Facile Laser Modified Synthesis and 808 nm NIR Light Triggered

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Hydrogenated Titanium Oxide Decorated Upconversion Nanoparticles: Facile Laser Modified Synthesis and 808 nm NIR Light Triggered Phototherapy Zhiyao Hou, Kerong Deng, Meifang Wang, Yihan Liu, Mengyu Chang, Shanshan Huang, Chunxia Li, Yi Wei, Ziyong Cheng, Gang Han, Abdulaziz A. Al Kheraif, and Jun Lin Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.8b03762 • Publication Date (Web): 04 Jan 2019 Downloaded from http://pubs.acs.org on January 5, 2019

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Chemistry of Materials

Hydrogenated Titanium Oxide Decorated Upconversion Nanoparticles: Facile Laser Modified Synthesis and 808 nm NIR Light Triggered Phototherapy Zhiyao Hou,†, ‡ Kerong Deng,‡ Meifang Wang,‡ Yihan Liu,§ Mengyu Chang,‡ Shanshan Huang,‡ Chunxia Li,*,ℓ Yi Wei,‡ Ziyong Cheng,‡ Gang Han,& Abdulaziz A. Al Kheraif,# and Jun Lin*,‡,£ Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Xinzao Town, Panyu District, Guangzhou, Guangdong 511436, P. R. China †

State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China ‡

ℓ

College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, P. R. China

§

Petrochina oil & gas pipeline control center, Beijing 100007, P. R. China

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA &

#

Dental Health department College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia

£

School of Applied Physics and Materials, Wuyi University, Jiangmen, Guangdong 529020, P. R. China

ABSTRACT: With multiphoton excited upconversion nanoparticles (UCNPs) as energy transducer, ultraviolet (UV) light responsive titanium dioxide (TiO2) can be triggered indirectly by near infrared (NIR) light for deep-tissue photodynamic therapy (PDT) through the fluorescence resonance energy transfer (FRET) strategy. Compared to pristine TiO2, absorption of hydrogenated black TiO2 (H-TiO2) in visible (Vis) and NIR regions presents a marked improvement in performance, which leads H-TiO2 to enhance its overall activity. Owing to the light absorption enhancement, the single component H-TiO2 can be served as Vis-driven photosensitizers (PSs) for PDT as well as NIR-triggered photothermal agents (PTAs) for photothermal therapy (PTT) simultaneously. Herein, H-TiO2 decorated Nd3+-sensitized-UCNPs (Nd:UCNPs@H-TiO2) nanocomposites (NCs) were synthesized by Nd:Y3Al5O12 (Nd:YAG) pulsed-laser irradiation of Nd:UCNPs@TiO2 precursors in suspended aqueous solution. Pulsed-laser modified synthesis is the optimum selection for preparing H-TiO2 to meet the requirement for dispersion of biomaterials. Nd:UCNPs can convert 808 nm light energy to upconverting green emission for activating the attached H-TiO2 to produce reactive oxygen species (ROS). Meanwhile, H-TiO2 can directly convert 808 nm light energy to hyperthermia together with infrared photothermal and photoacoustic signals. The Nd:UCNPs@H-TiO2 NCs exhibit remarkable photoconversion effects as NIRresponsive theranostic agents for accurate diagnosis and efficient phototherapy of tumors.

INTRODUCTION Phototherapy by near infrared (NIR) light irradiation,1–6 especially the combination of photothermal therapy (PTT)7–9 and photodynamic therapy (PDT),10–15 has attracted great attention owing to deeper penetration, minimal invasiveness and enhanced therapeutic effect.16–19 Due to the overlap between the optical absorption of photosensitizers (PSs) and photothermal agents (PTAs) in a single NIR region, various nanoplatforms could convert NIR light energy into hyperthermia and reactive oxygen species (ROS) simultaneously for cancer treatment.20–24 However, based on whether NIR direct energy conversion process or NIR-toultraviolet (UV)/visible (Vis) fluorescence resonance energy transfer (FRET) mode, such multi-component nanoplatforms generally are constructed by two different functional PSs and PTAs through the various combination and modification. In order to avoid the complicated designs, it is highly desirable to construct a multi-functional nanomaterial with single

