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Intelligent Hollow Pt-CuS Janus Architecture for Synergistic Catalysis-Enhanced Sonodynamic and Photothermal Cancer Therapy Shuang Liang, Xiaoran Deng, Yun Chang, Chunqiang Sun, Shuai Shao, Zhongxi Xie, Xiao Xiao, Ping'an Ma, Haiyuan Zhang, Ziyong Cheng, and Jun Lin Nano Lett., Just Accepted Manuscript • DOI: 10.1021/acs.nanolett.9b01595 • Publication Date (Web): 14 May 2019 Downloaded from http://pubs.acs.org on May 15, 2019
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Intelligent Hollow Pt-CuS Janus Architecture for Synergistic Catalysis-Enhanced Sonodynamic and Photothermal Cancer Therapy Shuang Liang†, ‡, #, Xiaoran Deng†, §, #, Yun Chang†, §, Chunqiang Sun†, Shuai Shao†, Zhongxi Xie†, ‡, Xiao Xiao†, ‡, Ping’an Ma†, Haiyuan Zhang†, ‡, Ziyong Cheng†, ‡, *, Jun Lin†, ‡, * † State
Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied
Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China ‡
University of Science and Technology of China, Hefei, 230026, P. R. China
§ University
of Chinese Academy of Sciences, Beijing, 100049, P. R. China
* Corresponding authors: Ziyong Cheng:
[email protected] Jun Lin:
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Abstract As a non-invasive treatment modality, ultrasound (US)-triggered sonodynamic therapy (SDT) shows broad and promising applications to overcome the drawbacks of traditional photodynamic therapy (PDT) in combating cancer. However, the SDT efficacy is still not satisfactory by out of oxygen (O2) assistance. In addition, there is also much space to explore the SDT-based synergistic therapeutic modalities. Herein, a novel Pt-CuS Janus composed of hollow semiconductor CuS and noble metallic Pt was rationally designed and successfully synthesized. The hollow CuS shows large inner cavity for loading sonosensitizer molecules (tetra-(4aminophenyl) porphyrin, TAPP) to implement SDT. Moreover, the deposition of Pt not only enhances photothermal performance compared with those of CuS nanoparticles (NPs) due to the effect of local electric field enhancement, but also possesses nanozyme activity for catalyzing decomposition of endogenous over-expressed hydrogen peroxide (H2O2) to produce O2 that can overcome tumor hypoxia and augment the SDT-induced highly toxic reactive oxygen species (ROS) production for efficient cancer cells apoptosis. Importantly, the generated heat of Pt-CuS by 808 nm laser irradiation can accelerate the catalytic activity of Pt and elevate O2 level that further facilitates SDT efficacy. Interestingly, the thermally sensitive copolymer coated around the Janus can act as a smart switch to regulate the catalytic ability of Pt and control TAPP release that have significant effect on modulating the therapeutic effect. The synergistic catalysisenhanced SDT efficiency and highly photothermal effect almost realized complete tumor resection without obvious reoccurrence and simultaneously displayed highly therapeutic biosafety. Furthermore, the high optical absorbance allows the as-synthesized Pt-CuS Janus for photoacoustic (PA) imaging and NIR thermal imaging. This work develops a versatile
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nanoplatform for multifunctional theranostics strategy and broadens the biological applications by rational designing their structure. Key words: sonodynamic therapy, Pt-CuS Janus, photothermal therapy, nanozymes, synergistic effect.
