Han Lin, Xiangyu Lu, Bowen Yang, Linlin Zhang, Yu Chen, and Jianlin Shi Nano Lett., Just Accepted Manuscript • DOI: 10.1021/acs.nanolett.9b00364 • Publication Date (Web): 25 Feb 2019 Downloaded from http://pubs.acs.org on February 26, 2019

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Inorganic Nanoshell-Stabilized Liquid Metal for Targeted Photo-Nanomedicine in NIR-II Biowindow Piao Zhu,1,2 Shanshan Gao,1,2 Han Lin,1,2 Xiangyu Lu,1,2 Bowen Yang,1,2 Linlin Zhang,1 Yu Chen1* and Jianlin Shi1* 1The

State Key Lab of High Performance Ceramics and Superfine Microstructure, Shanghai

Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, P. R. China. 2University

of Chinese Academy of Sciences, Beijing 100049, P. R. China.

E-mail: [email protected] (Y. Chen), phone number: 021-52412018, fax number: 86-2152413903; [email protected] (J. Shi), phone number: 021-52412712, fax number: 86-2152413903.

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ABSTRACT: Gallium and gallium-based alloys, typical types of liquid metals with unique physiochemical properties, are emerging as a new generation of functional materials in versatile biomedical applications. However, the exploring of their biomedical performances is still insufficient at current stage and their intrinsic low oxidative resistance is a key blocking their further clinical translation. Herein, we report on the surface engineering of liquid metalbased nanoplatforms by inorganic silica nanoshell based on a novel but facile sonochemical synthesis for highly efficient, targeted and near infrared (NIR)-triggered photothermal tumor hyperthermia in NIR-II biowindow. Especially, the inorganic silica-shell engineering of liquid metal significantly enhances the photothermal performances of the liquid-metal core as reflected by enhanced NIR absorption, improved photothermal stability by oxidation protection and abundant surface chemistry for surface-targeted engineering to achieve enhanced tumor accumulation. Systematic in vitro cell-level evaluation and in vivo tumor xenograft assessment demonstrate that (Arg-Gly-Asp) RGD-targeted and silica-coated nanoscale liquid metal substantially induces photo-triggered cancer-cell death and photothermal tumor eradication, accompanied with high in vivo biocompatibility and easy excretion out of the body. This work provides the first paradigm for surface-inorganic engineering of liquid metal-based nanoplatforms for achieving the multiple desirable therapeutic performances, especially on combating cancer.

KEYWORDS: Liquid metal, Photothermal therapy, NIR-II, Targeted nanomedicine, Cancer


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Liquid metal, as the name suggests, exhibits both fluidic liquidity and low viscosity, together with high metallic thermal/electrical conductivity and superior mechanical properties.1, 2 Due to the fascinating physiochemical properties, liquid metal has been widely explored in versatile scopes of research fields, such as materials science,1, 2 energy,3 catalysis4 and even recently developed biomedicine.5-10 In a broad sense, all of the metals and alloys that can keep liquidity at below or near room temperature are generally regarded as liquid metal.11, 12

Especially, gallium and gallium-based alloys with their melting points at nearly body

temperature are emerging as the new generation of functional materials in versatile biomedical fields based on its relatively high biocompatibility and intriguing physiochemical property for satisfying the biomedical requirements.7, 13-16 Hitherto, no evidence has ever been revealed to show the existence of free gallium in nature.12 Once exposed to ambient conditions, native gallium oxide layer will be generated on the surface of liquid metal immediately, which was reported to be between 0.5 and 5.0 nm in thickness in a growth condition-dependent manner.17-20 It should be noted that the mild environmental excitation and perturbation will unavoidably break the passivation layer, which induces further oxidation simultaneously.21 In this regard, transforming bulk liquid metal into nanoscale particles will sacrifice a fairly large fraction for passivation due to the exponential enlargement of specific surface area,22-26 which may deteriorate some performances of liquid metals such as reversing its flow behavior due to the viscoelastic surface.27 In addition, such oxidation process may be disadvantageous for stability and surface engineering of EGaIn nanoparticles in physiological condition when considering high application standards in biomedicine, because there is no typical functional group on liquid-metal surface for further modification.5,

13,

28

Taking the reported Cabrera−Mott oxidation mechanism into

consideration,29-31 the previous reports have made remarkable progresses in preventing oxygen adsorption by the competition of surface sites using organic coating.5, 8, 9, 13, 15, 25, 32-35 3 ACS Paragon Plus Environment

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However, none of these strategies can efficiently protect liquid metal from being oxidized because of either incomplete package or intrinsic unstable organic-surface coating. On this ground, we herein report, for the first time, on the surface inorganic engineering of liquid metals by silica-shell coating, which has been achieved by a novel but facile sonochemical synthesis. This work has demonstrated two unique advantages of inorganic silica shell engineering of liquid metals. On the one hand, the silica coating efficiently prevents further oxidation of liquid metals so as to significantly enhance its photostability for potential continuous therapeutic application. On the other hand, the abundant surface silanol chemistry of silica-coating makes the surface of liquid metals highly versatile for the conjugation of biomolecules for some specific purposes such as targeted modification/conjugation as demonstrated in this work,

36-39

i.e., RGD peptides for active

targeting recognition and binding to the overexpressed integrin αvβ3 on the U87 cancer-cell membrane.

