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  • KPT-185 br PEITC Fig S a The corresponding morphology of

    2020-08-18

    
    PEITC (Fig. S10a). The corresponding morphology of RBCs was shown in Fig. S10b–f, which could be found that a few RBCs have a morpho-logic change that was due to the influence of DOX. APTT, PT and TT time (Fig. S10g–i) of BPNs-PDA-PEG-PEITC/DOX were close to the control which indicated that the encapsulation of DOX have no effect on in vitro clotting time.
    BPNs was an ideal drug nanocarrier and had a high drug loading efficiency due to its high surface area. Because BPNs possess negative charge, the encapsulation of positively charged small molecule drugs into BPNs could be accomplished through electrostatic interaction. The process of drug encapsulation was accomplished before the coating of PDA. Herein, DOX was selected as positively charged drug model to study the loading and release behaviors of BPNs-PDA-PEG-PEITC/DOX. UV–vis spectra were used to demonstrate the successful encapsulation of DOX into BPNs-PDA-PEG-PEITC. As shown in Fig. 4a, the specific KPT-185 peak of the DOX (480 nm) was observed in the UV–vis spectra of BPNs-PDA-PEG-PEITC/DOX but not in BPNs-PDA-PEG-PEITC [64]. These results indicated the successful loading of the drug into the BPNs-PDA-PEG-PEITC. The drug loading capacity of DOX was 233%.
    Fig. 2. (a) UV–vis-NIR absorption spectra of BPNs-PDA-PEG-PEITC dispersions with different concentrations. (b) Photothermal responses of BPNs-PDA-PEG-PEITC with different concentrations exposed with 808 nm NIR laser (1.2 W/cm2) for 5 min. (c) Thermal images of BPNs-PDA-PEG-PEITC with different concentrations exposed with 808 nm NIR laser (1.2 W/cm2) for 5 min. (d) Change of temperature of BPNs-PDA-PEG-PEITC dispersion (100 µg/mL) under five cycles of continuous irradiation. (e) Photothermal responses of BPNs-PDA-PEG-PEITC before and after a week (stored at 4 °C) exposed with 808 nm NIR laser (1.2 W/cm2) for 5 min. (f) Linearity curves fitted from the temperature cooling time vs −ln(θ) of BPNs-PDA-PEG-PEITC. (g) ESR spectra of BPNs-PDA-PEG-PEITC, BPNs-PDA-PEG-PEITC + NaN3, and blank. (h) Absorption spectra of the DPBF with BPNs-PDA-PEG-PEITC under 660 nm laser irradiation at different time. (i) Normalized absorbance of the DPBF in the presence of BPNs-PDA-PEG-PEITC exposed 660 nm laser irradiation.
    Fig. 4b showed the drug release behaviors of the BPNs-PDA-PEG-PEITC/DOX in PBS at different pH. In PBS at pH = 7.4 for 24 h, the release cumulative amounts was 11.2%. However, at pH = 6.8 the re-lease rate was faster and the release cumulative amounts reached to 17.7%. When pH value of release midea was 5.0, the fastest release could be found and the release cumulative amounts could achieve 31.8%. Two factors lead to the pH-sensitive release behaviors. First, the dissociation of the PDA layer from the surface of the BPNs-PDA-PEITC-PEG/DOX under acidic medium could accelerate the drug release rate [7]. The existence of PDA layer could hamper the release of DOX. Second, the enhanced solubility of DOX could be at acidic medium also accelerate the drug release [65]. As everyone knows, pH value in normal tissue is nearly 7.4 and in tumor microenvironments is 6.0–6.8 and in the endosomes or lysosomes of tumor cells is 4.0–6.0 [66]. Therefore, the leakage of chemotherapy drug could be prevented in normal tissue during the blood circulation which could reduce the side effect of drug. In addition, the NIR-induced release behaviors of BPNs-PDA-PEG-PEITC/DOX were also investigated. The BPNs-PDA-PEG-PEITC/DOX solution was irradiated with 808 nm laser (1.2 W/cm2) for 300 s at different time points (Fig. 4c). It could be found that all of the release rates were promoted during the laser irradiation. The NIR-triggered burst release was attributed to the heat generated from BPNs 
    which decrease the electrostatic forces between drug and nanocarrier leading to the facile dissociation of DOX from the BPNs-PDA-PEG-PEITC [67]. As a result, pH-responsive and NIR-responsive capability enable an efficient, sequential and complete drug release from nano-carriers.
    2.6. Intracellular DOX release
    Because the quenching of DOX fluorescence after encapsulated with BPNs-PDA-PEITC-PEG, the intracellular drug release could be further evaluated by reoccurrence of DOX fluorescence. Cell nucleus were la-beled by 4′,6-diamidino-2-phenylindole (DAPI) with blue-fluorescence and the red-fluorescence was from DOX (Fig. 4d and e). It could be found that MCF-7/ADR cells show a very weak red-fluorescence after culture with BPNs-PDA-PEG-PEITC/DOX for 2 h without the NIR-laser (Fig. 4d), suggesting that low lose DOX was released from nanocarrier. In contrast, after irradiated with NIR laser, an intensive intracellular red-fluorescence could be observed in Fig. 4e, which was due to NIR-triggered heat effect accelerated release of DOX. In addition, corre-sponding fluorescence signal distribution marked with yellow square was shown in Fig. 4d and e which further confirmed the cells incubated with samples under NIR irradiation showed a stronger DOX