component to serve as NIR light triggered PSs and PTAs at the same time for synergistic PDT/PTT treatment.25–27 The optical characteristics of titanium oxide (TiO2) nanomaterials make them useful for functional purposes in photovoltaics, photoelectrochemical cells, and photocatalysts as well as phototoxicity in PDT for tumor inhibition.28–34 However, the wide band gap in TiO2 nanomaterials distributing between 3.2 eV and 3.7 eV is greatly hindered the applications due to irradiation only by UV light.35–38 The UV light accounts for a small proportion of the total solar irradiation, as well as a limited penetration distance in tissues, making nano-TiO2 with a serious limitation of the applications in photocatalysis, solar cell and PDT. Therefore, considerable effort and practice have been made to enhance the light absorption of TiO2 for efficient utilization of the solar energy spectrum, especially to improve the NIR light absorption with nearly half the proportion of solar energy spectrum and the deepest tissue penetration depth. For this purpose, many

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strategies have been used to make nano-TiO2 colorful for better optical absorption in visible light region,39 such as organic dyes surface sensitizing, narrow band gap semiconductor coupling, nonmetal ion or metal ion doping, noble metal depositing and so on.40–46 Compared with above traditional methodologies, hydrogenation is an effective and simple approach in extending the absorption region of TiO2 nanomaterials from UV to NIR light without introducing any other components.47– 49 Since 2011 Chen first reported a universal strategy to obtain black TiO2 nanoparticles (NPs) through hydrogenation,50 various alternative approaches have been developed to hydrogenate crystalline or amorphous TiO2 NPs by thermal treatment under hydrogen atmosphere, chemical vapor deposition, and hydrogen plasma bombardment.51–57 The hydrogenated TiO2 (H-TiO2) samples have been confirmed to show enhanced absorption in Vis/NIR region, which is induced by the localized surface plasmon resonance (LSPR) effect.58–60 Owing to the strong LSPR effect, nanostructured HTiO2 can absorb NIR light energy to produce thermal energy efficiently, thus to be served as high performance PTAs for NIR light induced PTT.61–65 It is worth noting that H-TiO2 samples, which contain the high concentration of charge carriers, also may convert Vis/NIR-light energy into ROS for PDT.66,67 The optical feature of H-TiO2 provides opportunity to construct a synergistic PTT/PDT nanopaltform by a single light-responsive component. Herein, we describe the Nd:YAG laser modified synthesis of H-TiO2 decorated Nd3+-sensitized upconversion NPs and the use for photoacoustic (PA)/infrared photothermal (PT)/upconversion luminescent (UCL) triple-modal imaging guided photothermal/photodynamic synergistic therapy (Scheme 1).

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PSs and NIR-light triggered PTAs simultaneously. The absorption of 808 nm light by Nd:UCNPs@H-TiO2 NCs will occur simultaneously with two energy conversion processes: i) H-TiO2 NPs can directly convert 808 nm light energy to hyperthermia together with infrared photothermal signal; ii) Nd:UCNPs can emit upconverting green light to trigger HTiO2 NPs for generating ROS, as well as the property of upconversion luminescent imaging. Moreover, H-TiO2 NPs with the absorption of 808 nm light can be used to generate photoacoustic (PA) signal with high ultrasonic spatial resolution based on thermo-elastic expansion, which can offer obvious contrasts in optical absorption between exogenous and endogenous environment to get over the limitation of fundamental depth.