37, 40

Especially and importantly, this work for the first time reveals the near

infrared (NIR)-II biowindow-responsive photothermal tumor hyperthermia by silica-coated liquid metals as the efficient photothermal-conversion nanoagents, which has been systematically evaluated and demonstrated both in vitro at cellular level and in vivo on tumorxenograft, and the high biocompatibility and easy excretion of liquid metals out of the body. “Bottom-up” and “top-down” are the two most representative approaches to fabricate metallic alloy nanoparticles. On the one hand, the bottom-up approach is feasible for controlling the size and topology of these nanoparticles,41-44 but it usually fails to tune the composition stoichiometry. On the other hand, the top-down approach can easily control the composition stoichiometry because of its simple synthetic procedure of transforming bulk materials into nanoscale particles by a certain level of external energy input.44, 45 Ultrasound, which can provide extremely high localized temperature and pressure in a short duration, has been extensively employed in top-down nanoconstrcution.46 Herein, 4 ACS Paragon Plus Environment

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ultrasound was used to develop a sonosynthetic top-down strategy for construction of inorganic silica nanoshell-stabilized liquid metal nanoplatforms (Figure 1). Typically, liquid metal (eutectic gallium/indium, abbreviated as EGaIn) was added into a glass bottle filled with ethanol (10 mL) in the glovebox for avoiding liquid-metal oxidation. After immersing the high-intensity ultrasonic titanium horn-type sonicator, the opening between the bottle and transducer microtip was firmly covered with Parafilm in tandem. The liquid metal nanoparticles were gradually generated beneath the thin gallium oxide at 20 ℃. Accelerated by the acoustic cavitation effect, a thin silica layer was deposited onto the surface of inert oxide layer by the hydrolysis and condensation of silicon sources under a weak alkaline environment as created by dilute ammonia solution.46, 47 It is noted that the protective inorganic silica layer (tetraethylorthosilicate, TEOS) can prevent the liquid-metal core from being further oxidized, and the thermal-insulating silica coating can avoid heat loss. Especially and importantly, the surface silica layer with rich silanol groups provides the anchoring points for further surface functionalization, e.g., RGD peptides anchoring in this study for positive tumor targeting by binding to the overexpressed integrin αvβ3 on the cancer-cell membrane and consequent enhanced accumulation into tumor tissue (designated as liquid metal@SiO2-RGD). The subsequent NIR irradiation in NIR-II biowindow activates the liquid metal@SiO2-RGD nanoparticles for photothermal conversion and further efficient photothermal cancer hyperthermia (Figure 1). During sonication, the bulk liquid metal was sheared into smaller fractions within a few minutes, and then reduced to micro- and/or nanoparticles, in which the fresh metal was divided and re-oxidized under the exposure to localized but extremely strong cavitation effect in the following sonication duration, finally resulting in dispersed nanoparticles without coalescence into a bulky and large sphere due to the smooth passivative “skin” on their newly-generated surfaces. Still, slight deformation was found at the point of contacting “skin” 5 ACS Paragon Plus Environment

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between particles since the thin viscoelastic gallium oxide layer about 2 nm is too soft to keep its original shape (Figure 2a, top-ranking images). By contrast, a rough silica shell was coated after additional 2-h continuous sonication of the slurry in alkaline ethanol-water solution, resulting in further thickened coating of the liquid metal core by additional 3 nm (Figure 2a, down-ranking images). The liquid metal suspension starts to precipitate within 30 min, while the liquid metal@SiO2 remains stable (Figure S1) for at least 30 min in both water and PBS, demonstrating that the inorganic SiO2 shell could efficiently improve the dispersion stability of the liquid metal particles. Digitally controlling the reaction parameters of the ultrasonic power density, reaction temperature and injection rate of silicon precursor (Figure 2b), the sonochemical syntheses by using other three silicon sources, 3mercaptopropyltriethoxysilane (MPTES), bis-(γ-triethoxysilylpropyl)-tetrasulfide (BTES), tetraethylorthosilicate + bis-(γ-triethoxysilylpropyl)-tetrasulfide (TEOS + BTES) (Figure S2, Table S1), have been achieved repeatably on the established platform. Detailed characterizations of the chemical composition by in-situ elemental mapping on the isolated composite nanoparticles reveal that EGaIn is uniformly distributed in the core of the composite nanoparticles and silica layer is deposited on their outer surfaces (Figure 2c, S3). Comparing the force-displacement measurement results, a distinct kink appeared in the approaching and retraction processes in the curve of a bare liquid metal nanoparticle, indicating the breakage of in the passivative “skin” upon external force, which, in contrast, could not be found in the liquid metal@SiO2 nanoparticle owing to the presence of a protective SiO2 layer (Figure S4). In addition, the hysteresis loop of the curve during the approaching and retraction processes implies the fluidic liquidity and adhesion of the inner core of the nanoparticle.32 The higher proportion of O and the larger atomic ratio of Ga of the bare liquid metal nanoparticle than those in the initial stoichiometric EGaIn, indicates that the passivative “skin” is gallium oxide(Table S2), since Ga has a lower standard reduction 6 ACS Paragon Plus Environment

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potential than In and is more likely to be oxidized. In addition, XPS spectrum of liquid metal@SiO2 shows strong signals originating from Ga (III), Ga (0) and In, reflecting the existence of gallium oxide (formulated as Ga2O3) in the composite nanoparticles (Figure 2d). The strong Si 2s and Si 2p signals at 154 eV and 103.6 eV also are present (Figure S5), which further indicates that the liquid metal nanoparticles have been coated by double oxide layers of Ga2O3 and SiO2 (Figure 2c, S2, S3). The prominent signal at –100.3 ppm and a shoulder at –109.6 ppm in the range between –90 and –150 ppm shown in the

