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  • br Herein we reported a strategy of

    2020-08-18


    Herein, we reported a strategy of using drug itself to stabilize BP. Platinum-based drugs are widely used anticancer agents in clinical, including the most representative cisplatin and oxaliplatin [41–43]. After enter the cells, they would hydrolyze into active species and form intrastrand cross-linking with DNA Vincristine through coordination, inducing apoptosis of cancer cells [41]. Furthermore, these active species were also reported to coordinate with electron-rich carboxyl polymer and self-assemble into stable nanocarriers for enhanced antitumor efficacy [44–46]. We hypothesized that the active species of oxaliplatin and cisplatin [(1,2-diaminocyclohexane)platinum(II), DACHPt; Pt(NH3)2] would also coordinate with the lone pair electrons-containing BP na-nosheets and improve their stability (Fig. 1A and S1). Thus this novel strategy of using drug itself to stabilize BP, would not only evade the potential clinical application risks, but also construct stable BP-based drug delivery system for combined photothermal and chemo cancer therapy.
    2. Materials and methods
    The bulk BP was purchased from Smart-Elements and stored in a dark Ar glovebox. DACHPtCl2, cisplatin and 1-Methyl-2-pyrrolidinone (NMP) were all purchased from Sigma-Aldrich (St. Louis, MO, USA). AgNO3 were purchased from J&K Chemical (Shanghai, China). PEG2k-NH2 was purchased from Shanghai 9i Technology Co., Ltd. All other chemicals and reagents were commercially available and used as re-ceived. Human cervical cancer cell line HeLa, human liver cancer cell line HepG2 and human non-small cell lung cancer cell line A549 were purchased from American Type Culture Collection (ATCC, Rockville, MD).
    2.2. Synthesis and characterization
    2.2.1. Synthesis of BP nanosheets
    The BP nanosheets were synthesized using a simple liquid exfolia-tion of corresponding bulk BP sample [21]. Firstly, the bulk BP was  Chemical Engineering Journal 375 (2019) 121917
    grinded in a mortar to get BP powder. Then the BP powder was sus-pended in NMP (2 mg/mL) and sonicated in ice water with a sonic tip for 6 h (Amplifier: 25%, On/Off cycle: 5 s/5 s). The resulting dispersion was centrifuged at 3500 rpm for 10 min to get rid of the unexfoliated bulk BP and the supernatant containing BP nanosheets was carefully collected. Afterwards, the supernatant was centrifuged at 9000 rpm for 10 min and the precipitate was redispersed in NMP for store or DI water for further use.
    2.2.2. Synthesis of micro-sized BP sheets
    The micro-sized BP sheets were synthesized according to other’s reported method [39]. Briefly, the BP powder was suspended in NMP (2 mg/mL) and sonicated in an ultrasonic ice bath at 40 kHz frequency and 80% power for 4 h to conduct liquid exfoliation. Then the solution was centrifuged at 2000 rpm for 10 min to remove the unexfoliated bulk BP and the supernatant containing the micro-sized BP sheets were collected. Afterwards, the supernatant was obtained by centrifuging at 7000 rpm for 10 min and the precipitate was vacuum-dried for further use.
    DACHPt solution was prepared according to our previous work and other reported references [44,46]. DACHPtCl2 (5 mM) was dissolved in H2O and mixed with silver nitrate (molar ratio: AgNO3/DACHPt = 2). The reaction was carried out in the dark at room temperature for 24 h. Then AgCl precipitate generated after the reaction was removed by centrifuging at 3000 rpm for 5 min. The remaining supernatant was purified with a 0.22 μm filter and freeze-dried for further use. Cisplatin was also treated with the similar method to remove chlorine and obtain Pt(NH3)2 solution.
    A certain amount of DACHPt was mixed with the BP nanosheets in NMP (2 mg/mL of BP) in the dark under stirring overnight. After cen-trifuging at 9000 rpm for 10 min, the precipitate BP/DACHPt was col-lected for further use. BP/Pt(NH3)2 was also prepared similarly. BP/ DACHPt-PEG was prepared by mixing BP, DACHPt and PEG2k-NH2 (weight ratio of BP/PEG as 1) in NMP under stirring overnight. After centrifuging at 9000 rpm for 10 min, the precipitate BP/DACHPt-PEG was freeze-dried for further experiments.
    Drug loading efficiency was defined as the weight ratio of element DACHPt to BP. The concentration of DACHPt and BP in various BP/ DACHPt (DACHPt/BP feeding weight ratio = 0.5, 1, 2, 3, 4, 5, 6 or 8) were calculated after quantifying their concentration of Pt and P ele-ments by Inductively coupled plasma mass spectrometry (ICP-MS, Thermoscientific, USA).
    2.2.6. Characterization of BP/DACHPt
    Transmission electron microscopy (TEM) and scanning transmission electron microscopy (STEM) images were acquired using FEI Tecnai G2 F30 transmission electron microscope. Atomic force microscopy (AFM) was carried out on Bruker Dimension® Icon™ microscope. The optical images of the Si/SiO2 substrates were acquired on the Keyence VHX-2000C optical microscope. Raman spectroscopy was conducted on a Horiba LabRam HR800 high-resolution confocal raman microscope with a 532 nm laser as the excitation light source. X-ray diffraction (XRD) were performed on a Philips X’Pert Pro Super diffractometer with Cu Kα radiation (λ = 1.54178 Å). X-ray photoelectron spectro-scopy (XPS) was performed using a Kratos Axis Ultra DLD spectrometer with Al Kα radiation (1486.6 eV photons, 150 W). UV–Vis-NIR ab-sorption spectra were obtained on a Cary 5000 spectrophotometer (Agilent) at room temperature.