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Prussian Blue Analogue Islands on BiOCl-Se Nanosheets for MR/ CT Imaging-guided Photothermal/Photodynamic Cancer Therapy Xiujin Chen, Rui Wang, Dongdong Liu, Yang Tian, and Ling Ye ACS Appl. Bio Mater., Just Accepted Manuscript • DOI: 10.1021/acsabm.8b00786 • Publication Date (Web): 20 Feb 2019 Downloaded from http://pubs.acs.org on February 26, 2019

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ACS Applied Bio Materials

Prussian Blue Analogue Islands on BiOCl-Se Nanosheets for MR/CT Imaging-guided Photothermal/Photodynamic Cancer Therapy Xiujin Chen,1 Rui Wang,2 Dongdong Liu,1 Yang Tian1* and Ling Ye,2*

1Beijing

Key Laboratory for Optical Materials and Photonic Devices, Department of

Chemistry, Capital Normal University, 105 North road of the Western 3rd Ring, Beijing 100048, China 2School

of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069,

China

Xiujin Chen and Rui Wang contributed equally Corresponding Author: Yang Tian and Ling Ye Email: [email protected] (Y. Tian); [email protected] (L. Ye)

1

ACS Paragon Plus Environment

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Abstract Precision therapy combines the advantages of multimodal imaging and a synergistic treatment, which can provide higher therapeutic efficacy and a more rigorous diagnosis than solitary imaging or ordinary therapy. In this research, we synthesized innovative Se-doped BiOCl nanosheets (Se-BiOCl) via a solvothermal method. Then, islands of Prussian blue analogues (PBA) Bi4[Fe(CN)6]3 were loaded on the Se-BiOCl nanosheets via surface ion-exchange reactions to obtain the Se-BiOCl/PBA composite nanosheets. The successful integration of PBA made progressive T1- and T2-weighted magnetic resonance imaging (MRI) possible. In addition, the advanced computed tomography (CT) capabilities matched the high X-ray attenuation coefficient of Bi, thereby realizing multimodal imaging for accurate diagnoses. The strong absorbance in the near infrared range provided by PBA offers high antitumor efficacy for photothermal therapy (PTT). In addition, with the doping of Se, the band gap of Se-BiOCl was adjusted from 387 nm (BiOCl) to 540 nm, thus resulting in effective photodynamic therapy (PDT) by visible light. The favorable tri-modal imaging and synergistic therapy were further confirmed to have significant positive effectiveness both in vitro and in vivo. These biocompatible theranostic nanoagents produced by surface ion-exchanges, highly integrated multimodal imaging and combined treatments may have high potential for clinical antitumor applications. Key words: Prussian-blue-analogues, contrast agent, nanosheet, imaging

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1. Introduction Precision therapy, which is a combination of multimodal imaging and therapeutic features, has become a central focus in cancer treatment for the past few years.1-2 For this purpose, numerous cancer treatment monitoring methods have been established to fulfill multiple purposes, such as magnetic resonance (MR), photoacoustics, and computed tomography (CT), which can realize multiple diagnoses for tumors and lay the foundation for further cancer therapy. MRI is an outstanding technique due to its multiple advantages, such as its high sensitivity, high temporal resolution, noninvasiveness and indefinite tissue penetration depth.3-4 CT imaging, possessing tremendous temporal resolution and avaluable deep tissue penetration, is also universally applied in various clinical disease screenings.5-6 Nevertheless, regardless of whether MR imaging or CT imaging is applied, each has its limitations in the diagnosis process. Multimodal imaging can fill the gaps caused by the low detection speed and constructed defects of MR imaging and the low treatment precision and radiation of CT imaging.7-8 On this basis, the necessity of multimodal imaging diagnosis for meticulously wrecking tumor and attaining precise therapy is shown. The integration of multiple imaging techniques can offer an ideal platform for precise diagnosis, while diverse treatments can lead to practical applications to cancer therapy. Photothermal therapy (PTT), a new type of cancer treatment, has become a significant therapy tool for tumors because of its high efficiency, minimal 3



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invasiveness, visualization and tumor-specific localization.9-11 Photodynamic therapy (PDT) has been certificated for clinical treatments by the U.S. Federal Drug Administration (FDA) since 1996 due to its low side effects, low tissue toxicity, minimal invasiveness and strong cell selectivity.12-14 With the combination of PTT and PDT, the above advantages can be easily achieved, which will lead to more precise therapy.15-16 Prussian blue (PB), Fe4[Fe(CN)6]3, is a clinical FDA-approved drug.17 Recently, PB nanoparticles have been widely investigated in some novel applications in the biologic and theranostic fields.18-19 For example, PB nanoparticles have been utilized as an burgeoning contrast agent for efficient photoacoustics with higher photostability. PB nanoparticles are also applied to the contrast agent in both T1-weighted and T2-weighted MR imaging on account of the unique structure of Fe(II)-, Fe(III)-N=C. Furthermore, because of the charge-transfer between Fe3+ and Fe2+, PB nanoparticles are able to convert NIR light into thermal energy

for disease

treatments.20-21 However, the efficiency of the imaging and photothermal therapy still needs to be improved for clinical applications. For example, the r1 and r2 for pure PB nanocrystals were reported to be only 0.079 and 0.488 mM-1·S-1, respectively.22 In addition, Prussian blue analogues have a chemical formula (MIII4[MII(CN)6]3) similar to PB in which the Fe ions of the PB are replaced by mixed metals.23 Nevertheless, there are few reports on the biomedical studies of Prussian blue analogue materials. Compounds including Bi have attracted much attention by reason of their in the 4