29Si

cross-polarization

MAS (CPMAS) spectrum, can be indexed to the resonances of (OH)Si(OSi)3 (3Q, d = –100.3 ppm) and Si(OSi)4 (4Q, d = –109.6 ppm) of SiO2, respectively (Figure 2e), further confirming that the deposition of SiO2. The low crosslinking degree with abundant Si-OH groups favors the further surface engineering of composite nanoparticles such as targeting moiety conjugation. The hydrolyzed particle diameter reveals that ultrasonic cavitation has sheared the EGaIn into micro- and nanoparticles with a broad size distribution due to the poor dispersion of the viscoelastic Ga2O3-coated nanoparticles. Following continuous surface modification, the average hydrodynamic diameters of liquid metal@SiO2, liquid metal@SiO2-NH4, liquid metal@SiO2-PEG and liquid metal@SiO2-RGD were reduced to about 190.86, 210.02, 235.11 and 236.43 nm, respectively (Figure 2f). The disappearing microdroplets and further size reduction of liquid metal@SiO2 are due to the continuous sonication for additional 2 h, and the abundant -OH on the surface of the coating SiO2 have largely improved the dispersion among the particles. The subsequently increased average hydrodynamic diameters and a series of changes of zeta potentials in each conjugating step further indicates a successive grafting of NH2, PEG, and RGD peptides (figure 2g).48 Meeting the criterion of LSPR (localised surface plasmon resonance), i.e., a large negative real and a small imaginary dielectric function, EGaIn particles with suitable 7 ACS Paragon Plus Environment

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polydispersity can strongly absorb and scatter light over the entire UV-Vis-NIR region.15, 49-51 The Vis-NIR absorbance spectra of liquid metal@SiO2-dispersed aqueous suspensions at varied concentrations show stronger absorptions in the NIR-I to NIR-II regions than those of bare liquid metal (Figure 3a, S6a). To evaluate the photothermal-heating performance, they were irradiated under 1064 nm NIR laser at elevated power densities (0.5, 1.0, 1.5 and 2.0 W·cm-2 at 200 µg·mL-1) and concentrations (50, 100, 200 and 400 µg·mL-1 at 1.5 W·cm-2) (Figure 3b, c and Figure S6b, c). Especially, at a concentration of 400 µg·mL-1, the solution temperature elevation of liquid metal@SiO2 reached 65 ℃ in 5 min of irradiation (1.5 W·cm2),

much stronger than bare liquid metal, and nearly no change was observed in pure water.

Accordingly, the main parameter of photothermal conversion efficiency, η, for assessing the capability of the liquid metal@SiO2 agent in converting the light into heat at 1064 nm was calculated to be 22.43 % (Figure 3d), which shows the noticeable advantage over bare liquid metal (η = 14.12 %) (Figure S6d) and several traditional photothermal nanoagents, such as SnSe nanorobs (20.3 %)52, Au nanorobs (21 %)53, Pd nanosheets (20 %)54. Furthermore, another parameter, mass extinction coefficient, ε, of liquid metal@SiO2 at 1064 nm was calculated to be 16.11 L·g-1cm-1, which is predictably higher than that of bare liquid metal 9.78 L·g-1cm-1 (Figure S7). To evaluate the photothermal stability, five laser on/off cycles were tested. The highest temperature of bare liquid metal is obviously downhill while no significant deterioration appears in the liquid metal@SiO2-dispersed aqueous suspensions after irradiation for 5 min (Figure 3e). Especially, the color of the liquid metal-dispersed aqueous solution became much brighter (Figure 3f) while the absorbance of the aqueous solution became much weaker (Figure 3g) during the laser irradiation. By conducting the same series of evaluations in NIRI window, the same trend was acquired (Figure S8a - h). To explore the specific mechanism, the microstructure and composition of the composite nanoparticles under NIR irradiation were 8 ACS Paragon Plus Environment

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analyzed. No significant morphology change has been observed in liquid metal@SiO2 group while the bare liquid metal has been severely deformed from the uniform sphere to a rocky shuttle after NIR irradiation (Figure 3h - i, S8i - j, S9 - 11), further indicating that the liquid metal particles have been completely and uniformly coated by SiO2 layers because the bare liquid metal exposed to ambient conditions will tend to be readily oxidized and then deformed. Collecting several typical morphologies in liquid metal-deformed samples, the deforming process of liquid metal during irradiation could be speculated (Figure S12). The nanoscale liquid metal was hyperthermally oxidized to Ga2O3 and then the remaining In gathered into other spheres to be excreted out the shuttle by exocytosis because of phase separation (dealloying). According to the estimated maximum escape depth (~10 nm), photoelectrons would penetrate through the formed Ga2O3 layer in both bare liquid metal and liquid metal@SiO2 but not the entire nanoparticles.55 Thus, comparing the ratios of Ga (III) to total Ga of the samples gives a straightforward evaluation of the relative oxidation degree. Further XPS analysis of the composite nanoparticles before and after NIR irradiation proves that [Ga (III)] / [Ga] ratios of the irradiated bare liquid metal increase by 16.19 % and 23.46 % in NIRI and NIR-II biowindow, respectively, while those of coated ones show limited changes (3.11 % and 4.69 %), indicating that the insufficient photothermal-conversion performance is due to the oxidation failure (Figure 3j - m, S8k - l). As a consequence, the effects of SiO2 coating in enhancing the absorbance of nanoparticles, protecting from being oxidized and thermal-insulating during heating, will guarantee a durable photothermal efficacy of liquid metal@SiO2 for efficiently and rapidly ablating the tumor. Based on the fact that the absorption and scattering of light in tissues proportionally decline with wavelength increase,54, 56-60 the in vitro and in vivo tissue-penetration depths of NIR-I and NIR-II biowindows were further assessed (Figure S13). The attenuation coefficient (α) of 808 nm laser irradiation (Figure S13c, α808 = 0.5256) is significantly higher 9 ACS Paragon Plus Environment

