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Engineered Exosomes-Mediated Near-Infrared-II Region V2C Quantum Dots Delivery for Nucleus-Target Low Temperature Photothermal Therapy Yu Cao, Tingting Wu, Kai Zhang, Xiangdan Meng, Wenhao Dai, Dongdong Wang, HaiFeng Dong, and Xueji Zhang ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.8b07224 • Publication Date (Web): 24 Jan 2019 Downloaded from http://pubs.acs.org on January 25, 2019
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Engineered Exosomes-Mediated NearInfrared-II Region V2C Quantum Dots Delivery for Nucleus-Target Low Temperature Photothermal Therapy Yu Cao, Tingting Wu, Kai Zhang, Xiangdan Meng, Wenhao Dai, Dongdong Wang, Haifeng Dong,* Xueji Zhang* Beijing Advanced Innovation Center for Materials Genome Engineering, University of Science and Technology Beijing, Beijing 100083, P.R. China Beijing Key Laboratory for Bioengineering and Sensing Technology, Research Center for Bioengineering and Sensing Technology, School of Chemistry & Biological Engineering, University of Science & Technology Beijing, Beijing 100083, P.R. China
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ABSTRACT: The limited penetration depth of photothermal agents (PTAs) active in the NIR-I biowindow and the thermo-resistance caused by heat shock protein (HSP) significantly limit the therapeutic efficiency of the photothermal therapy (PTT). To address the problem, we introduce a strategy of the low-temperature nucleus-targeted PTT in the NIR-II region achieving effective tumor killing by combing of the vanadium carbide quantum dots (V2C QDs) PTA and engineered exosomes (Ex) vector. The small fluorescent V2C QDs with good photothermal effect in the NIR-II region were modified with TAT peptides and packaged into Ex with RGD modification (V2C-TAT@ExRGD). The resulting nanoparticles (NPs) exhibited good biocompatibility, long circulation time and endosomal escape ability, and it could target the cell and enter into nucleus to realize low-temperature PTT with advanced tumor destruction efficiency. The fluorescent imaging, photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) capability of the NPs was also revealed. The low-temperature nucleustargeted PTT in NIR-II region provides more possibilities toward successful clinical application of PTT.
KEYWORDS: low-temperature PTT, nucleus-target, exosomes, NIR-II biowindow
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Photothermal therapy (PTT) utilizing near-infrared (NIR) laser radiation for tumor hyperthermia ablation mediated by photothermal agents (PTAs) has been extensively explored and attracted tremendous attention in recent years.1-4 Owing to the high temporal and spatial control of the local heat, PTT exhibits less the adverse side effects compared with conventional cancer treatment approaches.5-7 However, to achieve efficient tumor-tissue ablation, high temperature over 50 oC is required to overcome the thermo-resistance caused by heat shock protein (HSP), which may result in heating damage of normal organs nearby the tumor due to the nonspecific heating and heat diffuse.8-10 Additionally, most of the PTAs are active in the first NIR (NIR-I) region, and the limited penetration depth of the laser significantly affect the therapy efficiency.11,12 Alternatively, the second NIR (NIR-II) biowindow (1000-1350 nm) exhibited more efficient tissue penetration compared to the NIR-I biowindow (7501000 nm).13-15 The maximum permissible exposure (MPE) for skin exposure at NIR-II region is 1 W/cm2, which is much higher than that of 0.33 W/cm2 at NIR-I region (American National Standard for Safe Use of Laser, ANSI Z136.1-2007).16,17 Therefore, exploration of advanced PTAs active in the NIR-II biowindow for low-temperature PTT holds potential for the improved anti-tumor therapeutic efficiency. As a family of two-dimensional (2D) nanomaterials, MXenes are composed of transition metal carbides, and either nitride or carbonitrides, which share a general formula of Mn+1Xn (n = 1, 2, 3), where M represents an early transition metal and X is a carbon or nitrogen.18-20 Since the first MXene of Ti3C2 was reported in 2011,21 MXenes have revealed beneficial application in energy evolution, catalysis and sensing due to high energy storage capability and sensitive surface termination.22,23 Recently, nanosized MXenes have displayed great promise for biomedical application owing to some attractive properties such as natural hydrophily, good biocompatibility, readily functionalized and strong absorption in the NIR region.24,25 Although many calculations have theoretically predicted that several of MXenes have attractive properties,26 some of them have been rarely reported, such as magnetic MXenes and luminescent MXene QDs. Therefore, more efforts should be devoted to exploration of other scenarios of MXenes with specific properties to extend its biomedical application.
