Two-Dimensional Ultrathin MXene Ceramic Nanosheets for

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Two-dimensional Ultrathin MXene Ceramic Nanosheets for Photothermal Conversion Han Lin, Xingang Wang, Luodan Yu, Yu Chen, and Jianlin Shi Nano Lett., Just Accepted Manuscript • DOI: 10.1021/acs.nanolett.6b04339 • Publication Date (Web): 27 Dec 2016 Downloaded from http://pubs.acs.org on December 27, 2016

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Two-dimensional Ultrathin MXene Ceramic Nanosheets for Photothermal Conversion Han Lin,1,2 Xingang Wang,1 Luodan Yu,1,2 Yu Chen,1* and Jianlin Shi1* 1

State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai

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

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

E-mail: [email protected]; [email protected]

KEYWORDS. ultrathin MXene, Ti3C2 nanosheets, nanomedicine, photothermal conversion, tumor therapy

ABSTRACT. Ceramic biomaterials have been investigated for several decades, but their potential biomedical applications in cancer therapy have been paid much less attentions, mainly due to their lack of related material functionality for combating the cancer. In this work, we report, for the first time, that MAX ceramic biomaterials exhibit the unique functionality for the photothermal ablation of cancer upon being exfoliated into ultrathin nanosheets within atomic thickness (MXene). As a paradigm, biocompatible Ti3C2 nanosheets (MXenes) were successfully

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synthesized based on a two-step exfoliation strategy of MAX phase Ti3AlC2 by the combined HF etching and TPAOH intercalation. Especially, the high photothermal-conversion efficiency and in vitro/in vivo photothermal ablation of tumor of Ti3C2 nanosheets (MXenes) were revealed and demonstrated, not only in the intravenous administration of soybean phospholipid modified Ti3C2 nanosheets but also in the localized intratumoral implantation of a phase-changeable PLGA/Ti3C2 organic-inorganic hybrid. This work promises the great potential of Ti3C2 nanosheets (MXenes) as a novel ceramic photothermal agent used for cancer therapy, and may arouse much interest in exploring MXene-based ceramic biomaterials to benefit the biomedical applications.

Two-dimensional (2D) nanomaterials have been receiving great attention due to their ultrathin structure and intriguing physiochemical property since the discovery of graphene.1-3 Especially, researches on graphene analogues such as layered inorganic materials have bloomed in the last few years.4,5 Very recently, MXenes, a new family of multifunctional 2D materials containing a large group of transition metal carbides and carbonitrides with many attractive properties, have been developed by Gogotsi, Barsoum and colleague.6-10 MXenes were produced by the extraction of the A-element from the layered ternary carbides of MAX phases, where M is an early transition metal carbides, A is an A group element, and X is C or N. Many potential applications including energy storage and conversions,11-15 and ion sieving16 have been explored. However, despite very recent few reports on the biomedical applications of Ti3C2 MXenes on biosensors17 and antibacterial activity,18 the detailed investigations and evaluations of Ti3C2 MXenes on cellular and animal levels, including cytotoxicity, cellular uptake, in vivo toxicity,


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and other medical applications such as cancer therapy, are still not available in literatures. Extensive and detailed investigations on biomedicine applications of MXenes are expected to be explored. The near-infrared (NIR) window refers to a wavelength range of 700-1300 nm in which biological tissues are highly transparent.19 Photothermal therapy (PTT) of tumors based on NIR laser is a minimally or non-invasive therapeutic modality.20 In the past decade, a great number of NIR-induced nanomaterials, such as noble metal systems like gold nanorods,21 carbon-based nanomaterials,22 copper sulfide nanoparticles,23 rare earth compounds,24 as well as many organic nanoparticles and polymers,25 have been widely explored as photothermal agents for tumor ablation. Recently, 2D nanosheets have attracted considerable attention to act as PTT agents, due to their unique ultrathin nanostructure and high photothermal-conversion efficiency, including Mo2S,26-29 WS2,30,31 palladium (Pd) nanosheets,32 and black phosphorus.33 An ideal photothermal agent should not only possess a high enough extinction coefficient in the NIR region to ensure excellent NIR-photothermal performance, but can also satisfy the ever-strict biocompatibility demands in physiological environments. Herein, we report a novel photothermal agent based on ultrathin Ti3C2 nanosheets (MXenes) presenting remarkably high absorption in the NIR region for highly effective in vivo photothermal ablation of tumors in a mouse model, which suggests the potential applications of MXene in biomedicine, especially in PTT of tumors. As expected, the ultrathin Ti3C2 nanosheets show strong absorption and conversion efficiency of NIR laser irradiation (808 nm) owing to the localized surface plasmon resonance (LSPR) effect of Ti3C2 nanosheets of semimetal character. Importantly, the as-prepared Ti3C2 nanosheets modified with soybean phospholipid show no noticeable toxicity as evaluated both in vitro and in vivo. Especially, the high in vivo PTT