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than that of 1064 nm laser irradiation (Figure S13d, α1064 = 0.4104), Similarly, a more efficient heating around the tumor covered with the same thickness of chicken breast muscle was achieved in NIR-II biowindow than in NIR-I biowindow at the same power density (1 W·cm-2) (Figure S13e - g), suggesting the stronger tissue-penetration capability in NIR-II biowindow. Given a rather superior photothermal-convension performance in NIR-II biowindow as compared to NIR-I biowindow, the systemic-targeted photothermal therapy of RGD peptide-modified

liquid

metal@SiO2

nanopaiticles

(liquid

metal@SiO2-RGD)

was

investigated in NIR-II biowindow. Initially, the instrinct toxicities of liquid metal@SiO2-PEG (abbreviated as PEG) and liquid metal@SiO2-RGD (abbreviated as RGD) were tested on normal cells (human umbilical vein endothelial cells, HUVECs) and cancer cells (glioma U87 cells) by the standard cell-counting kit 8 (CCK-8) assay. After co-incubation with two cell lines, no significant cytotoxicity was observed even at a Ga concentration of 400 µg·mL-1 for 24 h and 48 h (Figure 4a, b), indicating a relatively high biocompatibility of surface-modified liquid metal@SiO2. Once exposed to 1064 nm laser, the RGD + NIR laser group shows obvious superiority in proliferation inhibitation of U87 cancer cell even at a rather low concentration (50 µg·mL-1) (Figure 4c). Typically, the active targeting of RGD peptides, which selectively binds to the integrin αvβ3 overexpressed on the surface of U87 cancer cells, could efficiently elevate the intracellular accumulation of the composite nanoparticles in the first 2 h as evidenced by both CLSM analysis and flow cytometry analysis (Figure 4d, S14). Subsequently, the advantage of RGD peptides in active targeting was gradually weakened in vitro in the time course of incubation. In order to outstand the superiority of active-targeted photothermal ablation of tumor cell, the photothermal-hyperthermia efficacy was assessed in 1-h incubation in NIR-II 10 ACS Paragon Plus Environment

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biowindow (Figure 4e). As expected, the notable advantage of RGD peptides active-targeting effect is evidenced by the elevated proliferation inhibition efficiency in RGD + NIR group than that in PEG+NIR group, and the cell apoptosis is negligible in the control groups including the U87 cells without any treatment, NIR-II laser irradiation only and nanoparticles only. Correspondingly in flow cytometry analysis, the liquid metal@SiO2 combined with NIR-II laser irradiation shows significant cell apoptosis, which is 30.8 % higher than that of PEG + NIR laser group (Figure 4f), demonstrating the marked effect of RGD targeting on enhancing the photothermal-hyperthermia efficacy. Initially, the major hematological indicators of the healthy female Kunming mice sacrificed in 30 days post-injection of liquid meatl@SiO2-RGD reveal no significant fluctuations in comparison to the control mice (Figure 5a). Among them, no detectable abnormality was observed in the key indexes of hepatotoxicity and nephrotoxicity, including ALT, AST, and BUN, suggesting that the liquid metal@SiO2 induces no obvious renal and hepatic toxicity in the treatment group.61 Subsequently, no significant sign of inflammatory lesions or damage was detected in the corresponding pathological H&E stained slices of the major organs, including heart, liver, spleen, lung, and kidney, harvested at the end of the biocompatibility evaluation duration (Figure S15), indicating no significant histological abnormalities in mice. During the whole biocompatibility evaluation duration, no evident abnormal behavior, no significant weight loss or death of mice were observed (Figure 5b). To quantify the circulation in the body, the blood of female Kunming mice intravenously injected with liquid metal@SiO2-RGD were collected at a certain internal, and the half-life was calculated to be 1.04 h (Figure 5c). By fitting the blood circulation time with the logarithm of blood concentration, the central chamber shows a fast elimination of liquid metal@SiO2-RGD at a rate constant of −0.476 μg·mL−1·h−1 (Figure 5d). Accordingly, gradual excretions out of liver and kidney were observed during the prolonging of feeding 11 ACS Paragon Plus Environment

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time. Typically, efficient accumulation of RGD peptides-modified liquid metal in tumor was calculated to be 8.7 % in 48 h (Figure 5e). After intravenous injection of liquid metal@SiO2RGD for 7 d, the cumulative excretion of Ga increased to be 55.7 % in total (Figure 5f). It is deduced that the high amount of Ga in urine is due to the gradual degradation of liquid metal@SiO2 during the circulation and metabolism since the inorganic SiO2 layer is too thin (about 3 nm in thickness) to resist the tumor microenvironment for biodegradation (table S1). According to previous reports, the acid-triggered fusion and degradation process of liquid metal would occur after removing the protecting coatings.5, 8 Therefore, the efficient targeting accumulation, high biocompatibility and easy excretion of the liquid metal@SiO2-RGD nanoparticles in vivo guarantee the high bio-application potential for tumor therapy. The superior photothermal stability and photothermal-conversion efficiency of SiO2coated liquid metal in NIR-II biowindow, accompanied with the high accumulation of RGD peptides active-targeting modification in vitro and the high biocompatibility in vivo indicates the potential photothermal tumor-ablation efficacy in NIR-II biowindow in vivo. In accordance with experimental groups setting in vitro, mice with tumor volume reaching about 150 mm3 were divided into five groups, including control group, RGD group, NIR laser only group, PEG + NIR laser group and RGD + NIR laser group. Based on the in vitro evaluation results of active targeting function of RGD peptides, the desirable time point for laser irradiation in vivo should be far beyond 2 h post-injection. Therefore the NIR laser only group, PEG + NIR laser group and RGD + NIR laser group were exposed to 1064 nm laser irradiation at the same time point of 4 h post-injections of saline, liquid metal@SiO2-PEG and liquid metal@SiO2-RGD. The tumor-site temperature of mice in RGD + NIR laser group dramatically increased to 55 ℃ in 10 min NIR-II laser irradiation at the power density of 1.5 W·cm-2 (Figure 6a, b), which is sufficiently high for tumor ablation. It is noteworthy to point out that the power density of 1.5 W·cm-2 was still safe for tumor photothermal ablation where 12 ACS Paragon Plus Environment