RESULTS AND DISCUSSION Synthesis of the Nd:UCNPs@H-TiO2. Nd3+-sensitized core/shell UCNPs with Er3+ upconverting emission and high crystallinity were fabricated by stepwise hot injection synthetic method (Figure 1a,b).68,69 Nd:UCNPs@TiO2 NCs were prepared by a simple hydrothermal process according to our previously studies (Figure1c,d).70 As shown in Figure 2a, the TiO2 shell with crystalline

Scheme 1. Schematic illustration for Nd:UCNPs@H-TiO2 nanocomposites synthesis process as well as the potential bioapplication for multi-modal imaging guided phototherapy via 808 nm laser irradiation.

Figure 1. TEM and HR-TEM images of Nd:UCNPs (a, b) and Nd:UCNPs@TiO2 (c, d).

As the donor, Nd:UCNPs can convert 808 nm light to strong green luminescence for activating the attached PSs by the FRET mode. Meanwhile, Nd:UCNPs also provide conjugation site for crystaling TiO2 NPs on the surface to synthesize core/shell structure Nd:UCNPs@TiO2 nanocomposites (NCs). A pulsed Nd:YAG laser (355 nm) was employed to bombard the crystalline TiO2 NPs for the preparation of monodispersed Nd:UCNPs@H-TiO2 NCs in aqueous solution for the first time. The disorder shell and oxygen vacancy (or Ti3+ species) were introduced to the surface of the H-TiO2 NPs which could absorb visible and NIR light. Therefore, the single component H-TiO2 NPs could perform as dual roles of Vis-light excited

NPs is attracted onto the surface of Nd:UCNPs to form core/shell structure Nd:UCNPs@TiO2 NCs. As the lightinduced production, charge carrier is the basic requirement for semiconductors in the application of photocatalysis.71,72 It has been reported that the photogenerated electrons with UV illumination can be trapped within the band gap of TiO2 at localized states, following by forming a Ti3+ on the surface of TiO2 powders.73,74 Owing to the requirement for dispersion of biomaterials, UV illumination is the optimum selection for preparing H-TiO2 due to avoid samples drying and high temperature calcination. Nd:UCNPs@H-TiO2 NCs were synthesized by 355 nm pulsed-laser interval irradiation of Nd:UCNPs@TiO2 suspension in water (Figure 2b). The diffraction peaks of as-prepared Nd:UCNPs@TiO2 (Figure 2c) can be assigned to TiO2 with anatase phase (JCPDs 21-1272)


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and β-NaYF4 with hexagonal phase (JCPDs 16-0334), which can confirm the successful coating of TiO2 shells. The laserirradiation NCs also presented core/shell morphology and HTiO2 still kept anatase phase after laser irradiation, as confirmed by results of transmission electron microscopy (TEM, Figure 2b) and X-ray powder diffraction (XRD, Figure 2d). The titanium (containing Ti3+ and Ti4+) and neodymium (Nd3+) concentrations were characterized by inductively coupled plasma mass spectrometry (ICP-MS). And coating HTiO2 and doping Nd3+ are determined to be 42 μg and 33 μg in the final Nd:UCNPs@H-TiO2 (200 μg), responsively.

Figure 2. TEM images of Nd:UCNPs@TiO2 (a) and Nd:UCNPs@H-TiO2 (b), inset: the digital photos of Nd:UCNPs@TiO2 and Nd:UCNPs@H-TiO2 dispersing in water, respectively. XRD patterns of Nd:UCNPs@TiO2 (c) and Nd:UCNPs@H-TiO2(d) NCs. The color of NCs dispersion changed from white (illustration of Figure 2a) to steel gray (illustration of Figure 2b), revealing the improvement of absorption in Vis/NIR regions by the laser modified strategy (Figure 3a). Highresolution TEM image (Figure 3b) gave more detailed information of Nd:UCNPs@H-TiO2 at the internal and surface regions. At the core area of Nd:UCNPs, obvious lattice fringes corresponding to hexagonal phase can be also detected. For HTiO2 NPs, in addition to clear lattice fringes belonging to anatase TiO2 phase, amorphous disorder layers surrounding the NPs (marked by white arrowhead) as well as some defects in the crystal lattice (circled by yellow dashed lines) were observed after laser irradiation. With UV pulsed-laser irradiation, photogenerated electrons will make the water molecules reduction to hydrogen gas and the photogenerated holes will make them oxidization to oxygen gas in overall water splitting. During the short interval of irradiation, hydrogen gas could convert surfaced Ti4+ into Ti3+ by introducing H doping, which increase charge carriers concentration.75 The disordered structure surrounding the

