27May2020

Nano-Micro Letters

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Antiangiogenesis-Combined Photothermal Therapy in the Second Near-Infrared Window at Laser Powers below the Skin Tolerance Threshold

Jian-Li Chen¹, Han Zhang², Xue-Qin Huang¹, Hong-Ye Wan¹, Jie Li¹, Xing-Xing Fan¹, Kathy Qian Luo³, Jinhua Wang⁴, Xiao-Ming Zhu^1,, Jianfang Wang^2,	Abstract \| Support Info Full Text Html PDF w/ Links Export Citation Figures
¹State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau SAR, People’s Republic of China ²Department of Physics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, People’s Republic of China ³Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, People’s Republic of China ⁴Beijing Key Laboratory of Drug Targets Research and New Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China +Show more
Nano-Micro Lett. (2019) 11: 93
First Online: 31 October 2019 (Article)
DOI:10.1007/s40820-019-0327-4
*Corresponding author. E-mail: xmzhu@must.edu.mo (X.-M. Zhu); jfwang@phy.cuhk.edu.hk (J. F. Wang)

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(Au NBP)@TiO2 nanostructures. a TEM image. b Extinction spectra of the uncoated NBP and NBP@TiO2 nanostructures in aqueous solutions. c HAADF-STEM and elemental mapping images of a single NBP@TiO2. The rightmost image is the overlapped image of the Au, Ti, and O elemental maps. d Temperature rise curves of the NBP@TiO2 nanostructures (2 mL, 120 μg mL–1) acquired under 1064-nm laser irradiation at different optical powers for 20 min. e Variation of the reached plateau temperature with the laser power. f Temperature decay curve. The data points (red circles) were measured during the cooling process after the NBP/TiO2 nanostructure solution (2 mL, 120 μg mL–1) was irradiated with a 1064-nm laser at 1.0 W for 20 min. The blue line was obtained from fitting
NBP@TiO2 nanostructures for CA4P loading. a Molecular structure of CA4P. b LC-MS chromatograms of CA4P for the initial CA4P solution and the supernatant solution after drug loading. c Desorption of CA4P in phosphate solutions and H2O after 12-h incubation. d pH- and time-dependent CA4P release profiles for the CA4P-loaded NBP@TiO2 nanostructures. The CA4P-loaded NBP/TiO2 nanostructures (120 μg Au) were dispersed in phosphate solutions (2 and 12 mM PO43–, 1 mL), citrate buffer (20 mM, pH 4.5, 1 mL) or H2O (1 mL) and incubated at 37 ℃. The CA4P release percentage was calculated by measuring the drug concentration in the supernatant. The shown data represent the mean ± S.E.M.. ***P < 0.001
PTT in A549 cells. a Effect of the NBP@TiO2 nanostructures at different concentrations on the viability of A549 cells. b Cell viabilities of A549 cells upon PTT at different optical power densities. c Calcein AM staining of the cells treated by PTT at different optical power densities as in b. A549 cells were incubated with the NBP@TiO2 nanostructures (100 μg-Au mL‒1) for 24 h, followed by 1064-nm laser irradiation at 0.4‒0.9 W cm‒2 for 5 min. The live cells were stained with green fluorescence by calcein AM. d Synergistic enhancement of the cytotoxicity of the CA4P-loaded NBP@TiO2 nanostructures by combined chemo-therapy and PTT. e Calcein AM staining of the A549 cells after the different therapy treatments as in d. A549 cells were treated with the CA4P-loaded NBP@TiO2 nanostructures (15 nM CA4P, 100 μg-Au mL‒1) or together with 1064-nm laser irradiation at 0.7 W cm‒2 for 5 min. The data shown represent the mean ± S.E.M.. **P < 0.01, ***P < 0.001
PTT-enhanced cytotoxic effect of the CA4P-loaded NBP@TiO2 nanostructures in HUVECs. a MTT assay. b Calcein AM staining. The HUVECs were treated with the CA4P-loaded NBP@TiO2 nanostructures (7 nM CA4P, 12 μg-Au mL–1) for 24 h, and then exposed to 1064-nm laser irradiation at 1.8 W cm–2 for 3 min. The assay and staining were performed after further incubation for 24 h. The shown data represent the mean ± S.E.M.. ***P < 0.001. c Synergistic disruption of tubulin in the HUVECs by the combined therapy. Immunofluorescent staining with β-tubulin (red) was performed on the HUVECs treated with the CA4P-loaded NBP@TiO2 nanostructures (3 nM CA4P, 12 μg-Au mL–1) in conjunction with 1064-nm laser irradiation (1.3 W cm–2, 3 min). The nuclei were stained with Hoechst 33342 (blue). In the control group, the tubulin shows a filamentous morphology. CA4P treatment induces a disordered change of tubulin and rounding of the cell morphology. The combined treatment further disrupts tubulin distribution and cell morphology (indicated by the white arrow)
Inhibition of the endothelial tube formation by the combined chemo-photothermal therapy using the CA4P-loaded NBP@TiO2 nanostructures. a Effect of PTT at different laser power densities (1.8–2.5 W cm–2) on the HUVEC tube formation. b Relative tube areas estimated from a. c Relative tube lengths estimated from a. d PTT-enhanced antiangiogenesis of the CA4P-loaded NBP@TiO2 nanostructures. e Relative tube areas estimated from d. f Relative tube lengths estimated from d. The HUVECs were seeded in a 48-well plate that was pre-coated with Matrigel and then treated with the NBP@TiO2 nanostructures (12 μg-Au mL–1) or the CA4P-loaded NBP@TiO2 nanostructures (7 nM CA4P, 12 μg-Au mL–1), followed by 1064-nm laser irradiation for 3 min. The tubular structures were visualized with calcein AM staining, and the relative tube areas and lengths were calculated. The as-shown results are the means ± S.E.M.. *P < 0.05, **P < 0.01, ***P < 0.001
In vivo PTT. a Infrared thermal images of the A549-bearing mice. b Tumor temperature change curves extracted from a. The A549-bearing mice intratumorally injected with the NBP@TiO2 nanostructures were subjected under 1064-nm laser irradiation at 0.4 or 0.8 W cm–2 for 5 min. The mice without the administration of the NBP@TiO2 nanostructures were subjected to the laser irradiation as control. The as-shown results are the means ± S.E.M.. c Photographs of the tumor captured at 48 h after PPT at 0.4 or 0.8 W cm–2.
In vivo antitumor effect. a Typical three-dimensional reconstructed CT image of an A549 tumor-bearing mouse after intratumoral injection with the NBP@TiO2 nanostructures. The arrow head points to the tumor site. b Tumor growth in the different groups at different time points. For the laser irradiation treatment groups, the mice were intratumorally injected with the NBP@TiO2 (25 mg-Au kg–1) or the CA4P-loaded NBP@TiO2 nanostructures (25 mg-Au kg–1, 2 mg CA4P kg–1). At 24 h after the injection, the mice were subjected to 1064-nm laser irradiation (0.4 W cm–2, 5 min). The as-shown results are the means ± S.E.M.. ***P < 0.001, n = 6. c Immunofluorescence images. The immunofluorescence staining of the tumor sections was performed to image the tumor micro-vessel density with anti-CD31 (green) and to evaluate cell proliferation with anti-Ki67 (red) at the tumor center. The nuclei were stained with Hoechst 33342 (blue)