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the temperature of tumor showed no significant elevation in control group without the administration of photothermal agents. It is noted that the temperature elevation in the group injected with liquid metal@SiO2-PEG was much lower than that of the RGD-modified composite nanoplatform, which is due to the RGD peptides active targeting-promoted accumulation in tumor-site. During the whole treatment, the digital images, volumes of tumor and body weights of mice were recorded every 2 days. Apparent enlargements of the tumor sizes were observed in control, RGD, and NIR laser only groups during the feeding period. Black scars were observed in the tumor sites in both PEG + NIR laser and RGD + NIR laser groups after the 1064 nm laser treatment. The recurrence appeared in the group injected with liquid metal@SiO2-PEG later in the residual tumor tissues owing to the incomplete tumor ablation (Figure 6c). Correspondingly, the tumors of control, RGD, and NIR laser only groups grew quite fast in the whole treatment, while those in PEG + NIR laser and RGD + NIR laser groups were substantially suppressed in the early period. Latter, the remaining tumor tissues of the liquid metal@SiO2-PEG group grew significantly during prolonged feeding period, but no further recurrence appeared in RGD + NIR laser group (Figure 6d). Importantly, no apparent body weight losses were found during the whole photothermal therapy durations (Figure 6e), indicating that the biocompatible composite nanoparticles have ignited negligible adverse consequence on the health of mice at the injecting dosage in vivo. For the further exploration on the mechanism of efficient photothermal ablation of tumor after NIR-II laser irradiation, tumor sections collected from the sacrificed mice 1 d after irradiation were stained with H&E (hematoxylin and eosin), TUNEL (TdTmediated dUTP nick-end labeling) and Ki-67 antibody. In the RGD + NIR laser group, the significant necrosis was observed in the H&E and TUNEL staining, which directly show the pathological changes in tumor tissues, while the strong proliferation suppression was observed in Ki-67 staining, an 13 ACS Paragon Plus Environment

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immunofluorescence staining for cellular proliferation in tumor sections. In comparison, tumor section in control, RGD and NIR laser only group shows no significant cell death (Figure 6f), further indicating the high photothermal hyperthermia efficacy of SiO2 coatingprotected liquid metal with RGD peptides conjugation. Returning to the question posed at the beginning of this study, it is now safe to state that a versatile approach to synthesize inorganic silica shell-coated liquid metal nanoparticles to meet the needs of surface engineering of liquid metal-based nanoplatforms has been successfully developed based on a novel but facile sonochemical synthesis. The constructed liquid metal@SiO2 nanoparticles show marked thermotherapy performance in NIR-II biowindow in terms of the enhanced absorption, improved photothermal stability by oxidation protection and thermal insulation, as well as advanced photothermal-conversion efficacy. In addition, the accompanying abundant surface chemistry for surface-targeted engineering makes tumor accumulation of the RGD peptides-modified liquid metal@SiO2 much more efficient, owing to the active RGD targeting recognition and binding to the overexpressed integrin αvβ3 on the U87 cancer-cell membrane. Corresponding to the in vitro evaluation results, highly effective in vivo photo-triggered photothermal tumor eradication by silicacoated and RGD-targeted liquid metal nanocomposite has also been demonstrated, together with the high biocompatibility at the administrated dose after the systematic assessment of toxicology of liquid metal@SiO2-RGD. The as-revealed encouraging performances by the novel surface inorganic engineering of liquid metal in this work are anticipated to provide a controllable paradigm for liquid metal-based nanomedicine construction to satisfy the needs of desirable therapeutic efficacy, especially on combating malignant tumors.


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Figure 1. Design of inorganic nanoshell-stabilized liquid metal for enhanced photonanomedicine. Schematic illustration of the stepwise synthesis of liquid metal@SiO2-RGD targeted core/shell nanoparticles, and their detailed composition/nanostructure and unique functionality for tumor-targeted accumulation and subsequent photothermal tumor hyperthermia in NIR-II biowindow.


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Figure 2. Characterization of liquid metal nanoparticles and liquid metal@SiO2-RGD composite nanoplatforms. (a) SEM and TEM images of liquid metal nanoparticles (topranking images) and liquid metal@SiO2 nanosystems (down-ranking images). (b) Schematic illustration of the experimental establishment for the sonochemical synthesis of liquid metal@SiO2 nanosystems. (c) Elemental mapping of liquid metal@SiO2 nanoparticles and the corresponding scheme of inorganic silica layer composition. (d) X-ray photoelectron spectroscopy (XPS) and (e) solid-state 29Si CP/MAS NMR spectrum of liquid metal@SiO2 nanoparticles. The changes of (f) particle-size distribution and (g) Zeta potential of samples as obtained from each synthetic step.