Nd:UCNPs@H-TiO2 was deemed to host the possible H2 dopant and made the H-TiO2 present the deep color.76–78 To confirm for the existence of Ti3+ at the H-TiO2, electron paramagnetic resonance (EPR) spectrum was characterized in Figure S1.79 The as-formed H-TiO2 presented an obvious EPR signal ascribing to Ti3+ spins with g-value of 1.988, and no EPR signal was detected from the pristine TiO2 NPs. XPS details of Nd:UCNPs@H-TiO2 were recorded to explore chemical states and presence of Ti ions (Figure S2). As displayed in the XPS spectrum after deconvolution (Figure 3c), the signals of Ti 2p orbit are fitted to four peaks at 457.85 eV (Ti3+ 2p3/2), 458.34 eV (Ti4+ 2p3/2), 463.55 eV (Ti3+ 2p1/2) and 464.35 eV (Ti4+ 2p1/2). The existence of Ti3+ ions can be demonstrated through the EPR and XPS results. As displayed in Figure 3d of O 1s XPS signals, two peaks from 532.51 eV and 531.13 eV arise from OH species on the surface, and another peak of 529.25 eV corresponds to typical signal of Ti– O–Ti.75 More surface OH species from Nd:UCNPs@H-TiO2 can be illustrated based on the O 1s spectra. H doping in the disorder shell of H-TiO2 produced the localized Ti3+states, resulting the enhanced the Vis/NIR light absorption.

Figure 3. Absorption spectra of as-obtained Nd:UCNPs@TiO2 and Nd:UCNPs@H-TiO2 (a) in UV-VisNIR region. HR-TEM image of Nd:UCNPs@H-TiO2 (b). XPS spectra of Nd:UCNPs@H-TiO2 NCs in Ti 2p (c) and O 1s (d) orbits. Photoconversion and bioimaging of the Nd:UCNPs@HTiO2. The absorption performance of H-TiO2 provides an opportunity for utilizing a single 808 nm NIR laser to irradiate Nd:UCNPs@H-TiO2 NCs for simultaneously producing hyperthermia by the direct LSPR effect for PTT and toxic ROS by the indirect FRET mode for PDT (Figure 4a). The Nd:UCNPs@TiO2 and Nd:UCNPs@H-TiO2 exhibit good dispersibility (Figure S3 and S4) and provide upconvertion luminescence in green light regions by 808 nm NIR laser irradiation (Figure S5). The spectral peaks can be derived from radioactive transitions of 2H9/2→4I15/2 (409 nm), 2H9/2→4I13/2 (439 nm), 2H11/2→4I15/2 (522 nm), 4S3/2→4I15/2 (542 nm), 4H →4I 4 4 3+ ions, 9/2 15/2 (655 nm), H9/2→ I11/2 (663 nm) from Er and quantum yield for Nd:UCNPs@H-TiO2 is 0.11%, agreeing to the reported values.80 After Nd:YAG laser modification, the emission intensity of