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With the rapid development of theranostic nanomedicine, a variety of treatment modalities have been widely investigated in cancer therapy. Compared to traditional treatments (surgery, chemotherapy, and radiotherapy), the development of external minimally invasive or noninvasive therapeutic modalities is considered to be of great significance because of their precise tumor specificity, spatial/temporal controllability, and fewer toxicity to body normal tissues.1-6 Among them, light-mediated photodynamic therapy (PDT) has been widely explored in the past decade, in which photosensitizers can be stimulated by light to produce cytotoxic ROS and induce cell death. However, it encounters an intrinsically hinder of limited penetrating depth of light, which leads to poor treatment efficacy against deep tumors.1, 7 In contract to traditional light-triggered PDT, ultrasound (US) is also capable of activating sonosensitizers to generate toxic ROS molecules for cancer therapy, thereby termed sonodynamic therapy (SDT).8-11 Thanks to the merits of noninvasiveness, low cost, and high tissue-penetrating depth, the SDT has been demonstrated to be more effective than conventional PDT.12,
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Among them, numerous
sonosensitizers have been employed for SDT, including organic molecules such as photofrin, hematoporphyrin, and some porphyrin derivatives.7 However, they are faced with the disadvantages of poor chemical stability, low bioavailability, and little tumor accumulation.14, 15 To solve these problems, the development of nanomedicine has provided experimental evidences to improve the therapeutic efficiency of organic sonosensitizers, such as encapsulation or linkage of them to nanomaterials. Besides, these nanomaterials can also function as the synergistic agents to enhance the therapy efficiency.7 On the other hand, through reviewing the SDT mechanism, it can be found that O2 plays an important role in the production of singlet oxygen (1O2). However, the solid tumor microenvironment (TME) is in severe hypoxia, which restricts the therapeutic efficacy of SDT to a great extent. Moreover, the O2 consumption during SDT
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would deteriorate tumor hypoxia, further lessening the SDT efficiency as a vicious circle.16-22 Therefore, alleviating the tumor hypoxia-associated barrier is of innovative significance for SDT efficacy. Near infrared (NIR) light-mediated photothermal therapy (PTT) is also a promising antitumor approach,23-25 which adopts photothermal transduction agents (PTAs) harvesting light energy to produce hyperthermia rapidly and trigger cancer cells death.26, 27 The PTAs could be normally divided into organic dyes28 and inorganic materials such as noble metal nanoparticles,29 semiconductor nanostructures.30 Compared with organic materials, the inorganic nanoparticles possess higher photothermal conversion efficiency and better photothermal stability that arouse an increased level of concerns. As widely studied inorganic PTAs, noble metal Au, Pt, and Pd NPs can absorb laser, make electrons jump from the ground state to the excited state, and then release energy in the form of heat through non-radiative decay 27, 31, 32 Compared with Au-based PTAs, the Pt- or Pd-based PTAs not only have better photothermal stability, but also possess excellent catalytic properties.33,
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In addition, copper sulfide (CuS) NPs as intrinsic p-type
semiconductor materials are also good candidates in PTAs because of their distinctly localized surface plasmon resonance (LSPR) in NIR region.35, 36 However, the employing of CuS in cancer treatment is still limited due to their relative low photothermal efficiency. Recently, the integration of noble metal nanomaterials with semiconductor is a promising approach to enhance the photothermal conversion efficiency by changing the electrons transport pathway.23,
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However, unlike other noble metal such as Au and Ag, the reports on CuS and Pt hybrids were very limited and their properties are still required for exploration. For all this, as one single therapeutic mode, PTT alone still cannot achieve better therapeutic effect. Therefore,
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combination therapy is becoming a promising approach to strengthen the advantages of different treatments to achieve synergistic therapeutic effect in cancer therapy.39-42 With the integration of nanotechnology in the biomedical field, the emergence of nanocarriers provides a new approach for selectively delivering multiple therapeutic agents to tumor site and reducing systemic toxicity simultaneously.43-45 Among them, novel Janus nanostructures have aroused wide attention for combining multiple functionalities and showing “all-in-one” theranostic capability.46-50 In this work, temperature-sensitive polymer modified hollow-structural Pt-CuS Janus was firstly developed through a facile and reproducible vacuum metal sputter deposition method. The deposited Pt can enhance the local electric field, following strongly improve the photothermal efficiency under 808 nm laser irradiation. Furthermore, the hollow interior of CuS provides large space for TAPP molecules loading to implement SDT. Meanwhile, the nano Pt can catalyze decomposition of endogenous H2O2 to modulate the concentration of O2 for overcoming tumor hypoxia and augmenting the SDT-induced ROS production. Importantly, the generated heat by 808 nm laser irradiation can enhance the catalaselike activity of Pt to induce more O2 production for sequentially heightening SDT efficacy. Finally, the covering of temperature-sensitive polymer (poly(oligo(ethylene oxide) methacrylateco-2-(2-methoxyethoxy) ethyl methacrylate) (p(OEOMA-co-MEMA)) onto the Pt-CuS NPs (PtCuS-P-TAPP, labelled as PCPT) not only increases the biocompatibility, but also regulates the catalytic activity of Pt and prevents premature release of the TAPP during the blood circulation. When the nanocarriers were enriched at the tumor site based on the enhanced permeability and retention effect (EPR),51,
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the 808 nm laser and US irradiation were used to trigger them
producing hyperthermia and a large amount of 1O2 to induce cell death. Astonishingly, the synergistically inhibiting effect of PCPT demonstrates complete tumor eradication in vivo.