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Figure 3. Photothermal-conversion performance of liquid metal@SiO2 nanoparticles and stability compared with bare liquid metal nanoparticle in NIR-II window. (a) VisNIR absorbance spectra of liquid metal@SiO2-dispersed aqueous suspensions at different concentrations (5, 10, 20 and 40 µg·mL-1). (b, c) Photothermal-heating curves of liquid metal@SiO2-dispersed aqueous suspensions at varied power densities (0.5, 1.0, 1.5 and 2.0 W·cm-2 at 200 µg·mL-1;) and concentrations (50, 100, 200 and 400 µg·mL-1 at 1.5 W·cm-2;). (d) Calculation of the photothermal-conversion efficiency of liquid metal@SiO2. (e) Recycling heating curves, (f) digital photographs and (g) Vis-NIR absorbance spectra of the aqueous suspensions of liquid metals with or without protective SiO2 coating for five laser on/off cycles (200 μg·mL-1, 1.5 W·cm-2). (h, i) SEM image of (h) liquid metal nanoparticles and (i) liquid metal@SiO2 nanoparticles after irradiation. (j - m) XPS spectra of (j, k) liquid metal nanoparticles and (l, m) liquid metal@SiO2 nanoparticles before and after irradiation. All images share the same scale bar (200 nm).


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Figure 4. In vitro photothermal therapy and endocytosis by cancer cells. (a, b) Cell viabilities of (a) HUVECs and (b) U87 cancer cells after treatments with liquid metal@SiO2PEG and liquid metal@SiO2-RGD at varied concentrations. (c) Cell viabilities of U87 cells after exposed to NIR-II biowindow at different power densities (0.25, 0.5, 1, 1.5, 2 W·cm-2), including laser only group, PEG + NIR laser group and RGD + NIR laser group. (d) Intracellular endocytosis of photothermal nanoagents with or without RGD peptides modification, Scale bar = 40 μm. (e) Schematic illustration of the RGD-targeting-directed photothermal cell ablation in NIR-II biowindow. (f) Confocal fluorescence images and flow cytometry analyses of cancer cells after various treatments, including control group, RGD group, laser only group, PEG + NIR laser group and RGD + NIR laser group. Scale bar = 40 μm.


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Figure 5. In vivo compatibility evaluation. (a) Hematological indexes of the mice sacrificed in 30 days post-injection of liquid metal@SiO2-RGD. (b) One-month weight diversity curves of mice post-injected with liquid metal@SiO2-RGD. (c) Blood circulation lifetime of Ga concentration after the intravenous administration of liquid metal@SiO2-RGD. (d) Doublechamber model simulating the elimination of liquid metal@SiO2-RGD based on the bloodcirculation curve. (e) In vivo biodistribution of Ga in tumor and major organs after intravenous injections of liquid metal@SiO2-RGD for 4 h, 24 h, and 48 h. (f) Accumulated Ga in faeces and urine excreted out of the mice body after the intravenous injection of liquid metal@SiO2-RGD for different durations (2 h, 6 h, 12 h, 24 h, 36 h and 48 h, 7 d).


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Figure 6. In vivo photothermal tumor hyperthermia in NIR-II biowindow. (a) IR thermal images and (b) the corresponding time-dependent temperature elevation at the tumor site of U87 tumor-bearing mice in each group, including laser only group, PEG + laser group, and RGD + laser group. (c) Digital images of mice from diverse groups of untreated, liquid metal@SiO2-RGD only, NIR-II laser only, liquid metal@SiO2-PEG combined with NIR-II laser and liquid metal@SiO2-RGD combined with NIR-II laser in different time intervals. (d) Tumor-growth and (e) body-weight curves of mice in each experiment group in the time course of therapy (*p < 0.05, **p < 0.01, ***p < 0.001). (f) H&E staining, TUNEL staining, and antigen Ki-67 immunofluorescence staining in tumor sections from each experiment group 6 h after the photothermal therapy. Scale bar = 200 μm.


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ASSOCIATED CONTENT Supporting Information. Supplementary experimental details, additional characterization data for liquid metal@SiO2-RGD . AUTHOR INFORMATION Corresponding Author *[email protected]; *[email protected]. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We greatly acknowledge the financial support from the National Key R&D Program of China (Grant No. 2016YFA0203700), National Nature Science Foundation of China (Grant No. 21835007, 51722211 and 51672303), Natural Science Foundation of Shanghai (Grant No. 13ZR1463500) and Program of Shanghai Subject Chief Scientist (Grant No. 18XD1404300).

REFERENCES (1)

Kazem, N.; Hellebrekers, T.; Majidi, C., Adv. Mater., 2017, 29, 1605985.

(2)

Dickey, M. D., Adv. Mater., 2017, 29, 1606425.

(3)

Kim, H.; Boysen, D. A.; Newhouse, J. M.; Spatocco, B. L.; Chung, B.; Burke, P. J.; Bradwell, D. J.; Jiang, K.; Tomaszowska, A. A.; Wang, K.; Wei, W.; Ortiz, L. A.; Barriga, S. A.; Poizeau, S. M.; Sadoway, D. R., Chem. Rev., 2013, 113, 2075-2099.

