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. 2023 Nov 13:18:6667-6687.
doi: 10.2147/IJN.S431221. eCollection 2023.

Endogenous H2O2 Self-Replenishment and Sustainable Cascades Enhance the Efficacy of Sonodynamic Therapy

Jia-Rui Du  1 , Deng-Ke Teng  1 , Yang Wang  1 , Qimeihui Wang  1 , Yuan-Qiang Lin  1 , Qiang Luo  1 , Jia-Nan Xue  1 , Ling-Yu Zhu  1 , Peng Dong  1 , Gen-Mao Zhang  1 , Yan Liu  1 , Zhi-Xia Sun  1 , Hui Wang #  1 , Guo-Qing Sui #  1
Affiliations

Endogenous H2O2 Self-Replenishment and Sustainable Cascades Enhance the Efficacy of Sonodynamic Therapy

Jia-Rui Du et al. Int J Nanomedicine. .

Abstract

Purpose: Sonodynamic therapy (SDT), with its high tissue penetration and noninvasive advantages, represents an emerging approach to eradicating solid tumors. However, the outcomes of SDT are typically hampered by the low oxygen content and immunosuppression in the tumor microenvironment (TME). Accordingly, we constructed a cascade nanoplatform to regulate the TME and improve the anti-tumor efficiency of SDT.

Methods: In this study, we rationally design cascade nanoplatform by incorporating immunostimulant hyaluronic acid (HA) and sonosensitizer chlorin e6 (Ce6) on the polydopamine nanocarrier that is pre-doped with platinum nanozymes (designated Ce6/Pt@PDA-HA, PPCH).

Results: The cascade reactions of PPCH are evidenced by the results that HA exhibits reversing immunosuppressive that converts M2 macrophages into M1 macrophages in situ, while producing H2O2, and then platinum nanozymes further catalyze the H2O2 to produce O2, and O2 produces abundant singlet oxygen (1O2) under the action of Ce6 and low-intensity focused ultrasound (LIFU), resulting in a domino effect and further amplifying the efficacy of SDT. Due to its pH responsiveness and mitochondrial targeting, PPCH effectively accumulates in tumor cells. Under LIFU irradiation, PPCH effectively reverses immunosuppression, alleviates hypoxia in the TME, enhances reactive oxygen species (ROS) generation, and enhances SDT efficacy for eliminating tumor cells in vivo and in vitro. Meanwhile, an in vivo dual-modal imaging including fluorescence and photoacoustic imaging achieves precise tumor diagnosis.

Conclusion: This cascade nanoplatform will provide a promising strategy for enhancing SDT eradication against tumors by modulating immunosuppression and relieving hypoxia.

Keywords: cascade reactions; sonodynamic therapy; tumor hypoxia; tumor microenvironment; tumor-associated macrophages.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Scheme 1
Scheme 1
Schematic illustration of PPCH synthesis and tumor therapy.
Figure 1
Figure 1
(A) Transmission electron microscopy (TEM) and magnification of PPCH. (B) Elemental mapping for PPCH. (C) XRD pattern of PPCH. (D) Size distribution of PP, PPC and PPCH. (E) FTIR spectra of HA, HA-PEG and PPCH.
Figure 2
Figure 2
(A) Ultraviolet–visible absorption spectra of Ce6, PP and PPCH. (B) Loading efficacy and entrapment efficacy of Ce6. (C) Ce6 controlled release curves of PPCH triggered by different pH values. (D) Schematic presentation of the CAT-like activity of PPCH. (E) Oxygen concentrations in the solutions of different groups. Insert: optical images of oxygen bubbles. (F) Changes in dissolved oxygen concentration after PPCH reacted with different concentrations of H2O2. (G) Ultraviolet–visible absorption spectra of DPBF and PPCH mixed solution with LIFU time. (H) ROS production by PPCH under different conditions. (I) Changes in the hydrated particle size and PDI of PPCH.
Figure 3
Figure 3
(A) Confocal microscopy images of M2 macrophages incubated with PPCH. (B) Flow cytometry results of M2 macrophages treated with PPCH. (C) Flow cytometric results of the expression of CD86 (M1 macrophages) and CD206 (M2 macrophages) after treatment with different formulations. (D) Levels of IL-12 released by macrophages before and after regulation of the polarization of M2 macrophages toward M1 macrophages in the different groups. (E) Levels of IL-10 secreted by macrophages in the different treatment groups. (F) Quantitative determination of H2O2 production in the different groups. (G) Intracellular hypoxia imaging using [Ru(dpp)3]Cl2 as an indicator. (H) Flow cytometric and (I) CLSM images of intracellular ROS in 4T1 cells in the different groups.
Figure 4
Figure 4
(A) CLSM image and (B) fluorescence intensity image of the subcellular localization of PPCH. (C) CLSM image of 4T1 cells after incubation with PPCH at different pH values (7.4 and 6.5) for 2 h. (D) Relative viability of 4T1 cells incubated with PPCH at different concentrations. (E) Relative viability of 4T1 cells treated with various treatments after LIFU. (F) Calcein-AM and PI stained fluorescence imaging of 4T1 cells subjected to various treatments after LIFU.
Figure 5
Figure 5
(A) The changes of RBC, WBC, PLT, HGB, ALT, AST, BUN and CR and (B) HE staining sections of mice after injection of PPCH for 5, 15 and 30 d.
Figure 6
Figure 6
(A) FL images and (B) signal values of PPCH at different time points after i.v. injection of PPCH. (C) FL imaging and (D) quantitative analysis of the intensity of tumor and major organs 24 h after injection of PPCH. In vivo (E) PA images and (F) PA signal intensities of tumors in 4T1 tumor-bearing mice at different time points after i.v. injection of PPCH.
Figure 7
Figure 7
(A) CD86 (M1/red), CD206 (M2/green), CD31, HIF-1α, TUNEL and HE staining of tumors after various treatments. (B) Representative flow cytometry plots of M1/M2 macrophages in tumor tissues after various treatments. (C) Oxyhemoglobin level of tumors injected with PPCH before and after different times.
Figure 8
Figure 8
(A) Schematic illustration of the tumor treatment process in vivo. (B) Body weight changes in the different groups. (C) Tumor volume changes in the different groups. (D) Representative photos of tumor tissues dissected from mice after different treatments at day 18. Values of *p < 0.05 and ***p < 0.001.
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