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medical field, such as for CT contrast and photothermal therapy.24 Among the Bi-based materials, BiOCl is a type of layered-structure compound that has been widely investigated in photocatalysis.25-26 However, the band gap of BiOCl is ca. 3.2 eV, meaning that its absorbent spectrum is in UV range (λ < 387 nm).12 Recently, Yang et. al reported on BiOCl driven by NIR with the upconversion of nanoparticles for effective photodynamic therapy.27 However, very few studies have reported on BiOCl with respect to its collaborative effect with MRI, CT imaging, PTT and PDT to meet the requirements of precision therapy. In this work, we employed an exchange method to synthesize a composite of Prussian blue analogues and inorganic Se-BiOCl nanosheets, in situ forming a germinated Bi4[Fe(CN)6]3 nanoislands decorated with Se-BiOCl (Se-BiOCl/PBA). The prepared process was illustrated by Scheme 1. The BiOCl nanosheets doped by Se were synthesized first, which adjusted the band gap of BiOCl inducing the absorption from 387 nm to 540 nm for Se-BiOCl. The absorbent wavelength therefore shifted to the visible light range. Then, the Prussian blue analogues - Bi4[Fe(CN)6]3 islands were integrated on the Se-BiOCl nanosheets via ion-exchanges at the surface,28-30 thus improving the efficiency of PTT and PDT. Furthermore, the Prussian blue analogues were used for T1-weighted and T2-weighted MR imaging, which was dramatically better than that of the single Prussian blue-based material.31 In addition, we added a layer of polydopamine （ PDA ）

on the Bi4[Fe(CN)6]3-decorated

Se-BiOCl nanosheets (Se-BiOCl/PBA-PDA), thus improving the preeminent 5



characters of the above material because of its better biocompatibility and enhanced PTT effect.32 At last, the prepared Se-BiOCl/PBA-PDA was shown to be a biocompatible theranostic nanoagent with both numerous imaging and therapy modals, proving its consequential potential for clinical cancer therapeutic potentials.

Scheme 1. (a) The process indication of the preparing Se-BiOCl/PBA-PDA; (b) Schematic illustration of Se-BiOCl/PBA-PDA theranostic-agents for MRI/CT/PTT trimodal imaging-guided simultaneous PTT/PDT for cancer therapy. 6


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2. Results and discussion.

Figure 1. TEM images of the synthesized Se-BiOCl (a) and Se-BiOCl/PBA (e). AFM images of Se-BiOCl (b) and Se-BiOCl/PBA (f). (c and g) corresponding height profiles. (d) XRD patterns of the prepared Se-BiOCl and Se-BiOCl/PBA. (h) HRTEM of the Se-BiOCl/PBA.

2.1 Compositional and structural characterizations for the Se-BiOCl and Se-BiOCl/PBA products Se-BiOCl nanosheets were first synthesized in a mixed solvent of n-octanol, n-octylamine and Oleic acid via a solvothermal method. The microstructures of the Se-BiOCl nanosheets was characterized using a transmission electron microscope (TEM) (Figure 1a), showing a wafer-like nanoplate with an average diameter of 40-80 nm. While the thickness of the Se-BiOCl nanosheets was confirmed to be ultrathin at ~2 nm using an atomic force microscope (AFM). Their crystalline phases were further measured using Powder X-ray diffraction (XRD), as shown in Figure 1d. Its XRD pattern shows that the representative diffraction peaks well matched the standard pattern of the tetragonal phase BiOCl (JCPDS card No. 73-2060). The EDX pattern in 7



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Figure S1a properly illustrates the correct elemental composition of Bi, Cl, O, and Se. Meanwhile, the Se-BiOCl nanosheets composed of PBA (Bi4[Fe(CN)6]3) islands were synthesized via the reaction between the BiOCl-Se and the K4Fe(CN)6 due to the exchange of Bi3+ and K+ ions (Equation 1). This cation exchange of K+ by Bi3+ occurs on the surface of the Se-BiOCl nanosheet, thereby inducing (Bi4[Fe(CN)6]3 islands to form at the nanosheet surface in situ.33 4BiCl3 + 3K4[Fe(CN)6] = Bi4[Fe(CN)6]3 + 12KCl

(1)

Figure 1e is the typical TEM image of the prepared Se-BiOCl/PBA, which demonstrates that the 2D nanosheet structure has a similar size as that of the Se-BiOCl product. However, the darker color of the Se-BiOCl/PBA nanosheets shows that they are thicker. The AFM images in Figures 1f and 1g reveal clear islands on the nanosheets, and the maximum thickness increased to ~5 nm. This well demonstrates the structure of the prepared PBA islands loaded on the Se-BiOCl nanosheets. In the high-resolution TEM (HR-TEM) image (Figure 1h), the lattice spacing of 0.197 belongs to the (511) plane of PBA and the lattice spacing of 0.368 nm is corresponding to the (002) plane of Se-BiOCl. Figure 1d is the XRD spectrum for the as-synthesized Se-BiOCl/PBA (red curves in Figure 1d). The delineative diffraction signals matched perfectly the standard BiOCl crystal. However, no clear diffraction peaks of the PBA were detected in the XRD pattern, which is caused by their small amount or weak crystallinity.