(4)

Taccardi, N.; Grabau, M.; Debuschewitz, J.; Distaso, M.; Brandl, M.; Hock, R.; 21 ACS Paragon Plus Environment

Nano Letters 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 22 of 26

Maier, F.; Papp, C.; Erhard, J.; Neiss, C.; Peukert, W.; Görling, A.; Steinrück, H. P.; Wasserscheid, P., Nat. Chem., 2017, 9, 862-867. (5)

Lu, Y.; Hu, Q.; Lin, Y.; Pacardo, D. B.; Wang, C.; Sun, W.; Ligler, F. S.; Dickey, M. D.; Gu, Z., Nat. Commun., 2015, 6, 10066.

(6)

Zhang, B.; Zhang, L.; Deng, W.; Jin, L.; Chun, F.; Pan, H.; Gu, B.; Zhang, H.; Lv, Z.; Yang, W.; Wang, Z. L., ACS Nano, 2017, 11, 7440-7446.

(7)

Yi, L.; Liu, J., Int. Mater. Rev., 2017, 62, 415-440.

(8)

Chechetka, S. A.; Yu, Y.; Zhen, X.; Pramanik, M.; Pu, K.; Miyako, E., Nat. Commun., 2017, 8, 15432.

(9)

Lu, Y.; Lin, Y.; Chen, Z.; Hu, Q.; Liu, Y.; Yu, S.; Gao, W.; Dickey, M. D.; Gu, Z., Nano Lett., 2017, 17, 2138-2145.

(10)

Deng, Y.; Liu, J., J. Med. Devices, 2015, 9, 014502-014502-4.

(11)

Lin, Y.; Liu, Y.; Genzer, J.; Dickey, M. D., Chem. Sci., 2017, 8, 3832-3837.

(12)

Yan, J.; Lu, Y.; Chen, G.; Yang, M.; Gu, Z., Chem. Soc. Rev., 2018, 47, 2518-2533.

(13)

Yamaguchi, A.; Mashima, Y.; Iyoda, T., Angew. Chem., Int. Ed., 2015, 54, 1280912813.

(14)

Sheng, L.; Zhang, J.; Liu, J., Adv. Mater., 2014, 26, 6036-6042.

(15)

Hohman, J. N.; Kim, M.; Wadsworth, G. A.; Bednar, H. R.; Jiang, J.; LeThai, M. A.; Weiss, P. S., Nano Lett., 2011, 11, 5104-5110.

(16)

Collin, L.; Ju‐Hee, S.; John, M.; D., D. M., Adv. Mater., 2013, 25, 5081-5085.

(17)

McGuiness, C. L.; Shaporenko, A.; Zharnikov, M.; Walker, A. V.; Allara, D. L., J. Phys. Chem. C, 2007, 111, 4226-4234.

(18)

Donev, S.; Brack, N.; Paris, N. J.; Pigram, P. J.; Singh, N. K.; Usher, B. F., Langmuir, 2005, 21, 1866-1874.

(19)

Regan, M. J.; Tostmann, H.; Pershan, P. S.; Magnussen, O. M.; DiMasi, E.; Ocko, B. M.; Deutsch, M., Phy. Rev. B, 1997, 55, 10786-10790. 22 ACS Paragon Plus Environment

Page 23 of 26 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

Nano Letters

(20)

Sodhi, R. N. S.; Brodersen, P.; Cademartiri, L.; Thuo, M. M.; Nijhuis, C. A., Surf. Interface Anal., 2017, 49, 1309-1315.

(21)

Gao, Y.; Liu, J., Appl. Phys. A: Mater. Sci. Process., 2012, 107, 701-708.

(22)

Zhang, W.; Naidu, B. S.; Ou, J. Z.; O’Mullane, A. P.; Chrimes, A. F.; Carey, B. J.; Wang, Y.; Tang, S.-Y.; Sivan, V.; Mitchell, A.; Bhargava, S. K.; Kalantar-zadeh, K., ACS Appl. Mater. Interfaces, 2015, 7, 1943-1948.

(23)

Lear, T. R.; Hyun, S.-H.; Boley, J. W.; White, E. L.; Thompson, D. H.; Kramer, R. K., Extreme Mech. Lett., 2017, 13, 126-134.

(24)

Glynos, E.; Sboros, V.; Koutsos, V., Mater. Sci. Eng., B, 2009, 165, 231-234.

(25)

Finkenauer, L. R.; Lu, Q.; Hakem, I. F.; Majidi, C.; Bockstaller, M. R., Langmuir, 2017, 33, 9703-9710.

(26)

Zhang, W.;

Ou, J. Z.;

Tang, S.-Y.;

Sivan, V.;

Yao, D. D.;

Latham, K.;

Khoshmanesh, K.; Mitchell, A.; O'Mullane, A. P.; Kalantar-zadeh, K., Adv. Funct. Mater., 2014, 24, 3799-3807. (27)

Dickey, M. D.; Chiechi, R. C.; Larsen, R. J.; Weiss, E. A.; Weitz, D. A.; Whitesides, G. M., Adv. Funct. Mater., 2008, 18, 1097-1104.

(28)

Yang, Y.; Qian, W.; Liting, Y.; Jing, L., Adv. Eng. Mater., 2014, 16, 255-262.

(29)

Sutter, E.; Sutter, P., J. Phys. Chem. C, 2012, 116, 20574-20578.

(30)

Litrico, G.; Proulx, P.; Gouriet, J. B.; Rambaud, P., Adv. Powder Technol., 2015, 26, 1-7.

(31)

Kraus, P.; Rodrigues, W. N.; Mönch, W., Surf. Sci., 1989, 219, 107-116.

(32)

Ren, L.; Zhuang, J.; Casillas, G.; Feng, H.; Liu, Y.; Xu, X.; Liu, Y.; Chen, J.; Du, Y.; Jiang, L.; Dou, S. X., Adv. Funct. Mater., 2016, 26, 8111-8118.