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Figure 4. Absorption and upconversion emission spectra of Nd:UCNPs@H-TiO2 (a). Absorption spectra of DPBF mixed with Nd:UCNPs@H-TiO2 via 808 nm light excitation for 15 min (b). Photothermal activity of Nd:UCNPs@TiO2 and Nd:UCNPs@HTiO2 NCs (1 mg·mL-1) via 808 nm laser excitation (4.7 W·cm-2) for 20 min (c). Intracellular ROS generation of Nd:UCNPs@HTiO2 co-incubated with Hela cells treated via 808 nm laser excitation (d). All the scale bars are 100 μm. Nd:UCNPs is obviously quenched owing to the emission of visible light absorb by the H-TiO2. Then, H-TiO2 can convert upconversion luminescence energy into chemical energy (ROS) through indirect energy conversion process, and the FRET efficiency is 24.78% between Nd:UCNPs and H-TiO2. Due to react with ROS to cause itself characteristic absorption intensity reduction at 420 nm irreversibly, the 1,3diphenylisobenzofuran (DPBF) was served as chemical probe to check the extracellular ROS production from the Nd:UCNPs@H-TiO2 upon 808 nm laser excitation (Figure 4b). The absorbance of DPBF probe showed no change in control groups containing groups of DPBF alone, 808 nm laser irradiation alone, with just Nd:UCNPs and H-TiO2 under 808 nm light (4.7 W·cm2) irradiation, which can exclude any other effect than FRET from Nd:UCNPs to H-TiO2. Upon irradiation with 550 nm light (4.7 W·cm2) and 808 nm light (4.7 W·cm2) on Nd:UCNPs@H-TiO2 respectively, the intensity of DPBF absorption decreased, indicating that the decreasing on the absorption spectra of DPBF was just due to ROS produced by the H-TiO2. Using 5,5'-dimethylpyrroline-1oxide (DMPO) as spin trap probe, the electron spin resonance (ESR) spectra were utilized to check the production of hydroxyl radicals (∙OH). 1:2:2:1 multiplicity attributing to the characteristic peaks of DMPO-OH adduct were existence in the ESR spectrum of Nd:UCNPs@H-TiO2 by 808 nm NIR light irradiation (Figure S6), suggesting the production of hydroxyl radicals.81,82 And at the same time, H-TiO2 can

transform 808 nm NIR energy into thermal energy via direct energy conversion process. The temperature of Nd:UCNPs@H-TiO2 dispersed solution can rise 28.8 °C during 20 min under 808 nm light excitation, and that of Nd:UCNPs@TiO2 dispersed solution only increase 6.0 °C with 20 min of exposure, as presented in Figure 4c. As shown in Figure S7, the photo-thermal converting efficiency (η) of Nd:UCNPs@H-TiO2 was 17.64% (calculation process in detail is presented in the Supporting Information), which approximated to the reported η value of other PTAs in the literatures.83-85 For checking the intracellular ROS, dichlorofluorescein diacetate (DCFH-DA) with nonfluorescence serving as a fluorogenic label is oxidized to green-fluorescent dichlorofluorescein (DCF) with the production of ROS. None DCF green light signal was detected in all control groups, while the green light signals appear in the Nd:UCNPs@H-TiO2 incubated groups via 808 nm laser excitation (as presented in Figure 4d and S8). All the ROS generating detection (containing extracellular and intracellular results) revealed that Nd:UCNPs@H-TiO2 possess strong photo-conversion ability to generate ROS and hyperthermia via 808 nm NIR laser. In vivo infrared thermal imagings, which are detected with an infrared thermal camera upon 808 nm light excitation, are presented in Figure 5. Intratumoral injection was selected to achieve better imaging effects. The changes of temperature at tumor site in the control, Nd:UCNPs@TiO2 and


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Nd:UCNPs@H-TiO2 groups are recorded by photos at 0, 5, 10, 15 minute during light irradiation. The temperature in tumor rises quickly in Nd:UCNPs@H-TiO2 group with the same irradiating condition, while the changes of temperature in control and Nd:UCNPs@TiO2 groups presented slow and limited performance which is accepted and tolerated by tissue. The images of TEM (a, b) and inverted fluorescence microscopy (c-e) confirmed the effective cellular uptake of Nd:UCNPs@H-TiO2 in vitro (Figure 6). The 808 nm excited up-conversion luminescence (UCL) images of Nd:UCNPs@HTiO2 NCs incubated with Hela cells were taken by an inverted fluorescence microscopy modified with NIR laser, and the green luminescent signals of Nd:UCNPs@H-TiO2 NCs can be detected. Overlaying luminescent images with the nuclei of cells further confirms that the monitored green luminescence islocalized in the cytoplasm of cells. More importantly, the above results demonstrate that

