Sulourea-coordinated Pd nanocubes for NIR-responsive photothermal/H2S therapy of cancer

Abstract

Background: Photothermal therapy (PTT) frequently cause thermal resistance in tumor cells by inducing the heat shock response, limiting its therapeutic effect. Hydrogen sulfide (H₂S) with appropriate concentration can reverse the Warburg effect in cancer cells. The combination of PTT with H₂S gas therapy is expected to achieve synergistic tumor treatment.

Methods: Here, sulourea (Su) is developed as a thermosensitive/hydrolysable H₂S donor to be loaded into Pd nanocubes through in-depth coordination for construction of the Pd-Su nanomedicine for the first time to achieve photo-controlled H₂S release, realizing the effective combination of photothermal therapy and H₂S gas therapy.

Results: The Pd-Su nanomedicine shows a high Su loading capacity (85 mg g^-1), a high near-infrared (NIR) photothermal conversion efficiency (69.4%), and NIR-controlled H₂S release by the photothermal-triggered hydrolysis of Su. The combination of photothermal heating and H₂S produces a strong synergetic effect by H₂S-induced inhibition of heat shock response, thereby effectively inhibiting tumor growth. Moreover, high intratumoral accumulation of the Pd-Su nanomedicine after intravenous injection also enables photothermal/photoacoustic dual-mode imaging-guided tumor treatment.

Conclusions: The proposed NIR-responsive heat/H₂S release strategy provides a new approach for effective cancer therapy.

Keywords: Gas therapy; Hydrogen sulfide; Nanomedicine; Pd nanocubes; Photothermal therapy.

Scheme 1.

Schematic illustration of the synthesis of Pd-Su nanomedicine (a), and the NIR-responsive release of heating and H₂S from Pd-Su nanomedicine (b)

Fig. 1

Characterization of Pd nanocubes and Pd-Su nanomedicine. a TEM images of Pd nanocubes and Pd-Su nanomedicine (scale bars, 100 nm). b DLS data of Pd nanocubes and Pd-Su nanomedicine. c EDS elemental mappings of Pd nanocubes and Pd-Su nanomedicine (scale bars, 5 nm). d FTIR spectra of Pd nanocubes, Pd-Su nanomedicine, and Su. e UV–Vis-NIR spectra of Pd nanocubes, Pd-Su nanomedicine, and Su (20 μg mL⁻¹)

Fig. 2

NIR-photothermal effect of the Pd-Su nanomedicine and NIR-responsive H₂S release from the Pd-Su nanomedicine. a photothermal curves of Pd nanocubes and Pd-Su nanomedicine in water (200 μg mL⁻¹) at different laser power densities. b Photothermal heating and cooling process of the Pd-Su solution (2 mg mL⁻¹) under 808-nm laser irradiation (0.5 W cm⁻²) which was turned off after irradiation for 5 min, together with the plot of cooling time versus negative natural logarithm of the temperature driving force obtained from the cooling stage. c Recycling heating profiles of the Pd-Su nanomedicine for evaluating the photothermal stability. d Monitoring H₂S release from the Pd-Su nanomedicine (4 mg mL⁻¹) under the irradiation of 808-nm laser with different power densities (0.0, 0.2, 0.5, and 1.0 W cm⁻²) at different time points (0, 3, 8, 15, 20, 25, and 30 min) by the HSN-2 probe

Fig. 3

In vitro outcomes of combined photothermal/H₂S therapy against CT26 (a) and 4T1 (b) cancer cells (n = 6). c Intracellular HSP90 and HSP70 expression in 4T1 cells with different treatments. d Fluorescence images of 4T1 cells co-stained with calcein-AM/PI after incubation with Pd or Pd-Su solution (200 μg mL⁻¹, 4 h) and exposure to 808-nm laser irradiation (0.5 W cm⁻², 30 min). The white dashed lines represent the boundary between the light-irradiated area and the dark area. Scale bar, 100 μm. The data were presented as mean ± SD (standard deviation). P values were calculated by two-tailed Student’s t-test (*p < 0.05; **p < 0.01; ***p < 0.001; ns, no significance)

Fig. 4.

a PAI images of 4T1 tumor treated with the Pd-Su nanomedicine. b Relative photoacoustic (PA) intensity change with time after intravenous injection with the Pd-Su solution to evaluate the intratumoral accumulation and retention of Pd-Su (n = 3). The data were presented as mean ± SD. c Photothermal curves of tumors treated with PBS, Pd, or Pd-Su and then exposed to 808-nm laser irradiation (n = 3). d Photothermal images of corresponding 4T1 tumor-bearing mice at different NIR-irradiation time points.

Fig. 5.

a Tumor growth curves of the mice treated with PBS (blank control), PBS + NIR, Pd, Pd + NIR, Pd-Su, and Pd-Su + NIR. The tumor volume was normalized to the initial tumor volume (Day 0). b Mean weight of the tumors harvested from the mice of various groups on the last day. The data were presented as mean ± SD. P values were calculated by two-tailed Student’s t-test (***p < 0.001; ns = no significance). c Photos of the tumors from various groups on the last day. d Histological examination of tumor sections from the mice that received various treatments by the H&E, TUNEL, and Ki 67 staining methods (scale bar, 50 μm).