8


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Figure 2. Characterizations of the Se-BiOCl/PBA nanostructures. (a) HAADF-STEM-EDS images of the Se-BiOCl/PBA nanostructures. The inner is the SAED pattern. The elemental maps show the distribution of (b) Bi (green), (c) Cl (blue), (d) O (purple), (e) Se (yellow) and (f) Fe (red). (g) The UV-vis-NIR curves of the prepared Se-BiOCl and Se-BiOCl/PBA. (h) The FTIR absorbance spectra of the Se-BiOCl and Se-BiOCl/PBA.

We used High-angle annular dark field scanning transmission electron microscopy (HADDF-STEM-EDS) with elemental mapping to prove that the PBA was decorated on the Se-BiOCl nanosheet. Figures 2a-2f show the elemental distributions of Bi (green), Fe (red), O (purple), Cl (blue) and Se (yellow) corresponding to Figure 2a. The EDX spectrum in Figure S1b indicates that the atomic ratio of the Bi, Cl, Fe and Se is approximately 4:3:2:1. Moreover, the molar percentage of the modified PBA was calculated to be approximately 16.0 % in Se-BiOCl/PBA. The corresponding selected-area electron diffraction (SAED) pattern 9



(the inset of Figure 2a) reveals the polycrystalline structure of the prepared Se-BiOCl/PBA composite. The results demonstrated the definite construction of the Se-BiOCl/PBA. To further confirm the integration of PBA islands on the nanosheets, the UV-Vis-NIR absorption spectra of Se-BiOCl/PBA were analyzed by using UV-Vis-NIR. In Figure 2g, the Se-BiOCl/PBA (red curves in the Figure) displayed a absorption peak between 500 nm and 900 nm. The maximum absorption peak located at 715 nm, shown as the black curve in Figure 2g. This was caused by the charge transfer between Fe2+ and Bi3+, thus indicating the presence of Prussian blue analogues. The strong absorption in the NIR region (700–900 nm) was essential for NIR laser driven photothermal applications.34-36 Moreover, as shown in Figure 2h, it can also be proved using a Fourier transform infrared (FTIR) instrument that the strong characteristic absorption peak (2025 cm-1) is the exact spectrum of the Fe-CN-Bi stretching vibration. The 1218 and 1154 cm−1 peaks can be attributed to the C≡N stretching and out-of-plane bending vibration of Se-BiOCl/PBA, confirming the formation of PBA on the Se-BiOCl nanosheet.37

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Figure 3. XPS photoelectron line of (a) the survey patterns and the HR-XPS patterns of (b) Bi 4f, (c) Cl 2p, (d) Se 3d, (e) Fe 2p and (f) N 1s.

With the purpose of reconfirming the prepared Se-BiOCl/PBA surface state, XPS was further applied, as can be seen in Figure 3. The XPS survey pattern (black) in Figure 3a shows the corresponding Bi, Cl, Se and O for the Se-BiOCl nanosheet. In contrast, additional elements of Fe and N can be detected for the prepared Se-BiOCl/PBA composite, thus verifying the formation of PBA in the sample. Figure 3b demonstrates the two signals at 158.25 and 163.55 eV for the Se-BiOCl nanosheet sample, which are in accordance with Bi4f7/2 and Bi4f5/2, respectively.38 After integrating PBA, the binding energies of Bi4f7/2 and Bi4f5/2 shifted right, which were induced by the charge transition between the PBA and the Se-BiOCl nanosheet. Figures 3c-3d show the peaks for the Cl 2p and for the Se 3d orbit binding energy.39 Similarly, when the Se-BiOCl nanosheets were integrated with the PBA, the binding energy peaks all shifted a little right, thus illustrating the combination of the PBA 11



with the Se-BiOCl. Additionally, Figure 3e shows the peaks at 720.8 eV and 707.6 eV, which coincide with the Fe2p1/2 and Fe(II) in the PBA composition, respectively.40 As shown in Figure 3f, the binding energy of 399.2, 397.5 and 397.0 eV match with quatemary-N, pyrrolic-N and pyridinic-N, respectively, which is in good agreement with the N 1s of the -CN group in the prepared PBA islands.41 2.2 Surface modification and stability of the Se-BiOCl/PBA product

Figure 4. (a) The optical image of the dispersion stability of the Se-BiOCl, Se-BiOCl/PBA and Se-BiOCl/PBA-PDA dispersed in H2O, PBS and BSA. (b) The zeta potentials of the Se-BiOCl, Se-BiOCl/PBA, and Se-BiOCl/PBA-PDA, respectively. (c) The DLS results of the Se-BiOCl, Se-BiOCl/PBA and Se-BiOCl/PBA-PDA dispersed in water.