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efficiency of Ti3C2 nanosheets on tumor xenograft has been successfully demonstrated by two typical tumor-therapeutic modalities, including intravenous injection of Ti3C2-SP (20 mg/kg) and intratumoral implantation of phase-changeable PLGA/Ti3C2 implant (2 mg/kg). This work demonstrates the possibility of MXene nanosheet for biomedical applications, especially on combating the cancer. Two-dimensional Ti3C2 nanosheets were synthesized by a modified chemical exfoliation method according to the literatures.8 The MAX phase Ti3AlC2 were etched by 40% HF aqueous solution to remove the Al layer. To delaminate the MAX phase, the etched Ti3C2 powder was intercalated with TPAOH in water (Figure 1a). Traditional exfoliation procedure generally produces Ti3C2 with extremely large sheet sizes, which will not be possible to be up-taken by cancer cells or for intravenous administration. Herein, it has been found that the prolonged HF etching (3 days) could substantially reduce the planar dimensions of the Ti3C2 nanosheets, making the biomedical application of MXene possible following an intercalation step by TPAOH (3 days). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images show the microstructure of HF-etched Ti3C2 powder from solid Ti3AlC2 (Figure 1b), which is well stacked by uniform sheets (Figure 1c,d and S1). High-resolution TEM images (HRTEM) clearly shows the crystalline lattice of multilayer Ti3C2 nanosheets with hexagonal structure, indicating the well-crystallized feature of the as-synthesized Ti3C2 nanosheets (Figure 1e). After further TPAOH intercalation, TEM images reveal thin, transparent flakes of exfoliated Ti3C2 nanosheets, which exhibit the typical 2D sheet-like morphology with an average lateral size of around 150 nm (Figure 1f,g and S2). The HRTEM image and corresponding selected area electron diffraction (SAED) patterns of Ti3C2 nanosheets exhibit the unchanged well-defined hexagonal structure after exfoliation (Figure S2d inset). The prepared Ti3C2 nanosheets can be


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well dispersed in water for several weeks if tightly sealed in a bottle. A digital photo of Ti3C2 nanosheets dispersed in water with typical Tyndall effect indicates their excellent hydrophilicity and dispersity (Figure 1g inset). X-ray diffraction (XRD) pattern shows the successful synthesis of MAX phase Ti3AlC2. In addition, XRD pattern of freeze-dried Ti3C2 nanosheets (abbreviated as Ti3C2 nanosheets in the following description) reveals the disappearance of the most intense peaks of Ti3AlC2 at 2θ ≈ 39° because of the exfoliation. Peaks from 20° to 40° are still available, suggesting a remained periodicity at the stacks Ti3C2 MXene layers (Figure 2a).8 The chemical composition of Ti3AlC2 phase and the Ti3C2 nanosheets were determined by X-ray photoelectron spectroscopy (XPS) after the powder samples were sputtered for 10 s to remove surface contaminants (Table S1). The Ti3C2 nanosheets display Ti-C (2p3) and Ti-O (2p3) doublets at 455.7 eV and 461.5 eV, respectively, which are characteristic of Ti3C2 nanosheets (Figure S3).34 Elemental analysis (TEM-EDS) of intercalated Ti3C2 nanosheets showed the existence of Ti and C elements, and the absence of Al and F (Figure S4). The electron energy loss spectra (EELS) analysis also confirmed the presence of Ti and C (Figure 1h). The thickness of the as-prepared Ti3C2 nanosheets measured by atomic force microscopy (AFM) shows a height of about 0.6 nm, which is consistent with the dimension of a monolayer Ti3C2 nanosheet. The real thickness of a monolayer Ti3C2 nanosheet is slightly larger than its theoretical one, which is caused by the surface absorption of O or OH (Figure 2b,c and S5) after exfoliation. The UV-vis-NIR absorption spectra acquired on the Ti3C2 nanosheets show a unique absorption in NIR region range from 750 to 850 nm (Figure 2d), which is similar to traditional metal nanoparticles showing a LSPR effect (e.g., Au,35 Ag36). Such an absorption feature is significantly different from traditional 2D layer nanosheets where only a broad absorption band