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Besides, the candidate can be used as enhanced photoacoustic (PA) imaging agent and NIR thermal imaging agent simultaneously to provide instant diagnostic functions. Meanwhile, the characteristics of extraordinary biocompatibility and easily excreted out of the body guarantee their further clinical translation. Results and Discussion Construction and characterization of PCPT. The main synthesis procedures and antitumor mechanism of PCPT are illustrated in Scheme 1. Firstly, the spherical hollowstructural CuS NPs were synthesized by sacrificial template method. Then, they were spread evenly onto a clean silicon wafer to form a two-dimensional CuS monolayer (Figure S1). Subsequently, the catalytic Pt layer was asymmetrically deposited onto the top surface of CuS spheres through the vacuum metal sputter deposition method. After sonication in deionized water, the Pt-CuS Janus NPs were released from substrates and suspended in water. Finally, the thiol-terminated temperature-sensitive copolymer p(OEOMA-co-MEMA) was modified onto the surface of Pt-CuS Janus by Pt-S and Cu-S bonds,53, 54 and then the TAPP molecules were loaded into the hollow interior of CuS to construct the novel and intelligent theranostic nanoplatform. Transmission electron microscopy (TEM) image reveals that the CuS NPs are spherical with a hollow structure and have a diameter of roughly 120 nm (Figure 1a). After deposition of Pt thin layer, the hetero-nanostructures were formed (Figure 1b). Figure 1c shows the energy dispersive X-xay spectroscopy (EDS) line scanning profile of Pt-CuS nanocomposite, demonstrating the intensity changing of Pt element on CuS. Figure 1d presents the high-angle annular dark field scanning transmission electron microscopy (HAADF- STEM) image and the corresponding in situ elemental distribution mapping pictures. The Cu and S signals further
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Scheme 1. Schematic illustration of the main synthesis procedures and antitumor mechanism of PCPT.
reveal the hollow nature of NPs, while the Pt element asymmetric distribution on CuS NPs illustrates an unconventional Janus structure. The powder X-ray diffraction (XRD) characterization also proves the formation of CuS and Pt-CuS. The patterns of the as-obtained CuS and Pt-CuS Janus are consistent with the standard data of hexagonal phase CuS (JCPDS No. 06-0464) and cubic phase Pt (JCPDS No. 04-0802), respectively (Figure S2). Meanwhile, the existence of Cu, S and Pt elements on the surface of NPs were convinced by X-ray photoelectron spectroscopy (XPS) spectra (Figure S3). The N2 adsorption-desorption isotherms of the Pt-CuS NPs are shown in Figure 2a. The type-IV isotherms with H1 hysteresis loop suggest a typically hollow mesoporous structure. The Brunauer–Emmett–Teller (BET) surface area and total pore volume were estimated to be 77.463 m2 g-1 and 0.272 cm3 g-1, respectively. These results
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Figure 1. (a) TEM image of CuS. (b) TEM image of Pt-CuS Janus. (c) Energy dispersive spectroscopy (EDS) line scanning profile analysis of Pt-CuS Janus with the Pt layer, the inset gives a scanning transmission electron microscopy (STEM) image of Pt-CuS Janus. (d) Elemental mappings of Cu, S and Pt of Pt-CuS Janus.
demonstrate that the mesoporous and hollow structure can serve as a reservoir to load multiple agents for varied treatment purposes. To improve the biocompatibility, prevent the loaded cargo premature release and protect the Pt catalytic activity in blood circulation, the thiol-terminated thermo-responsive polymer p(OEOMA-co-MEMA) was employed to modify the nanocarrier. Fourier transform infrared (FTIR) spectra (Figure 2b) demonstrate the successful modification of
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the polymer onto Pt-CuS. Typically, the new characteristic absorption peaks at 1722 cm-1 (the C=O stretching vibration in the ester group) and 1110 cm-1 (the C-O stretching vibration) obviously come from the p(OEOMA-co-MEMA). Meanwhile, the amount of polymer on Pt-CuS was measured by thermogravimetric analysis (TGA) (Figure S4), revealing that the Pt-CuS and Pt-CuS-P had a weight loss of 16.1% and 29.1%, respectively. Therefore, the content of polymer on Pt-CuS was calculated to be about 13.0% (w/w). The evolution of zeta potential and particle sizes based on dynamic light scattering (DLS) both indicated the successful modifications in each preparation step (Figure 2c). The final hydrodynamic particle diameter and zeta potential value of Pt-CuS-P was 285 nm and -17.2 mV, respectively. In addition, the stability of Pt-CuS NPs in PBS and culture medium were tested by DLS, respectively. From Figure S5, it can be seen that the NPs remain well dispersed without aggregation in PBS or DMEM after 7 days. Moreover, the NPs still possess intact morphology after treated with 808 nm laser irradiation under 0.8 W cm-2 for 10 min and US irradiation at 1.0 W cm-2 for 5 min (Figure S6), indicating the stability of the samples during the PTT/SDT treatment. Photothermal effect of Pt-CuS in solution. The optical property of the as-prepared CuS and Pt-CuS aqueous dispersion were measured by UV–vis–NIR absorption spectra (Figure 2d). Typically, a broad and intense absorption band of Pt-CuS extends from the NIR to whole visible region compared to that of pure CuS. The 808 nm laser was chosen as the excitation source because of its minimal absorption coefficient of water (