Nd:UCNPs@H-TiO2 can be directly served as biological fluorescence agents without modifying other organic fluorescent molecules. As a kind of noninvasive bio-imaging strategy, photoacoustic (PA) tomography can provide in vivo three-dimensional functional and structural informations of tumor site owing to NIR induce thermal expansion of Nd:UCNPs@H-TiO2 NCs.86,87 To demonstrate the PA property of Nd:UCNPs@H-TiO2 NCs, in vivo three-dimensional PA images of the tumor region were conducted for NCs intratumorally injected mice. For treated with Nd:UCNPs@HTiO2 NCs, obvious PA amplitude for mice was revealed in comparison to the untreated tumor (Figure 7). Such excellent imaging performances (containing infrared thermal, UCL and PA imaging) can demonstrate Nd:UCNPs@H-TiO2 NCs could serve as potential multimodal imaging contrast agents. In vitro phototoxicity and in vivo phototherapy of the Nd:UCNPs@H-TiO2. To estimate cytotoxicity and phototoxicity of Nd:UCNPs@H-TiO2 NCs, the methyl thiazolyltetrazolium (MTT) standard assay was utilized to detect the survival rates of SKOV-3, GES-1 and HeLa cells. Various concentrations of Nd:UCNPs@H-TiO2 NCs being cultured with cells for 24 h protecting from light, no obvious cell death is detected even at the concentration of 800 μg·mL−1 (Figure S9 and S10a). In the phototoxicity experiment, HeLa cells were incubated with non-dark-cytotoxicity concentration of 800 µg·mL-1 NCs at various light irradiation times. In order to investigate the phototoxicity from photothermal effect in Nd:UCNPs@H-TiO2, UCNPs@H-TiO2 NCs were synthesized by replacing Nd:UCNPs with non-Nd3+-doped UCNPs to avoid the generation of ROS. As described in Figure S10b, UCNPs@H-TiO2 NCs lead to an irradiation-dependent

Figure 5. Representative thermal images of mice subjected to 808 nm laser irradiation after injection of saline, Nd:UCNPs@TiO2, and Nd:UCNPs@H-TiO2 NCs.

Figure 6. TEM images of Nd:UCNPs@H-TiO2 NCs incubated with HeLa cells for 6 h (a, b). Inverted florescence microscope images of Nd:UCNPs@H-TiO2 NCs incubated with HeLa cells, images of Hoechst 33324 dyed nuclei (c), images of upconversion emission (d) and overlay images (e), all scale bars are 20 μm.

Figure 7. PA signal intensity of pure water (a) and Nd:UCNPs@H-TiO2 NCs solution (b) at various wavelengths. Inset: PA imaging phantoms in agar gel cylinders. Representative PA images at the tumor region for mice before (c) and after (d) intratumoral injection of Nd:UCNPs@H-TiO2 NCs, respectively. drastic descend in cell survival rates with exposure to 808 nm laser, and the inhibition on HeLa cells is 50.6% after 30 min irradiation. As a contrast, the phototoxicity from PDT and PTT were evaluated by incubating HeLa cells with Nd:UCNPs@H-



TiO2. The Nd:UCNPs@H-TiO2 presented enhanced cell lethality (69.7%) compared to UCNPs@H-TiO2 under the identical irradiation conditions.88 Based on the MTT results, the combination index is calculated to be 0.383 (

Facile Laser Modified Synthesis and 808 nm NIR Light Triggered

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