As for applications in the biomedical field, the agents should have their biostability assessed in an analogue biotic environment. PDA has been used as a prevalent coating 12


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reagent due to its tenacious adhesion ability, which helps to form a thin film on nanomaterials in order to improve the biocompatibility of the material and reduce the toxicity as desired. Hence, we coated the Se-BiOCl/PBA nanosheets with PDA to obtain the Se-BiOCl/PBA-PDA sample.42 We then investigated the aqueous stability of the Se-BiOCl, Se-BiOCl/PBA and Se-BiOCl/PBA-PDA samples in the H2O, the phosphate buffer saline (PBS) and the Bovine Serum Albumin (BSA) solutions. According to ICP data, the mass percentage of the modified PDA is approximately 34.8% in the Se-BiOCl/PBA-PDA product. Figure 4a shows the photographs of the samples in water, PBS, and BSA after 48 h. We can clearly see that the Se-BiOCl/PBA with the PDA modification (Sample C) is the most homogeneous solution regardless of whether it is in water, BSA or PBS. Conversely, the samples with no surface modification (Se-BiOCl and Se-BiOCl/PBA) produced clear sediment of differing amounts. Figure 4b shows the zeta potential results of the Se-BiOCl, Se-BiOCl/PBA and Se-BiOCl/PBA-PDA in water, which are -0.182, -30.1 and -51.9 mV, respectively. The most negative zeta potential value, 51.9 mV for the surface-modified Se-BiOCl/PBA-PDA sample, represents its excellent stability due to its large electrostatic repulsion.43 Correspondingly, the dynamic size distribution of the Se-BiOCl, Se-BiOCl/PBA and Se-BiOCl/PBA-PDA are confirmed by DLS to be 840 nm, 815 nm and 220 nm (Figure 4c), respectively. All the results prove that the surface modification of PDA for the Se-BiOCl/PBA nanosheets provides good 13



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biostability for the complex, which is significantly available for further in vivo imaging and treatment. 2.3 In vitro cell cytotoxicity of the Se-BiOCl/PBA product

Figure 5. Relative viabilities of HCT cells (a), HeLa cells (b), glioma cells (c) and HUVEC cells (d) incubated with the prepared Se-BiOCl/PBA sample at several concentrations for 12 h and 24 h.

The

standard

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium

bromide

(MTT) assay is characterized for further validating potential application of the resulting Se-BiOCl/PBA in vitro. 43-44

In our work, HCT cells (a colon cancer stem

cell line in the human body), HeLa cells (a epithelioid cervix carcinoma cell line in the human body), glioma cells (a neuroglioma cell line in the human body) and HUVEC cells (a umbilical vein endothelial cell line in the human body) were incubated with the Se-BiOCl/PBA in various concentrations for 12 and 24 h, 14


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respectively. Figure 5 shows that the viability of the untreated cells was presumed to be 100%. After 12 h of incubation, the cell viability still persisted higher than 95%. While after 24 h of incubation, it preserved no less than 80% at 1000 µg·mL -1. All the related results revealed that very few decline of the viability

occurred caused by the

Se-BiOCl/PBA nanosheets in various concentrations in a long time, thereby indicating a low toxicity in vitro. This means that the material can be safely used in the following bio-experiments. 2.4 In vitro MRI/CT/PTT/PDT based on the Se-BiOCl/PBA-PDA materials.

Figure 6. (a) T1-weighted MR image and Relaxation rate (1/T1). (b) T2-weighted MR image and Relaxation rate (1/T2) at varying Fe concentrations versus various mass concentrations of the Se-BiOCl/PBA-PDA at room temperature (0.5 T). (c) CT images and the corresponding HU values of the Se-BiOCl/PBA-PDA nanoparticles at different Bi concentrations. (d) Absorbance spectra of DPBF with Se-BiOCl/PBA-PDA irradiated by the 532 nm light. (e) Temperature increases for various samples. (f) Temperature increases for different concentrations under 808-nm laser irradiation for 10 min. (g) and (h) are the IR thermal images that correspond to (e) and (f), respectively. 15



The MR imaging contrast performance of the prepared Se-BiOCl/PBA after surface modification and being dispersed in water was characterized using a range of solutions with various concentrations. Figures 6a and 6b clearly show the brightening and darkening effects for the tested solution for both the T1-weighted and T2-weighted MR images, respectively. Figure 6a and 6b show that the r1 relativity value is 3.038 mM−1·s−1 and the r 2 relativity value is 4.912 mM−1·s−1. These values approach the commercial MRI contrasts, and both are larger than the reported pure PB nanoparticles whose r1 is 0.079 and r2 is 0.488 mM-1·S-1.22, 45 This should be related to the unique island structure. Bi has a high atomic number with a high X-ray attenuation coefficient [Bi (5.74) > Au (5.16) > I (1.94) cm2·kg-1 at 100 keV).46 From this, Se-BiOCl/PBA-PDA can be used as an promising CT contrast.