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ranging from UV to NIR region was observed, such as graphene oxide (GO),22 black phosphorus (BP),33 and tungsten disulfide (WS2).30 It has been well-demonstrated that traditional MAX ceramics show metal-like property while the corresponding exfoliated MXene nanosheets exhibit semimetal-like energy-band structure similar to 2D Ti2S nanosheets,37 which easily induces the LSPR effect, similar to metal nanoparticles. It is noted that such an absorption in the range of 750-850 nm, just right within the biological NIR window, is greatly favorable for biomedical applications. The normalized adsorption intensity over the length of the cell (A/L) at λ = 808 nm at varied concentrations (C) (30, 15, 8, 4 and 2 ppm) was determined. According to the LambertBeer law (A/L = αC, where α is the extinction coefficient), a linear dependence of A/L on the concentration has been obtained, and the extinction coefficient at 808 nm was measured to be 25.2 Lg-1 cm-1 (Figure 2d inset). This extinction coefficient of the Ti3C2 nanosheets is remarkably higher than that of GO nanosheets (3.6 Lg-1 cm-1),22 and also slightly larger than that of WS2 nanosheets (23.8 Lg-1 cm-1),30 implying a strong NIR laser absorption property of Ti3C2 nanosheets. Furthermore, the photothermal-conversion efficiency η of Ti3C2 nanosheets was calculated based on the results of time constant for heat transfer and the maximum steady-state temperature (Equation S2-S11 and Figure S6)38, which gave the value to be 30.6%, higher than that of Au nanorods (21%),39 Cu2-xSe NCs (22%)23,40 and Cu9S5 NCs (25.7%).[26] Ti3C2 nanosheets at varied concentrations (72, 36, 18, 9 ppm, and pure water) were exposed to an 808 nm laser at a power density of 1.5 W cm-2 (Figure 2e) to investigate their photothermal performance. At a relative low Ti3C2 concentration (72 ppm), the solution temperature reached 57 °C in 6 min of irradiation. In contrast, the temperature of pure water shows nearly no charge, indicating that the presence of Ti3C2 nanosheets can efficiently and rapidly convert NIR light into thermal energy. More detailed experiments were conducted to investigate the photothermal