(33)

Hoshyargar, F.; Crawford, J.; O'Mullane, A. P., J. Am. Chem. Soc., 2017, 139, 14641471.

(34)

Farrell, Z. J.; Tabor, C., Langmuir, 2018, 34, 234-240. 23 ACS Paragon Plus Environment

Nano Letters 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 24 of 26

(35)

Sudo, S.; Nagata, S.; Kokado, K.; Sada, K., Chem. Lett., 2014, 43, 1207-1209.

(36)

Chen, Y.; Chen, H.; Guo, L.; He, Q.; Chen, F.; Zhou, J.; Feng, J.; Shi, J., ACS Nano, 2010, 4, 529-539.

(37)

Pan, L.; Liu, J.; He, Q.; Shi, J., Adv. Mater., 2014, 26, 6742-6748.

(38)

Pan, L.; He, Q.; Liu, J.; Chen, Y.; Ma, M.; Zhang, L.; Shi, J., J. Am. Chem. Soc., 2012, 134, 5722-5725.

(39)

Landskron, K.; Ozin, G. A., Science, 2004, 306, 1529-1532.

(40)

Zhen, Z.; Tang, W.; Chuang, Y.-J.; Todd, T.; Zhang, W.; Lin, X.; Niu, G.; Liu, G.; Wang, L.; Pan, Z.; Chen, X.; Xie, J., ACS Nano, 2014, 8, 6004-6013.

(41)

Templeton, A. C.; Wuelfing, W. P.; Murray, R. W., Acc. Chem. Res., 2000, 33, 27-36.

(42)

Jin, R.; Cao, Y.; Mirkin, C. A.; Kelly, K. L.; Schatz, G. C.; Zheng, J. G., Science, 2001, 294, 1901-1903.

(43)

Jackson, A. M.; Myerson, J. W.; Stellacci, F., Nat. Mater., 2004, 3, 330-336.

(44)

Daniel, M.-C.; Astruc, D., Chem. Rev., 2004, 104, 293-346.

(45)

Panthani, M. G.; Akhavan, V.; Goodfellow, B.; Schmidtke, J. P.; Dunn, L.; Dodabalapur, A.; Barbara, P. F.; Korgel, B. A., J. Am. Chem. Soc., 2008, 130, 1677016777.

(46)

Bang, J. H.; Suslick, K. S., Adv. Mater., 2010, 22, 1039-1059.

(47)

Morel, A.-L.;

Nikitenko, S. I.;

Gionnet, K.;

Wattiaux, A.;

Lai-Kee-Him, J.;

Labrugere, C.; Chevalier, B.; Deleris, G.; Petibois, C.; Brisson, A.; Simonoff, M., ACS Nano, 2008, 2, 847-856. (48)

Wu, M.; Meng, Q.; Chen, Y.; Zhang, L.; Li, M.; Cai, X.; Li, Y.; Yu, P.; Zhang, L.; Shi, J., Adv. Mater., 2016, 28, 1963-1969.

(49)

Tiwari, A. D.; Mishra, A. K.; Mishra, S. B.; Kuvarega, A. T.; Mamba, B. B., Carbohydr. Polym., 2013, 92, 1402-1407.

(50)

Wei, Z.; Zhen, O. J.; Shi‐Yang, T.; Vijay, S.; D., Y. D.; Kay, L.; Khashayar, K.; 24 ACS Paragon Plus Environment

Page 25 of 26 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

Nano Letters

Arnan, M.; P., O. M. A.; Kourosh, K. z., Adv. Funct. Mater., 2014, 24, 3799-3807. (51)

Kumamoto, Y.; Taguchi, A.; Honda, M.; Watanabe, K.; Saito, Y.; Kawata, S., ACS Photonics, 2014, 1, 598-603.

(52)

Tang, Z.; Zhao, P.; Ni, D.; Liu, Y.; Zhang, M.; Wang, H.; Zhang, H.; Gao, H.; Yao, Z.; Bu, W., Mater. Horiz., 2018, 5, 946-952.

(53)

Zeng, J.; Goldfeld, D.; Xia, Y., Angew. Chem., Int. Ed., 2013, 52, 4169-4173.

(54)

Zhang, L.; Li, S.; Chen, X.; Wang, T.; Li, L.; Su, Z.; Wang, C., Adv. Funct. Mater., 2018, 28, 1803815.

(55)

M., W. W. S., Surf. Interface Anal., 1992, 18, 217-228.

(56)

Smith, A. M.; Mancini, M. C.; Nie, S., Nat. Nanotechnol., 2009, 4, 710-711.

(57)

Jiang, Y.; Pu, K., Adv. Biosyst., 2018, 2, 1700262.

(58)

Jiang, Y.; Pu, K., Acc. Chem. Res., 2018, 51, 1840-1849.

(59)

Jiang, Y.; Li, J.; Zhen, X.; Xie, C.; Pu, K., Adv. Mater., 2018, 30, e1705980.

(60)

Zhou, J.; Jiang, Y.; Hou, S.; Upputuri, P. K.; Wu, D.; Li, J.; Wang, P.; Zhen, X.; Pramanik, M.; Pu, K.; Duan, H., ACS Nano, 2018, 12, 2643-2651.

(61)

Lin, H.; Gao, S.; Dai, C.; Chen, Y.; Shi, J., J. Am. Chem. Soc., 2017, 139, 1623516247.


Nano Letters 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

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For TOC only


Inorganic Nanoshell-Stabilized Liquid Metal for Targeted

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