Figure 6c shows the phantom images of

CT contrast for the prepared Se-BiOCl/PBA-PDA solutions in various concentrations. From the upper black-and-white picture, we can see the CT images of the material solutions became brighter with the concentrations arising, thereby showing the enhancive CT response intensity. The derived CT value showed a linear increase with the Bi concentration. The slop indicated the very high X-ray absorption coefficient of 84.16 HU·mL·mg−1, which is much larger than those of the reported Bi-based materials (for example, 35.7 HU·mL·mg-1 for Bi2Se3) and the clinical agents (16.4 HU·mL·mg-1 for iopromide,1 and 19.7 HU·mL·mg-1 for iodine47). The superiority of our material therefore makes it a promising CT imaging contrast agent. 16


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To verify the photodynamic effect of the Se-BiOCl/PBA that originated from the Se-BiOCl composition, we assessed the stability of producing reactive oxygen species (ROS) using our sample. For this purpose, 1,3-Diphenylisobenzofuran (DPBF) was employed as a probe in the Se-BiOCl/PBA solution, which can be degraded by ROS (1O2, HO • , RO • , ROO • , and 2-cyanoisopropyl radical) with a transformation to 1,2-dibenzoylbenzene, resulting in a dwindling of absorbance peak at the wavelength of 410 nm.27, 48-49 In Figure 6d, the absorbance intensities of DPBF clearly dwindled over time by using 532 nm visible-light irradiation. The results pointed out that 532 nm visible-light can assuredly produce ROS, which has high efficiency but causes no physical damage compared to UV light. Prussian blue is well known to act as a potential photothermal therapy agent by converting NIR light into thermal energy due to the charge transfer between Fe3+ and Fe2+ via cyanide ions. In the same way, Prussian blue analogues also cause charge transfers between Fe2+ and Bi3+. As we all know, light-sensitive material with a high optical absorption capability in the NIR range and a high thermal conversion efficiency are two essential requirements for PTT agents. Figure 2 shows that the Se-BiOCl/PBA sample is good at adsorption in the NIR range (700-900 nm). Figure 6e shows the photothermal results for the pure water, Se-BiOCl, Se-BiOCl/PBA and Se-BiOCl/PBA-PDA (1 mg·mL-1) irradiated by 808 nm (0.7 W·cm-2) NIR light for 10 min. It shows that the Se-BiOCl/PBA had an excellent photothermal effect, which increased the temperature by approximately 38.8 °C and was more efficient than the 17



water (∆T=2.3 °C), Se-BiOCl (25.1 °C), and PBA (22.1 °C) (Figure S4d). The temperature increase depended on the concentration of Se-BiOCl/PBA, as indicated in Figure 6f. Moreover, PDA can serve as a photothermal therapeutic agent. Therefore, the modification of PDA can both achieve favorable biological compatibility and optimize the photothermal efficiency. Figure 6e shows that the Se-BiOCl/PBA modified with PDA resulted in a higher temperature (∆T = 42.2℃). Additionally, we can intuitively see the high IR thermal imaging properties from the visual pictures (Figures 6g and 6h), which show the perfect visual imaging effect for further photothermal therapy. The photothermal conversion efficiency (η value) of Se-BiOCl/PBA (0.5 mg·mL-1) under the NIR irradiation was inferred using the following eq.:

η=

hATmax  Qs I (1  10  A )

hA=

mC p



(2)

(3)

The detailed calculation method and explanations are listed in the supporting information. After calculation, the η value of Se-BiOCl/PBA turns out to be 35.1% at 808 nm compared to the 26.2% of the pure PBA (Figures S4e, f). It is also higher than those reported for gold nanorods (23.7%), Cu2-xSe (22%) and Cu2-xS (25.7%),50 which are the most reported photothermal coupling agents. Furthermore, the Se-BiOCl/PBA modified with PDA exhibited a higher η of 45.7%. The efficient NIR absorbance and 18


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the preferable η value mean that the prepared Se-BiOCl/PBA -PDA is a highly promising PTT nanoagent. 2.5 In Vivo MRI/PTT/CT trimodal-Imaging

Figure 7. (a)T1 and T2-weighted MR images in vivo at different time points (0, 0.5, 1, 4, and 24 h) after treatment with Se-BiOCl/PBA-PDA. (b) The CT images of front view and side view with and without injected Se-BiOCl/PBA-PDA. (c) IR thermal images of the mice irradiated by an 808 nm laser at different time points. (d) Corresponded temperature change curves for the tumor locations.

Based on the above MRI tests, the Se-BiOCl/PBA product with surface modification was administered into the HeLa tumor-bearing ICR mice via intravenous injection45 at the dose of 20 mg·kg-1. We then added 2 mg·kg-1 of product to improve the intratumoral concentration and the tumor-to-organ ratio of the nanomaterials. Figure 7a shows the T1 and T2-weighted MR images from preinjection to injecting the Se-BiOCl/PBA-PDA agent after 24 h. It clearly shows the positive contrast for T1-weighted imaging and the negative contrast for T2-weighted imaging, thereby 19