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performance of Ti3C2 nanosheets at varied concentrations (72, 36, 18, 9 ppm, and pure water) under laser power density of 1.0 W cm-2 (Figure S7a). To further evaluate the photothermal stability of the Ti3C2 nanosheets, the recycling temperature variations of Ti3C2 nanosheets dispersion were recorded under heating with an NIR laser radiation for 5 min (laser on) followed by natural cooling to room temperature (laser off) for five laser on/off cycles. The photothermal performance of the Ti3C2 nanosheets does not show any significant deterioration during the recycling, highlighting the potential of Ti3C2 nanosheets as a durable photothermal agent for PTT cancer treatment (Figure 2f and S7b). Although the as-prepared Ti3C2 nanosheets can be well dispersed in water and ethanol for up to several weeks without apparent aggregation, the stability of Ti3C2 nanosheets in saline is rather poor. To solve this critical issue, the surface of Ti3C2 nanosheets was modified with soybean phospholipid (noted as SP) to improve their stability in physiological conditions (Figure 2g and S8). Owing to the steric hindrance of organic chains, the surface modification by SP chains endows Ti3C2 nanosheets with excellent colloidal stability in physiological environments. In addition, the STEM images show that Ti3C2-SP nanosheets remained the two-dimensional sheet-like morphology (Figure S9a-d). The corresponding element line scanning further confirms the successful surface modification of with Ti3C2 nanosheets with soybean phospholipid (Figure S9e-h). The SP-modified Ti3C2 nanosheets (designated as Ti3C2-SP) exhibit high dispersity in various solvents after the surface modification, including H2O, PBS, SBF, saline and DMEM with fetal bovine serum (Figure 2h,S10 and Table S2). It has also been found that the photothermal-conversion property and stability of Ti3C2-SP nanosheets show no obvious change compared to non-modified Ti3C2 nanosheets (Figure S11), indicating that the SP modification has no significant influence on the photothermal property of Ti3C2 nanosheets.


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The potential in vitro toxicity of Ti3C2-SP to cells was tested by a standard CCK-8 assay. Breast 4T1 cancer cells were incubated with Ti3C2-SP at varied concentrations (400, 200, 100, 50, 25, 12, 6 and 0 µg/mL) for 24 h and 48 h. The Ti3C2-SP shows negligible effect on the survival of 4T1 cells, even at the concentration up to 400 µg/mL (Figure 3a). Confocal laser scanning microscopy (CLSM) images clarly show the efficient intracellular uptake of FITC (fluorescein isothiocyanate)-labeled Ti3C2-SP nanosheets after the co-incubation for 4 h (Figure S12). Then, Ti3C2-SP nanosheets as photothermal agents for in vitro cancer ablation under laser irradiation was conducted. 4T1 cells were incubated with Ti3C2-SP nanosheets at 100 µg/mL for 4 h and then exposed to 808 nm laser of varied power densities (0, 0.25, 0.5, 1.0, 1.5 and 2.0 W cm-2). It was revealed that with the increase of laser power density, more cells incubated with Ti3C2-SP nanosheets were killed upon the NIR laser irradiation (Figure 3b). Furthermore, 4T1 cells were incubated with Ti3C2-SP nanosheets at varied concentrations (0, 6, 12, 25, 50, and 100 µg/mL) for 4 h and then exposed to the 808 nm laser at a power density of 1.0 W cm-2. It can be observed that the photothermal ablation effect of Ti3C2-SP exposed to NIR laser is significantly enhanced at elevated Ti3C2-SP concentrations (Figure 3c). Additionally, the cell apoptosis after photothermal ablation was further confirmed by confocal microscopic imaging. After NIR laser irradiation, the live and dead cells were differentiated by calcein-AM (green) and PI (red) costaining, respectively. The control groups including the 4T1 cells without any treatment, only NIR laser irradiation, and only Ti3C2-SP treatment are not significantly affected by the treatments. In contrast, the majority of 4T1 cells were killed by the photothermal ablation after treated with Ti3C2-SP under NIR laser irradiation. These results clearly demonstrate the remarkable in vitro photothermal effect of the Ti3C2-SP nanosheets in promoting cancer cell ablation (Figure 3d).