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In this work, a type of ultra-small 2D vanadium carbide quantum dots (V2C QDs) was synthesized, which exhibited intense photothermal effect at NIR-II biowindow for PTT and good capability for fluorescent imaging, photoacoustic imaging and magnetic resonance imaging (MRI) (Scheme 1). Effective and specific delivery of PTAs into target cell, in particularly, organelle in the cell is crucial for efficient PTT treatment of cancer.27,28 Considering that the nucleus contains most of the intracellular genetic materials, which is the most important organelle in the cell, we modified the V2C QDs with cell nucleus-target TAT peptides (V2C-TAT)29,30 and encapsulated the V2C-TAT QDs into endogenous exosomes (Ex)31,32 engineered with cell target Arg-Gly-Asp (RDG) peptide to obtain the cancer cell membrane & nucleus organelle dual-target system (V2C-PEG-TAT@Ex-RGD). Ex are lipid membrane vesicles with diameter of 50-150 nm which released by cells.31 They have attracted much attention in recent years because they involved transporting molecules like protein, lipids and RNAs and acted as intercellular communication roles.33 Furthermore, the good biocompatibility, nonimmunogenicity, and long blood circulation ability resulted from their endogenous origin and the appropriate size made exosomes outstanding nano-platforms for drug and gene delivery compared to traditional lipid layers.34 The Ex exhibits the properties of shielding from the immune system for long circulation times and full biocompatibility, and the RGD modification endow it with satisfactory cancer-targeting ability while small-size V2C-TAT QDs could readily enter into the cell nucleus to destroy the genetic substances directly for low-temperature PTT. With the irradiation by a 1064 nm laser at the power density of 0.96 W cm-2, the V2CTAT@Ex-RGD caused significant cell necrosis at ultra-low temperature of ≈ 45 oC in vitro. In regard to the in vivo anti-cancer treatment, efficient tumor accumulation of the V2C-TAT@Ex-RGD was achieved due to the long blood circulation time and good cancer cell target ability, leading to attractive anti-tumor therapeutic efficiency. Meanwhile, multi-model tumor in vivo imaging capability was also demonstrated. Therefore, the as-prepared V2C-TAT@Ex-RGD realized multimodal imaging-guided cell nucleus-targeted PTT in NIR-II biowindow at low-temperature, indicating good potential for further biomedical clinical applications.
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Scheme 1. A) Preparation procedure of the V2C-TAT@Ex-RGD. B) Schematic diagram of cancer cell membrane & nucleus organelle dual-target V2C-TAT@Ex-RGD nanoagent for multimodal imaging-guided PTT in NIR-II biowindow at low-temperature.
RESULTS AND DISCUSSION Synthesis and Characterization of V2C-TAT@Ex-RGD. In order to synthesize the 2D V2C QDs, 2D V2C nanosheets were first synthesized through a chemical exfoliation process as previous reports. As shown in Figure S1A, the V2AlC powder precursor (Figure S1B) was first etched with HF to remove the Al layer and then intercalated in the TPAOH solution to exfoliate into V2C nanosheets. The V2C QDs were then prepared through a facile hydrothermal method using the resulting V2C nanosheets. It was obvious that V2C bulk after HF etching was well stacked as uniform sheets (Figure S1C). After TPAOH intercalation and exfoliation, ultrathin V2C nanosheets were generated as shown in the transmission electron microscopy (TEM) image (Figure S1D). The Fourier transform (FFT) pattern showed that the hexagonal crystalline structure of the V2C nanosheets. The atomic force microscopy (AFM) images (Figure S1E,F) indicated that the average thickness of the V2C nanosheets was
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1-1.5 nm. The 2D ultrathin and small V2C QDs were synthesized after the hydrothermal process. Figure 1 A showed the typical TEM images of the monodispersed V2C QDs with mean lateral size of about 16 nm. The high-resolution TEM (HRTEM) and the FFT pattern depicted that the V2C QDs also possessed typical hexagonal structure and the corresponding original SAED pattern confirmed the preserved hexagonal symmetry structure (Figure 1A inset and Figure 1B). The average thickness of the as-prepared V2C QDs was examined to be 0.8 nm, revealing that most of the V2C QDs were singlelayer atomic crystals (Figure S1G). As shown in Figure 1C, typical X-ray diffraction (XRD) pattern of V2AlC exhibited the main diffraction peaks located around 13.32o, 41.04o, 55.39o and 63.58o in agreement with PDF#29-0101. After HF etching the peak at 41.27° was obvious weakened, the new peaks located at 11.78o and 43.18o indicating the successful fabrication of layered V2C.35 The V2C QDs showed broadened and lowintensity XRD peaks at 41.27° and 43.18o compared to the layered V2C, which was resulted from the small size. The high-resolution XPS spectra of V 2p for the V2C QDs presented two peaks at 519.7 and 512.1 assigned to Vδ+ (V-C bond) where 0