demonstrating that our designed material could be used as a T1–T2 MRI dual-mode contrast agent in vivo. The T1-weighted images indicate that a graded light change in the tumor was shown by the Se-BiOCl/PBA-PDA with the dependent time. In it, the signal-to-noise ratio (SNR) increased from 36.30 to 78.42 (4 h), and it finally returned to 37.32 after 24 h, which proves the metabolism of our material. Meanwhile, the T2 SNR shows that the value decreased from 76.50 to 33.85 at 4 h, and then ended at 64.93 after 24 h. Meanwhile, its distinct damping effect 24 h after injection proves the favorable metabolic capacity and low toxicity of our material. All the results support the practical application of our Se-BiOCl/PBA-PDA agent in living systems. Hela tumor-bearing ICR mice injected with the Se-BiOCl/PBA-PDA nanocomposites were used for scrutinizing the CT contrast in vivo. The left pictures and right pictures in Figure 7b respectively show the top and cross-sectional views of a mouse with the injection of the Se-BiOCl/PBA-PDA solution (5 mg·kg-1). A momentous contrast enhancement was detected from the tumor location (red line circled) 1 h after the injection, following the evident SNR changes from 29.24 to 82.12 that were detected by an animal X-ray CT imaging system and ImageJ analysis software. Here, a favorable result and a low concentration (only 5 mg·kg-1) were simultaneously realized in the comparison of the previous works.51,52,24 The results demonstrated that the Se-BiOCl/PBA-PDA is a feasible in vivo CT contrast agent. Photothermal imaging, a necessary process towards in vivo treatment, offers plentiful key information on the tumor. For instance, it includes the location, the heat 20


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distribution and the amplitude of the variation, which greatly contribute to the guidance of photothermal imaging for further therapy. HeLa tumor-bearing mice were used with the injection of Se-BiOCl/PBA-PDA (80 μL, 0.25 mg·mL-1) for the photothermal imaging characterization. 10 min after the injection (to allow for better uptake), an NIR laser irradiation (10 min, 0.7 W·cm−2) was conducted for another 10 min. The temperature variation is indicated in Figure 7c. It shows only a slight tumor temperature increasing (16.4 °C) for the control PBS+NIR group. On the contrary, a high temperature increase (37.7 °C) happened for the Se-BiOCl/PBA-PDA+NIR group. This indicates a rapid high-contrast NIR thermal imaging could be achieved via the Se-BiOCl/PBA-PDA material in vivo. The temperature changes rapidly than that of the in vitro experiment (29.3 ℃ ) because of the insulation system of mice, which can reduce the heat dissipation leading to a higher temperature.53 Figure 7d digitally shows the temperature change between the control group and the Se-BiOCl/PBA-PDA group. More importantly, the distinct photothermal effect can provide feedback on the tumor temperature and precise imaging, which can exactly guide further practical photothermal therapy. 2.6 Combined Photothermal and Photodynamic Cancer Therapy

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Figure 8. (a) Representative photos of HeLa tumor-bearing mice after PTT and PDT treatments for 20 days. Five groups were used in the experiments including the PBS injection, Se-BiOCl/PBA-PDA

injection,

Se-BiOCl/PBA-PDA

injection

with

NIR

irradiation,

Se-BiOCl/PBA-PDA injection with 532 nm laser irradiation, and Se-BiOCl/PBA-PDA injection 22


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with both NIR and 532 nm laser irradiation. (b) Tumor growth curves for different treatments. The relative tumor volumes were standardized with the initial sizes. (c) Body weight from different mice 20 days after treatments. (d) H&E-stained images of the major organs (heart, liver, spleen, lung and kidney) collected from untreated healthy mice.

Imaging-guided thermal therapy for tumors is widely known because of its significant imaging information, high efficiency, high selectivity, innocuousness, low toxicity and restorability.54 With NIR laser treatments, tumors can be more efficiently cured compared to traditional chemotherapy, attesting its significant application potential for in vivo cancer treatments. The high-efficiency of the PTT properties for our Se-BiOCl/PBA-PDA product has been supported by the above experiments. We used HeLa tumor-bearing mice to test the photothermal therapeutic efficacy in vivo at various treatments, including (1) PBS only (control group), (2) Se-BiOCl/PBA-PDA only, and (3) Se-BiOCl/PBA-PDA + NIR laser irradiation (10 min, 0.7 W·cm−2). The injected dose of the PBS or Se-BiOCl/PBA-PDA is mg·kg-1 (0.25 mg·mL-1, 80 μL) occurred for only one therapy appointment for 10 min. For the following 20 days, we meticulously recorded the tumor situations and took vivid photos of each treated mouse. In Figure 8a, the Se-BiOCl/PBA-PDA + laser group efficiently inhibited the tumor growth with 10 min irradiation for only one treatment after 8 days because of the overt incrustation of the tumors, thereby indicating the benign treatment for the Se-BiOCl/PBA-PDA with NIR irradiation. Conversely, without NIR irradiation, the Se-BiOCl/PBA-PDA or the PBS possessed no perceptible antitumor effects due to the growth of the tumor. All the evidences give

23



rise to highly efficient PTT therapeutic ability originated from Se-BiOCl/PBA-PDA for in vivo antitumor treatments. Synergistic treatment is a combination of several therapeutic modalities, resulting in enhanced effects and cooperative merits. It has various prominent advantages such as a high cure rate, high sensitivity, low recurrence rate and perfect therapeutic effect, and therefore offers a fundamental method for clinical cancer treatments.55-56 Here, we further investigated the combined PDT and PTT treatment therapy for Hela-tumor-bearing mice with the Se-BiOCl/PBA-PDA materials. Two laser irradiation patterns, the (1) 532 nm wavelength and (2) NIR + 532 nm wavelength, were conducted on the tested Hela-tumor-bearing mice. During the therapeutic process, the mice were respectively treated with a 532 nm laser and an NIR laser for only one treatment that lasted for 10 minutes after intraperitoneal narcosis. The curves of the mice tumor volumes (V/V0) in various conditions over 20 days are shown in Figure 8b, which were tested using a Vernier caliper. It verified that the Se-BiOCl/PBA-PDA injection with visible 532 nm irradiation restrained tumor size, and the tumors of the mice started scarring after 12 days of treatment. Meanwhile, the combined PTT and PDT treatment in the Se-BiOCl/PBA-PDA + NIR + 532 nm irradiation condition shows an extremely faster and more prominent inhibitory effect than either the simplex PTT treatment or the PDT treatment due to it having the fastest incrustation in only 2 days (Figure 8a). Meanwhile, Figure 8c shows that the body weights of each group maintained 24