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A detailed in vivo investigation of the biocompatibility of Ti3C2-SP was further conducted to explore its in vivo translation potential. Healthy Kunming mice were divided into the control group and three treatment groups at three different dosages (Ti3C2-SP dosages of 5 mg/kg, 10 mg/kg and 20 mg/kg). The mice after intravenous injections of Ti3C2-SP were euthanized at the 30th day. During a month period, the body weight of mice was recorded without abnormality, and no significant behavioral changes were observed in treatment groups compared to control group (Figure 3e). The biodistribution of Ti3C2-SP in main organs and tumor was investigated in 24 h intravenous injection on nude mice with 4T1-bearing tumor model, which showed that around 1.73% of Ti3C2-SP had accumulated into tumor through the enhanced permeability and retention (EPR) effect (Figure 3f). The circulation of Ti3C2-SP in blood stream was investigated and the blood circulation half-time of Ti3C2-SP was calculated to be 0.67 h (Figure 3g). The hematoxylin and eosin (H&E) staining results of major organs (heart, liver, spleen, lung, and kidney) after one-month feeding show no significant acute, chronic pathological toxicity and adverse effects among the control group and the treatment groups (Figure 3h). The blood indexes, including key biochemistry parameters, in the treatment groups have no abnormity compared to the control group (Figure S13). These results demonstrate that Ti3C2-SP is biocompatible for further in vivo PTT of cancer. Encouraged by the high NIR absorbance and in vitro PTT efficacy of Ti3C2-SP nanosheets, further in vivo PTT experiments were performed by the intravenous injection of Ti3C2-SP. 4T1 tumor-bearing mice were divided into four groups: control (n = 5), NIR laser only (n = 5), Ti3C2SP only (n = 5, dose of 20 mg/kg), and Ti3C2-SP + NIR laser (n = 5, dose of 20 mg/kg). Laser irradiation was carried out on the NIR laser only group and Ti3C2-SP + NIR laser group in 4 h post-injection. The tumor surface temperature of the Ti3C2-SP + NIR laser group increased from


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~30 °C to ~58 °C in 10 min of laser irradiation, which was sufficient to ablate the tumor (Figure S14). In contrast, the tumor temperature of mice group under the same irradiation dose showed very slight change in temperature (Figure 4c). In two days after PTT, tumors in Ti3C2-SP + NIR laser group disappeared, leaving black scars in the initial tumor sites. The tumor volumes of four groups were measured every two days using a digital caliper (Figure 4a), and the digital photos of tumor regions were taken every two days during half a mouth after the treatments (Figure S15). Remarkably, tumors on mice of Ti3C2-SP + NIR laser group were completely eliminated, without reoccurrence in an observation period of 16 days (Figure S16). In comparison, fast increases of the tumor volumes in groups of the control, NIR laser only and Ti3C2-SP only were observed during the 16 days’ period after the treatments. H&E and TUNEL (TdT-mediated dUTP Nick-End Labeling) staining results show the highly significant necrosis of tumor cells of Ti3C2-SP + NIR laser group compared to the mice groups of the control, NIR laser only and Ti3C2-SP only. The in vivo proliferative activities were measured by Ki-67 antibody staining, and the Ti3C2-SP + NIR laser group presents a strong suppression effect on the cell proliferation, while the groups of the control, NIR laser only and Ti3C2-SP only shows almost no adverse effects on the proliferative activity of cancer cells (Figure 4d). Finally, all the mice demonstrate negligible weight fluctuations, thus confirming little adverse effects of these treatments on the health of mice (Figure 4b). 2D Ti3C2 nanosheets can also be used for the construction of 3D organic/inorganic hybrid implants for localized tumor PTT. As a typical paradigm, phase-changeable PLGA/Ti3C2 implant was synthesized by taking the advantages of high biocompatibility and unique hydrophobicity of ploy(lactic-co-glycolic acid) (PLGA).41-43 The PLGA/Ti3C2 bio-injection exhibits a unique phase-transformation behavior after the injection into tumor tissue, which can confine the


