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. 2024 Jan 3;22(1):7.
doi: 10.1186/s12951-023-02268-5.

A continuously efficient O2-supplying strategy for long-term modulation of hypoxic tumor microenvironment to enhance long-acting radionuclides internal therapy

Jingchao Li #  1 , Tingting Wang #  1 , Yuanfei Shi #  2 , Zichen Ye  3 , Xun Zhang  1 , Jiang Ming  3 , Yafei Zhang  1 , Xinyan Hu  3 , Yun Li  4 , Dongsheng Zhang  1 , Qianhe Xu  1 , Jun Yang  1 , Xiaolan Chen  5 , Nian Liu  6 , Xinhui Su  7
Affiliations

A continuously efficient O2-supplying strategy for long-term modulation of hypoxic tumor microenvironment to enhance long-acting radionuclides internal therapy

Jingchao Li et al. J Nanobiotechnology. .

Abstract

Radionuclides internal radiotherapy (RIT) is a clinically powerful method for cancer treatment, but still poses unsatisfactory therapeutic outcomes due to the hypoxic characteristic of tumor microenvironment (TME). Catalase (CAT) or CAT-like nanomaterials can be used to enzymatically decompose TME endogenous H2O2 to boost TME oxygenation and thus alleviate the hypoxic level within tumors, but their effectiveness is still hindered by the short-lasting of hypoxia relief owing to their poor stability or degradability, thereby failing to match the long therapeutic duration of RIT. Herein, we proposed an innovative strategy of using facet-dependent CAT-like Pd-based two-dimensional (2D) nanoplatforms to continuously enhance RIT. Specifically, rationally designed 2D Pd@Au nanosheets (NSs) enable consistent enzymatic conversion of endogenous H2O2 into O2 to overcome hypoxia-induced RIT resistance. Furthermore, partially coated Au layer afford NIR-II responsiveness and moderate photothermal treatment that augmenting their enzymatic functionality. This approach with dual-effect paves the way for reshaping TME and consequently facilitating the brachytherapy ablation of cancer. Our work offers a significant advancement in the integration of catalytic nanomedicine and nuclear medicine, with the overarching goal of amplifying the clinical benefits of RIT-treated patients.

Keywords: Continuous hypoxia relief; Moderate NIR-II photothermal therapy; Pd-based nanomaterials; Radionuclides internal therapy.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Characterizations, CAT-like activity and NIR-II photothermal property of Pd@Au-PEG NSs. (a) TEM image of Pd@Au-PEG NSs (Scale bar = 50 nm). (b) Element mapping analysis of Pd@Au-PEG NSs (Scale bar = 20 nm). (c) AFM image and the thickness measurement of Pd@Au-PEG NSs. (e) The UV-Vis-NIR absorption spectrum of Pd@Au-PEG NSs. (d) Schematic diagram of mechanism regarding the enzymatic activity and photothermal responsiveness of Pd@Au-PEG NSs. (e) CAT-like activity of Pd@Au-PEG NSs and their property of continuously decomposing H2O2 for O2 evolution with repeated H2O2 addition. (f) NIR-II surface plasmon resonance-boosted enzymatic activity of Pd@Au-PEG NSs. (g) Photothermal stability of Pd@Au-PEG NSs. (h) Infrared thermal images of saline (control group) and Pd@Au-PEG NSs solution under the excitation of NIR-II laser (1064 nm, 0.3 W cm− 2)
Fig. 2
Fig. 2
Cell assays. (a) Confocal fluorescence microscope images of 4T1 cancer cells treated by Hochest (blue fluorescence), Mito-tracker (green fluorescence) and Pd@Au-Cy5.5 (red fluorescence) to demonstrate their mitochondria-targeting ability (Scale bar: 10 μm). (b) The cell-level biocompatibility of Pd@Au-PEG NSs. (c) Cells viabilities of 4T1 cancer cells after different treatments for 24 h. (d) Western blotting images of HIF-1α expression of 4T1 cancer cells after different treatments for 24 h under the hypoxic culture condition. (e) Fluorescence microscopy images of 4T1 cancer cells dual-stained with Calcein-AM (green fluorescence) and PI (red fluorescence) after different treatments for 24 h (Scale bar: 50 μm)
Fig. 3
Fig. 3
Living imaging and in vivo HIF-α-inhibiting effect of NIR-II-enhanced Pd@Au-PEG NSs. (a) PA imaging of Pd@Au-PEG NSs-injected mice (n = 3) and the quantitative PA signal analysis in tumor at various time points (pre, 2 h, 6 h, 12 and 24 h). (b) CT imaging of Pd@Au-PEG NSs-injected mice (n = 3) at 6 and 24 h post-injection (Red arrows represent the tumor sites). (c) In vivo CT signal in tumor sites post-injection of Pd@Au-PEG NSs. (d) In vivo biodistributions of Pd@Au-PEG NSs by ICP-MS detection (n = 5). (e) Immunofluorescence staining of HIF-α expressions in tumors of Pd@Au-PEG NSs-injected mice at day-1, -3, -5 and  -7 post-injection (Scale bar = 50 μm). (f). The quantitative analysis of HIF-α fluorescence signal intensities
Fig. 4
Fig. 4
In vivo 90Y-resin spheres brachytherapy enhanced by continuous hypoxia relief and NIR-II moderate PTT. (a) Schematic diagram of the therapeutic progress. (b). The average tumor growth curves of 4T1 subcutaneous tumors with various therapeutics (n = 5). Group I: Saline (control group); Group II: Pd@Au-PEG NSs + laser (moderate PTT); Group III: 90Y-micropsheres; Group IV: 90Y-micropsheres + Pd@Au-PEG NSs + laser. (c) The survival curves of tumor-bearing mice in each treatment group. (d) The weight curves of mice in each treatment group. (e) H&E staining, TUNEL assay and Ki67 staining of tumor samples from mice in four treatment groups (Scale bar = 50 μm)
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