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durative increasing with a survival rate of 100%, suggesting the good biocompatibility of the Se-BiOCl/PBA-PDA. Then, the mice were put down and necropsied after the treatments. The corresponding H&E-stained images of the main tissues and organs from each group is shown in Figure 8d. No clear inflammatory lesions or destroy can be detected in any of the organs treated with different conditions, thus further confirming that there was rare observable toxicity in vivo with the present used dosage. All the experimental results showed a better positive inhibitory effect of Se-BiOCl/PBA-PDA under the combined PTT and PDT treatment, good biocompatibility and its inappreciable side effects.

3. Conclusions In summary, the novel multifunctional PBA-based Se-BiOCl composite nanosheets were synthesized via a surface ion-exchange method. The fabricated nanocomposites showed the desired T1 and T2-weighted MR signals, a high X-ray attenuation ability and strong NIR absorbance, thereby giving rise to strong MR, CT, and IR thermal multimodal imaging. Meanwhile, the outstanding photothermal conversion efficiency, low band-gap, the low toxicity and the high biocompatibility give the nanoagent formidable capabilities for highly synergistic PTT and PDT efficacy in vitro/in vivo. These biocompatible theranostic nanoagents with highly integrated multimodal imaging and combined treatments may have substantial potential for precision therapy and clinical anticancer applications.

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4. Experimental section The preparation of Se-ODE at 0.1 M The Se-ODE was prepared according to a previous report.57 The preparation of Se-BiOCl Precursor The Se-BiOCl precursor was synthesized via a hydrothermal method. The specific steps are listed below. A precursor solution was prepared by mixing BiCl3·6H2O (0.0157 g, 0.05 mmol), 1 mL N-octylamine and 1 mL Oleic acid in 7 mL n-octanol. The mixture was violently stirred for 10 min (1000 r·min-1) at room temperature. Then, 0.5 mL of Se-ODE was gently dropwise added with another stir. Then the mixture was transferred into a Teflon autoclave under nitrogen condition. The Teflon autoclave was enclosed in a stainless autoclave and put in a preheated oven with the reaction condition of 200 °C for an hour. After completed, the Teflon autoclave was immediately cooled down to room temperature. The productions were collected and centrifugated with the speed of 5500 rpm. Finally, it was washed with ethanol for three times. The precursor was kept in ethanol for further synthesis. The preparation of Se-BiOCl/PBA The premade Se-BiOCl nanosheets via cation exchange would be converted partially into Se-BiOCl/PBA. The specific steps are as follows. 0.0422 g of K4Fe(CN)6·3H2O was dispersed into 2 mL deionized water. The mixture was violently stirred for 10 26


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min (1000 r·min-1) at room temperature. Then, the Se-BiOCl precursor (0.05 mmol) that was diluted in 4 mL ethanol was slowly added dropwise into the mixture under stirring. After being stirred 12 hours at 60 °C, the solution was harvested by centrifugation at the speed of 5500 rpm and washed with deionized water three times. The sample was kept in water for further modification. The modification of Se-BiOCl/PBA by PDA The modified method of PDA (polydopamine) is expounded as follows. Briefly, hydrochloric acid (0.1 M) is needed to adjust the pH value of the tris (hydroxymethyl) aminomethane aqueous solution (0.05 M, 5 mL) to 8.5, thus leading to the formation of the Tris buffer (pH 8.5). Then, 0.025 g of dopamine was quickly added into the Tris buffer (pH 8.5) under dark conditions. The mixture was well stirred and kept at a revolving speed of 1000 r·min-1; meanwhile, the Se-BiOCl/PBA aqueous solution was dropwise added into the former solution. After 4 hours of stirring, the mixture was harvested by centrifugation at the speed of 5500 rpm and washed using BSA (4.82 mg·mL -1) to obliterate the extra polydopamine. Our Se-BiOCl/PBA was finally dispersed in moderate BSA for further bio-experimentation. Relaxivity measurements Five samples of Se-BiOCl/PBA-PDA with concentrations varying from 0 to 0.63 mM Bi in the aqueous BSA solution were measured using a 0.47T MesoMR-60 MRI system (Shanghai Niumag Corporation). The detailed calculation method of r1 and r2 27