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PLGA/Ti3C2 implant within the tumor centers. The injectable nature of PLGA/Ti3C2 bioinjection can endow them with the improved comfort and compliance of less invasiveness and pain for patients. Typically, the PLGA/Ti3C2 oleosol can undergo a rapid liquid-solid phase transformation upon contacting water in vitro to form a visible solid called PLGA/Ti3C2 implant (Figure S17) based on a solvent-exchange mechanism. The microstructure and composition of PLGA/Ti3C2 implant were visualized by electronic microscopic observation and element mapping. The secondary electron image of implant shows a rough surface with homogeneously distributed pore channels (Figure S18a). The back-scattered electron image exhibits that Ti3C2 nanosheets have been randomly incorporated within the PLGA matrix (Figure S18b). The corresponding Ti element mapping precisely matches the distribution of Ti3C2 nanosheets in the implant (Figure S18c-f). These characterizations support the successful incorporation of Ti3C2 nanosheets within the PLGA matrix. The photothermal performance of PLGA/Ti3C2 implant in vitro was tested where the PLGA/Ti3C2 implant presents Ti3C2 content- and laser power densitydependent temperature elevation profiles (Figure S19). Subsequently, the photothermal therapeutic effect by localized intratumoral injection of PLGA/Ti3C2 oleosol was assessed. The localized injection of phase-changeable PLGA/Ti3C2 could effectively form the solid implant within tumor tissue (Figure S20). The 4T1 tumorbearing mice were divided into the control group and the PLGA/Ti3C2-implanting group (dose of 2 mg/kg, designed as implant group). To examine the efficacy of PTT, the mice in two groups were exposed to NIR laser irradiation for 6 min. As monitored by an IR thermal camera during irradiation, the surface temperature of the tumors in PLGA/Ti3C2-implanted group rapidly increased from 30 °C to 80 °C in 5 min, a temperature sufficiently high for tumor ablation (Figure S21). In contrast, the temperature of tumors in control group increased by ~ 5 °C under


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laser irradiation (Figure 4g). Monitoring on the tumor volumes over a period of 16 days (Figure 4e) demonstrates that the tumors in PLGA/Ti3C2-implanted mice have been significantly regressed, whereas the control group show no significant inhibition effect on tumor growth (Figure S22). All the mice demonstrate negligible weight fluctuations, thus confirming insignificant adverse effects of these treatments on the mice health (Figure 4f). The H&E and TUNEL staining were performed on tumor sections from each group after 16 days’ treatment. It was found that most of tumor cells were severely damaged in implanted group after an 808 nm laser irradiation. Comparatively, there was no significant tumor-cell death in the control group, indicating the successful destruction of tumor cells by PTT using PLGA/Ti3C2 implant. Additionally, the high in vivo anti-proliferative activities were demonstrated by Ki-67 antibody staining (Figure 4i). Tumors on implanted mice were completely eliminated after the NIR-laser irradiation, without reoccurrence in an observation period of 16 days. In comparison, a notable increase of the tumor volume in control group was observed (Figure 4h). Together with the significant advantage of PLGA/Ti3C2 oleosol restriction via liquid-solid phase transformation within tumor tissue upon implanting, these results suggest that PLGA/Ti3C2 implant is a powerful agent for in vivo PTT of tumors. Considering the high biocompatibility of both PLGA and Ti3C2 component, it is highy expected that the physically combined PLGA/Ti3C2 implant is also highly bicompatible for in vivo applications. In summary, a novel kind of Ti3C2 nanosheets (MXenes) has been obtained and its high photothermal-conversion and in vitro/in vivo photothermal ablation effects of tumors are revealed and demonstrated for the first time (Figure 5). A two-step exfoliation approach of HF etching followed by TPAOH intercalation has been developed to substantially reduce the lateral sizes of Ti3C2 MXene and to satisfy the strict application requirements for biomedicine. Ti3C2


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nanosheets exhibit strong NIR absorption and photo-thermal conversion efficiency upon NIR laser irradiation (808 nm) owing to the LSPR effect. The SP-modified Ti3C2 nanosheets (Ti3C2SP) show no noticeable toxicities both in vitro and in vivo. Highly attractively, Ti3C2 nanosheets are revealed to be a highly effective PTT agent for tumor therapy, which enables excellent NIR light-induced tumor ablations without recurrence by either intravenous injection of Ti3C2-SP (20 mg/kg) or localized intratumoral injection of PLGA/Ti3C2 phase-changeable implant (2 mg/kg). Importantly, the phase transformation characteristics of PLGA/Ti3C2-SP implants not only enables the tumor eradication, also guarantees no leakage of implanted components into the body circulation, thus ensuring excellent in vivo biosafety. Our results not only promise the great potential of Ti3C2 nanosheets (MXenes) as a novel photothermal agent used for cancer therapy, but may also initiate more explorations on MXenes to benefit the biomedical applications.


