Anti-EGFR Peptide-Conjugated Triangular Gold Nanoplates for

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Biological and Medical Applications of Materials and Interfaces

Anti-EGFR Peptide Conjugated Triangular Gold Nanoplates for Computed Tomography/Photoacoustic Imaging Guided Photothermal Therapy of Non-Small Cell Lung Cancer Ying Zhao, Wenfei Liu, Ying Tian, ZhenLu Yang, Xiaofen Wang, Yunlei Zhang, Yuxia Tang, Shuang Zhao, Chunyan Wang, Ying Liu, Jing Sun, Zhaogang Teng, Shouju Wang, and Guangming Lu ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b19013 • Publication Date (Web): 03 May 2018 Downloaded from http://pubs.acs.org on May 4, 2018

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ACS Applied Materials & Interfaces

Anti-EGFR Peptide Conjugated Triangular Gold Nanoplates for Computed

Tomography/Photoacoustic

Imaging

Guided

Photothermal Therapy of Non-Small Cell Lung Cancer Ying Zhao,† Wenfei Liu,# Ying Tian,† Zhenlu Yang†, Xiaofen Wang,† Yunlei Zhang,† Yuxia Tang,† Shuang Zhao,§ Chunyan Wang,† Ying Liu,† Jing Sun,† Zhaogang Teng,*,†,‡ Shouju Wang,*,† and Guangming Lu*,†,‡

†

Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University,

Nanjing, 210002, P.R. China.

#

Department of Respiration, Nanjing First Hospital, Nanjing Medical University, 210029, Jiangsu,

P. R. China

‡

State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and

Chemical Engineering, Nanjing University, Nanjing, 210093, Jiangsu, P. R. China

§

Department of Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing,

210002, P.R. China.

ABSTRACT: Non-small cell lung cancer (NSCLC) is difficult to cure since the high recurrence rate and the side effects of current treatments. It is urgent to develop a new treatment that is safer and more effective than current treatments against NSCLC. Herein, we constructed anti-EGFR peptide conjugated PEGylated triangular gold nanoplates (TGN-PEG-P75) as a targeting photothermal therapy (PTT) agent to treat

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NSCLC under the guidance of computed tomography (CT) and photoacoustic imaging (PAI). The surface of TGNs is successfully conjugated with a novel peptide P75 that has the specific affinity with epidermal growth factor receptor (EGFR). It is found that the EGFR is overexpressed in NSCLC cells. The TGN-PEG-P75 has uniform edge length (77.9 ± 7.0 nm) and neutrally charged surface. The cell uptake experiments demonstrate remarkable affinity of the TGN-PEG-P75 to high EGFR expression cells than low EGFR expression cells (5.1-fold). Thanks to the strong near-infrared (NIR) absorbance, high photothermal conversion efficiency and the increased accumulation in tumor cells via the interaction of P75 and EGFR, TGN-PEG-P75 exhibits 3.8-fold superior therapeutic efficacy on HCC827 cells than TGN-PEG. The in vivo CT/PA dual-modal imaging of the TGN-PEG-P75 is helpful in selecting the optimal treatment time and providing real-time visual guidance of PTT. Furthermore, treatments on HCC827 tumor-bearing mouse model demonstrate that the growth of NSCLC cells can be effectively inhibited by the TGN-PEG-P75 through PPT, indicating the great promise of the nanoplatform for treating NSCLC in vivo. KEYWORDS: non-small cell lung cancer, photothermal therapy, epidermal growth factor receptor, triangular gold nanoplates, computed tomography, photoacoustic imaging 1. INTRODUCTION


