Supporting Information

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1 Supporting Information Nuclear-Targeted Photothermal Therapy Prevents Cancer Recurrence with Near-Infrared Triggered Copper Sulfide Nanoparticles Na Li, Qiaoqiao Sun, Zhengze Yu, Xiaonan Gao, Wei Pan, Xiuyan Wan and Bo Tang* College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan , P. R. China. Instruments. High resolution transmission electron microscopy (HRTEM) was taken on a JEM-2100 electron microscope. Fluorescence spectra were acquired from FLS-920 Edinburgh Fluorescence Spectrometer with a Xenon lamp. Absorption spectra were carried out on a pharmaspec UV-4100 UV-visible spectrophotometer (Hitachi, Japan). Absorbance was measured in a microplate reader (Synergy 2, Biotek, USA) in the MTT assay. Success of each reaction step was confirmed by monitoring the changes in zeta potential with a Malvern Zeta Sizer Nano (Malvern Instruments). A TCS SP5 confocal laser scanning microscopy (Leica Co., Ltd. Germany) was used for performing the confocal fluorescence imaging. Cell culture. HeLa cells were cultured in Dulbecco s modified Eagles medium (DMEM) with 10% fetal bovine serum and 100 U/ml 1% antibiotics penicillin/streptomycin and maintained at 37 C

2 in a 100% humidified atmosphere containing 5% CO 2. Animal tumor xenograft models. All animal experiments were conducted and agreed with the Principles of Laboratory Animal Care (People's Republic of China). Nude mice (4-6 weeks old, female, ~20 g) were fed with normal conditions of 12 h light and dark cycles and given access to food and water ad libitum. To establishing the tumor xenograft models, HeLa cells were approximately HeLa cells in 150 µl RPMI 1640 and injected subcutaneously into the flanks of the nude mice. The tumor volume (V) was computed as V=L W 2 /2 by measuring length (L) and width (W). The relative tumor volumes were calculated for each sample as V/V 0 (V 0 was the original tumor volume). The treatments were carried out only once when the tumor volume reaches to about 100 mm 3. Calculation of the photothermal conversion efficiency The photothermal conversion efficiency of CuS@MSN NPs was determined according to previous method. 1,2 Detailed calculation was given as following: η= (hs T max -Q s )/I(1-10 -A 980) equation (S1) hs=mc/τ s equation (S2) t=-τ s ln(θ) equation (S3) θ=(t-t surr )/ T max equation (S4) where h is the heat transfer coefficient, S is the surface area of the container, T max is the temperature difference of the maximum steady-state temperature and the environmental temperature. Qs represents heat dissipated from the laser mediated by the solvent and container. I is the laser power (1.5 W/cm 2 ), and A 980 is the absorbance of the nanoparticles at 980 nm, which is obtained from Figure 1C. (equation S1)

3 m is the mass of the solution containing the photoactive material (0.1 mg/ml); C is the specific heat capacity of the solution. (equation S2) τ s is the associated time constant, which is gained from Fig. S1b. (equation S3) T surr is the environmental temperature. (equation S4)

4 30 Zeta Potential (mv) CuS CuS-MSN CuS-MSN-NH 2-30 Figure S1. Zeta-potential of CuS, and 2. Temperature Change ( o C) Time (s) Time (s) ln (θ) Figure S2. Photothermal effect of the irradiation of the aqueous solution of the CuS@MSN with the NIR laser (980 nm, 1.5 W/cm 2 ), in which the irradiation lasted for 560 s, and then the laser was shut off. (b) Linear time data versus -ln(θ) obtained from the cooling period of (a). Pearson's Correlation The content of TAT peptides (µmol) Figure S3. Pearson s correlation was calculated at each amount of TAT.

5 Figure S4. Bio-TEM images of HeLa cells loaded (left) and (right). Figure S5. Co-localization images of the nuclear targeted NPs using imaging flow cytometry. (A) NPs and (B) NPs. Bottom: Co-localization parameters of cells under different treatments corresponding to cells. Figure S6. TEM images of 2(65) NPs with an average size of 65 nm.

6 Figure S7. Co-localization images of HeLa cells after incubated with 2(65) NPs Figure S8. Distribution of cells according to the number of γ-h2ax foci/ per cell. The green line is control group, the yellow line is with irradiation, the red line is with irradiation. 1.8 Relative Intensity (a.u.) Figure S9. Relative fluorescence intensity of the cells with different content of RGD for NPs The content of RGD peptides (µmol)

7 Figure S10. H&E staining images of five major organs (heart, liver, spleen, lung, and kidney). They were in HeLa tumor-bearing mice at 7 days after different treatment groups: control, irradiation only, CuS@MSN with irradiation for 5 min, CuS@MSN-TAT with irradiation for 5 min. The power density of the irradiation was 1.5 W cm -2, and no histopathological abnormalities were observed in each group. Body Weight (g) control NIR CuS@MSN+NIR CuS@MSN-RGD+NIR CuS@MSN-TAT-RGD+NIR Time (day) Figure S11. Mice body weight curves of different groups of tumor-bearing mice. They were measured at 2 days interval for 20 days.