was brought out from the supporting information. In vitro magnetic resonance imaging The T1 and T2 weighted imaging of the samples in the physiological concentration of bovine serum albumin (BSA, 4.82 mg·mL -1) was tested by a 0.47T MesoMR-60 MRI system. The parameters of the sample are as follows: the TR and TE of the T1 weighted imaging are respectively 380 and 20, and the TR and TE of the T1 weighted imaging are respectively 5000 and 200. Magnetic resonance imaging in vivo The T1-weighted and T2-weighted MR images of mice subcutaneous tumors were acquired using a 7T MRI scanner (Bruker Pharmascan, Germany) before and after the intravenous injection of 200 μL of Se-BiOCl/PBA-PDA nanoparticles at a dosage of 1.36 mg·mL -1 Fe and the intratumor injection of 20 μL (0.136 mg·mL -1). In vitro computed tomography imaging To evaluate the effect of the synthesized materials as a CT contrast agent, five samples of PDA modified Se-BiOCl/PBA were prepared in different concentrations between 0.4 and 6.8 mg·mL

-1

Bi in an aqueous BSA solution and were measured

using a Siemens Inveon PET/CT system (Germany). Computed tomography imaging in vivo For the in vivo CT, the tumor-bearing mice were intratumorally injected with the 28


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Se-BiOCl/PBA NPS for the concentration of 5 mg· mL −1, 200 μL in preference to imaging. Then, the mice were anesthetized and imaged with the parameters of 80 kV, slice thickness of 190 μm, FOV = 48×48 mm2. CT images before and after the injection of Se-BiOCl/PBA-PDA NPS were analyzed using a Sante DICOM Viewer. In vitro photothermal therapy For the in vitro photothermal therapy, HeLa cells (5×105) were seeded into 96-well cell culture plates under 100% humidity and were cultured at 37 C and 5% CO2 for 12 hours. Then, different concentrations (62.5, 125, 250, 500, and 1000 μL·mg-1, diluted in PBS) of the Se-BiOCl/PBA materials were added into the wells of the experimental group for 24 h when the cells were adherent. Untreated Hela cells was the control group. After 24 h, cells in various concentrations of Se-BiOCl/PBA were exposed to an 808-nm NIR laser at a power density of 0.7 W·cm-2 for 10 min for the photothermal therapy treatment. 12 h incubation was carried out followed by MTT assays43 for examing the cell viability. In vitro photodynamic therapy ROS detection: 10 mg of the Se-BiOCl/PBA complex was mixed with 2 mL (0.5 mg·mL-1) of DPBF solution under dark condition, avoiding the metamorphism of DPBF. After ultrasonic treatment of 10 minutes, 532 nm laser was carried out for specific time intervals (30 min and 60 min). DPBF without irradiation was set as blank experiment. Then the absorbance of the supernatant at 410 nm was tested by a 29



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UV-vis spectrophotometer (UV-2550) after centrifugation. The synthesis of Se-BiOCl/PBA nanosheets are based on the previous reports. Evaluation of PTT and PDT in Vivo. For in vivo photothermal therapy and photodynamic therapy, five group tumor-bearing mice (two mice per group) were intravenously injected with PBS (80 μL) or the Se-BiOCl/PBA-PDA NPS (0.5 mg·mL−1, 80 μL) for the PTT and PDT experiments under different test conditions: PBS, Se-BiOCl/PBA-PDA, the Se-BiOCl/PBA-PDA + 808 nm laser (10 min for PTT), Se-BiOCl/PBA-PDA NPS + 532 nm laser (10 min for PDT), Se-BiOCl/PBA-PDA NPS + 808 nm laser + 532 nm laser (10 min for PTT and PDT respectively). During our treatment, an IR thermal imager (Ti25, Fluke, USA) was utilized to measure the temperature of tumors. The tumor volume was about 100 mm3 before used, measured in terms of the following equation: 58 Vtumor = ( a·b2 ) / 2

(4)

Where a is the maximum diameter of the tumor, and b is the minimum. Cell culture HUVECs cells, Hela cells, HCT 116 cells and brain glioma cells were supported by Capital Normal University of college of life and science. All cells were grown in DMEM culture growth medium, supplemented with 10% fetal bovine serum (FBS) 30


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and 1% Penicillin-Streptomycin Liquid. The cells were incubated at 37 °C under a humidified atmosphere containing 5% CO2. Subcutaneous tumor model All animal experiments were carried out in accordance with the protocols evaluated and approved by the ethical committee of Capital Medical University. For the tumor-model establishment, ICR mice were anesthetized and subcutaneous injected with 5 × 106 Hela cells in 100 μL PBS per mouse. When the tumors volume were about 100 mm3 , MR imaging, CT imaging, photothermal therapy and photodynamic therapy were conducted.

Supporting Information Characterizations, chemicals, calculation methods, related parameters of MRI, temperature elevation tests, cytotoxicity assay, EDX, cooling stage of PTT, cell viability, TEM and SEM images, XRD patterns, Cellular uptake, and UV-vis spectrum, as well as the chemical structure of the materials.

Acknowledgement: We are thankful for the financial support of Beijing Natural Science Foundation (No. 2182013), High-level Teachers in Beijing Municipal Universities in the Period of 13th Five–year Plan (IDHT20180517), Capacity Building for Sci-Tech Innovation Fundamental Scientific Research Funds, and Youth Innovative Research Team of Capital Normal University. 31



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J. Radiat. Oncol. Biol. Phys. 1993, 26, 171-179.

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