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Figure 1. (a) Scheme of Ti3C2 nanosheet exfoliation process based on a ball-and-stick model (top) and layer model (below), including HF etching, TPAOH intercalation and centrifugation collection. (b) Photograph of Ti3AlC2 ceramic bulk (MAX phase). (c, d) SEM image of layered Ti3C2 after HF etching. (e) HRTEM image of multilayer Ti3C2 after HF etching. Inset shows the overall SAED pattern. (f) dark-field TEM images of Ti3C2 nanosheets after exfoliation. Inset shows lateral size distribution. (g) bright-field TEM images of Ti3C2 nanosheets after exfoliation. Inset shows a digital photo of Ti3C2 nanosheets dispersed in water exhibiting Tyndall effect. (h) Electron energy loss spectra (EELS) of intercalated Ti3C2 nanosheets.


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Figure 2. (a) XRD patterns of Ti3AlC2 phase and Ti3C2 nanosheets. (b) AFM image of Ti3C2 nanosheets. (c) AFM-measured thickness of Ti3C2 nanosheets. (d) Absorbance spectra of Ti3C2 nanosheets dispersed in water at varied concentrations (30 ppm, 15 ppm, 8 ppm, 4 ppm and 2 ppm). Inset: Normalized absorbance intensity at λ = 808 nm divided by the characteristic length of the cell (A/L) at varied concentrations. (e) Photothermal heating curves of pure water and Ti3C2 nanosheets-dispersed aqueous suspension at different concentrations (72, 36, 18, and 9 ppm) under irradiation using an 808 nm laser (1.5 W cm-2). (f) Recycling heating profiles of a Ti3C2 nanosheets-dispersed suspension (36 µg/mL, 100 µL) using an 808 nm laser (1.5 W cm-2) for five laser on/off cycles. (g) Schematics of surface modification of exfoliated Ti3C2 nanosheets modified with soybean phospholipid (Ti3C2-SP). (h) Diameter changes of Ti3C2-SP dispersed in different solvents at varied time points. Insets are the corresponding digital images.


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Figure 3. In vitro cell experiments and in vivo toxicity assay. (a) Relative viabilities of 4T1 cells after being incubated with varied concentrations (concentration of 400, 200, 100, 50, 25, 12, 6 and 0 µg/mL) of Ti3C2-SP nanosheets. Error bars were based on the standard deviations (s. d.) of six parallel samples. (b) Relative viabilities of 4T1 cells after Ti3C2-SP (100 µg/mL)-induced photothermal ablation at different laser power densities (0, 0.25, 0.5, 1.0, 1.5 and 2.0 W cm-2). (c) Relative viabilities of 4T1 cells after Ti3C2-SP (concentration of 0, 6, 12, 25, 50, and 100


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µg/mL)-induced photothermal ablation at laser power density of 1.0 W cm-2. (d) Confocal fluorescence imaging of Ti3C2-SP induced photothermal ablation after the various treatments (The control, Ti3C2-SP only, NIR laser only and Ti3C2-SP + NIR laser group). (e) Timedependent body weight curves of Kunming mice within a month period. (f) The biodistribution of Ti (% ID of Ti per gram of tissues) in main tissues and tumor after 24 h of intravenous administration of Ti3C2-SP dispersed in PBS (n = 6). (g) The blood circulation curve of Ti3C2-SP after intravenously injection into mice (n = 6). The half-time(T1/2) was calculated to be approximately 0.76 h. (h) Histopathological examinations via H&E staining of major organs (heart, liver, spleen, lung and kidney) of the control group and three treatment groups (at different Ti3C2-SP dosages of 5 mg/kg, 10 mg/kg and 20 mg/kg) for 30 days. All the scale bar are 100 µm.