Abstract

Photothermal agents with strong light absorption in the second near-infrared (NIR-II) region (1000–1350 nm) are strongly desired for successful photothermal therapy (PTT). In this work, titania-coated Au nanobipyramids (NBP@TiO₂) with a strong plasmon resonance in the NIR-II window were synthesized. The NBP@TiO₂ nanostructures have a high photothermal conversion efficiency of under 1064-nm laser irradiation. They are also capable for loading an anticancer drug combretastatin A-4 phosphate (CA4P). In vitro PTT studies reveal that 1064-nm laser irradiation can efficiently ablate human lung cancer A549 cells and enhance the anticancer effect of CA4P. Moreover, the CA4P-loaded NBP@TiO₂ nanostructures combined with PTT induce a synergistic antiangiogenesis effect. In vivo studies show that such CA4P-loaded NBP@TiO₂ nanostructures under mild 1064-nm laser irradiation at an optical power density of 0.4 W cm^–2, which is lower than the skin tolerance threshold value, exhibit a superior antitumor effect. This work presents not only the development of the NBP@TiO₂ nanostructures as a novel photothermal agent responsive in the NIR-II window but also a unique combined chemo-photothermal therapy strategy for cancer therapy.

Keywords

Antiangiogenesis therapy; Core@shell nanostructures; Gold nanobipyramids; Photothermal therapy; Plasmon resonance

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