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Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer, which is the leading cause of cancer deaths worldwide.1 Due to the complications and contraindications of surgery, lots of NSCLC patients rely on non-surgical therapeutics. However, the existing non-surgical therapeutics (radiotherapy, radiofrequency ablation, etc.) have many side effects, such as radiation pneumonitis, pneumothorax and pleural effusion.2 Therefore, there is a great demand for a new non-surgical therapeutic strategy for NSCLC. Currently, there are several clinical trials using photosensitizers (such as porfimer sodium, mono-L-aspartyl chlorine e6, etc.) to perform transbronchial photodynamic therapy (PDT) for lung cancer,3-5 suggesting that localized phototherapy may be a noninvasive method for NSCLC tumor-specific ablation with no radiation. Photothermal therapy (PTT) has been an emerging method of phototherapy for tumors in recent years.6-11 Compared with PDT, PTT has no systemic phototoxicity and represents robust oxygen-independent therapeutic efficacy.12-14 Previous work has reported the feasibility of using nanoparticles (NPs) as PTT agents for the treatment of lung cancer,15-16 but there are still considerable limitations, such as lack of targeting, the single modality of imaging and the potential toxicity, which may hinder clinical potential. The selection of tumor-specific receptors and the corresponding target components is pivotal for improving the efficiency and reducing the toxicity of tumor-specific PTT. Epidermal growth factor receptor (EGFR) is overexpressed in approximately 80% of NSCLC,17-19 making it a promising receptor for this cancer.19 Studies published in



the last few years suggest that the surface modification with EGFR antibody can enhance the accumulation of nanoparticles (NPs) in tumor cells.20-21 However, most antibodies are difficult and expensive to produce and have low tumor tissue penetrating ability due to their relatively large size.22 The short peptide may be a good substitute because of the easy synthetic method, the superior stability, the enhanced biological activity and the excellent affinity to its receptor.23 Very recently, a novel EGFR-targeting peptide, P75 (sequence: KYFPPLALYNPTEYFY), has been screened out from a one-bead-one-compound (OBOC) library and showed a significantly high affinity for high EGFR expression tumor cells.24 However, the potential for the use of this peptide as a target component to increase the accumulation of NPs and enhance the therapeutic efficacy of PTT to NSCLC has not as yet been reported. Herein, we constructed P75-modified triangular gold nanoplates (TGN-PEG-P75) to target EGFR overexpressed NSCLC both in vitro and in vivo. The composition of this nanoplatform and its applications in computed tomography (CT) and photoacoustic (PA) imaging-guided PTT is depicted in Scheme 1. Triangular gold nanoplates (TGNs) were selected because of their small size (1.0 cm in Diameter. Clin Cancer Res. 2010, 16, 2198-2204. (5) Diaz-Jimenez, J. P.; Martinez-Ballarin, J. E.; Llunell, A.; Farrero, E.; Rodriguez, A.; Castro, M. J. Efficacy and Safety of Photodynamic Therapy versus Nd-YAG Laser Resection in NSCLC with Airway Obstruction. Eur Respir J. 1999, 14, 800-805. (6) Jiang, X.; Zhang, S.; Ren, F.; Chen, L.; Zeng, J.; Zhu, M.; Cheng, Z.; Gao, M.; Li, Z. Ultrasmall Magnetic CuFeSe2 Ternary Nanocrystals for Multimodal Imaging Guided Photothermal Therapy of Cancer. ACS Nano. 2017, 11, 5633-5645. (7) Zhao, X.; Yang, C. X.; Chen, L. G.; Yan, X. P. Dual-stimuli Responsive and Reversibly Activatable Theranostic Nanoprobe for Precision Tumor-Targeting and Fluorescence-guided Photothermal Therapy. Nat Commun. 2017, 8, 14998. (8) Shi, S.; Liu, Y.; Chen, Y.; Zhang, Z.; Ding, Y.; Wu, Z.; Yin, J.; Nie, L. Versatile pH-response Micelles with High Cell-Penetrating Helical Diblock Copolymers for Photoacoustic Imaging Guided Synergistic Chemo-Photothermal Therapy. Theranostics. 2016, 6, 2170-2182. (9) Wang, S.; Weng, J.; Fu, X.; Lin, J.; Fan, W.; Lu, N.; Qu, J.; Chen, S.; Wang, T.; Huang, P. Black Phosphorus Nanosheets for Mild Hyperthermia-Enhanced Chemotherapy and Chemo-Photothermal Combination Therapy. Nanotheranostics. 2017, 1, 208-216. (10) Xia, Y.; Wu, X.; Zhao, J.; Zhao, J.; Li, Z.; Ren, W.; Tian, Y.; Li, A.; Shen, Z.; Wu, A. Three Dimensional Plasmonic Assemblies of AuNPs with an Overall Size of



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Anti-EGFR Peptide-Conjugated Triangular Gold Nanoplates for

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