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Figure 4. (a) Time-dependent tumor growth curves (n = 5, mean ± s.d., P < 0.05, P < 0.01) after different treatments. All treatments were performed only once. (b) Time-dependent bodyweight curves of nude mice after different treatments. (c) IR thermal images of 4T1 tumorbearing nude mice with or without receiving the intravenous injection of Ti3C2-SP (dose of 20 mg/kg) under 808 nm laser irradiation (1.5 W cm-2) taken at different time intervals. (d) H&E staining for pathological changes in tumor tissues from each group to reveal the effectiveness of in vivo PTT by intravenous injection of Ti3C2-SP (scale bar, 25 µm). TUNEL staining for apoptosis in tumor sections (scale bar, 50 µm). Antigen Ki-67 immunofluorescence staining for cellular proliferation in tumor sections (scale bar, 50 µm). (e) Time-dependent tumor growth curves (n = 5, mean ± s.d., P < 0.01) after different treatments. The treatments were performed only once. (f) Time-dependent body weight curves of nude mice after different treatments. (g) IR thermal images of 4T1 tumor-bearing nude mice with or without receiving localized intratumoral injection of PLGA/Ti3C2 implant (dose of 2 mg/kg) under 808 nm laser irradiation (1.0 W cm-2) taken at different time intervals. (h) Photographs of 4T1 tumor-bearing mice and tumor region (the control group and PLGA/Ti3C2 implant + NIR laser group) at the 16th day. (i) H&E staining for pathological changes in tumor tissues from each group to reveal the effectiveness of in vivo PTT by the implantation of PLGA/Ti3C2 implant (scale bar, 50 µm). TUNEL staining for apoptosis in tumor sections (scale bar, 50 µm). Antigen Ki-67 immunofluorescence staining for cellular proliferation in tumor sections (scale bar, 50 µm).


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Figure 5. (a) Two therapeutic approaches based on photothermal effect of Ti3C2 nanosheets (intravenous injection of Ti3C2-SP nanosheets and intratumoral injection of phase-changeable PLGA/Ti3C2 implant). (b) The Ti3C2-SP nanosheets reach and accumulate at tumor tissues by enhanced permeability and retention (EPR) effect via the intravenous injection of Ti3C2-SP nanosheets. (c) Photothermal ablation of cancer cell by Ti3C2-SP exposed to NIR laser.


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ASSOCIATED CONTENT Supporting Information Transmission electron microscopy (TEM) images, scanning transmission electron microscopy (STEM) analysis, XPS spectra, photothermal property and stability, confocal laser scanning microscopic (CLSM) images, hematological assay of Ti3C2 nanosheets. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]. *E-mail: [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We greatly acknowledge the financial support from National Key Research and Development Program of China (Grant No. 2016YFA0203700), National Nature Science Foundation of China (Grant No. 51302293 and 51132009), Natural Science Foundation of Shanghai (Grant No. 13ZR1463500), and Youth Innovation Promotion Association (Grant No. 2013169). REFERENCES (1) Novoselov, K. S.; Jiang, D.; Schedin, F.; Booth, T. J.; Khotkevich, V. V.; Morozov, S. V.; Geim, A. K. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 10451. (2) Geim, A. K.; Novoselov, K. S. Nat. Mater. 2007, 6, 183.


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Graphical TOC Entry

Two-dimensional Ultrathin MXene Ceramic Nanosheets for Photothermal Conversion. Biocompatible Ti3C2 nanosheets (MXenes) were successfully synthesized based on a twostep exfoliation strategy of MAX phase Ti3AlC2 by the combined HF etching and TPAOH intercalation. Especially, the strong NIR laser absorption, high photothermal-conversion efficiency and in vitro/in vivo photothermal ablation of tumor of Ti3C2 nanosheets (MXenes) were revealed and demonstrated, not only in the intravenous administration of soybean phospholipid-modified Ti3C2 (Ti3C2-SP) nanosheets but also in the localized intratumoral implantation of a phase-changeable PLGA/Ti3C2 organic-inorganic hybrid.


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Two-Dimensional Ultrathin MXene Ceramic Nanosheets for

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