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BY 4.0 license Open Access Published by De Gruyter Open Access October 12, 2022

Sonodynamic therapy for breast cancer: A literature review

  • Hai-ying Zhou , Yi Chen , Ping Li , Xiaoxin He , Jieyu Zhong , Zhengming Hu , Li Liu , Yun Chen , Guanghui Cui , Desheng Sun EMAIL logo and Tingting Zheng EMAIL logo
From the journal Open Chemistry

Abstract

Breast cancer (BC) is a malignant tumor with the highest incidence among women. Surgery, radiotherapy, and chemotherapy are currently used as the first-line methods for treating BC. Sonodynamic therapy (SDT) in combination with sonosensitizers exerts a synergistic effect. The therapeutic effects of SDT depend on factors, such as the intensity, frequency, and duration of ultrasound, and the type and the biological model of sonosensitizer. Current reviews have focused on the possibility of using tumor-seeking sonosensitizers, sometimes in combination with different therapies, such as immunotherapy. This study elucidates the therapeutic mechanism of interaction between SDT and tissue as well as the current progress in medical applications of SDT to BC.

1 Introduction

Breast cancer (BC) is a malignant tumor with the highest incidence among women, and it is the leading cause of cancer-related death in women [1]. Advances in diagnosis and treatment in the past few decades have led to the use of surgery, radiotherapy, and chemotherapy as the current first-line methods for treating BC [2,3,4]. However, the use of chemotherapeutic drugs leads to drug resistance and systemic toxicity and increases the risk of tumor recurrence, resulting in unsatisfactory outcomes [5].

The treatment of BC is hindered by the relatively complex pathological mechanisms due to the coexistence of different cellular phenotypes. It is a highly heterogeneous malignant tumor with high rates of relapse. The classification of BC is based on the expression of estrogen receptor or progesterone receptor and amplification of the ERBB2 gene [6]. Yumita et al. first reported the synergistic effect of ultrasound combined with hemoporphyrin on tumor growth inhibition in mice [7]. This finding led to a new technique utilizing ultrasound to assist BC therapy, which was named sonodynamic therapy (SDT). SDT is based on photodynamic therapy (PDT) [8], which is a noninvasive and effective treatment that involves the synergistic interaction of low-energy light and photosensitizers [9]. Although PDT is a noninvasive and precisely directed therapy that has attracted increasing attention and has been widely used in the past few decades, it is limited to superficial lesions owing to the weak penetration of light. Compared with PDT, SDT uses low-intensity ultrasound waves to activate a sonosensitizer and thereby overcomes the depth limitation, enabling penetration of deep tissues to treat cancer.

Several studies of SDT have demonstrated significant therapeutic effects on a variety of tumor cell lines and tumors, without obvious toxicity or side effects. Therefore, as a new therapeutic strategy, SDT holds great promise for treating a variety of cancers, including cancers of the liver, stomach, and prostate, and glioma. However, few reviews have been published specifically to study the effect of SDT on BC. To understand the specificity and potential of SDT in treating BC, this study reviews the therapeutic mechanism of interaction between SDT and tissue, as well as current research progress in its medical application to treat BC. In addition, we believe that the type of sonosensitizer or chemotherapeutic drug and the mode of ultrasound action are key to their therapeutic effect in BC. These aspects are reviewed along with the recent trends in ultrasound application in BC treatment.

2 SDT of cancers: Definitions and mechanisms

SDT is based on PDT. The activity of SDT involves multiple mechanisms. The therapeutic effect of SDT depends on many factors, including the intensity, frequency, and duration of ultrasound, and the type and the biological model of sonosensitizer. Therefore, it is difficult to elucidate the detailed mechanism. The possible mechanisms underlying SDT include the following: (i) ultrasonic cavitation; (ii) induction of apoptosis in cancer cells; (iii) ultrasound thermal effect; and (iv) antitumor immunity (Figure 1).

Figure 1 
               The possible mechanisms of SDT.
Figure 1

The possible mechanisms of SDT.

2.1 Ultrasonic cavitation

Ultrasonic cavitation refers to the induction of microbubbles by ultrasound, which changes the pressure rapidly in the tissue fluid. It involves the following two main dynamic changes: noninertial cavitation (steady-state cavitation) and inertial cavitation (transient cavitation). Noninertial cavitation refers to the oscillation of small bubbles at an equilibrium position without breaking. This stable mechanical motion prolongs the life cycle. In comparison, during inertial cavitation, bubbles burst at high speed, instantly resulting in an area of high temperature and pressure known as “hot spot,” which can trigger the production of active substances, such as reactive oxygen species (ROS), and eventually lead to cellular apoptosis [10].

In summary, the mechanical action of ultrasonic cavitation during SDT triggers cell and tissue damage, while ROS generated by inertial cavitation is associated with cell damage.

2.2 Induction of apoptosis in cancer cells

The sonodynamic effect on tumor cell apoptosis has also been confirmed from morphological and molecular biology perspective [11,12,13,14,15,16]. Liu et al. explored the damage and morphological changes in S180 cells by using ultrasound at a frequency of 1.1 MHz and different intensities to activate hematoporphyrin derivatives. The study has shown that SDT promotes apoptosis by induction of cytochrome C, which can decrease the activity of antioxidant enzymes, with increasing damage to intracellular substructures [17].

2.3 Thermal effect of ultrasound

The intensity and frequency of ultrasound determine the depth of tissue penetration and accuracy of focus on the cancer target accumulating the sonosensitizer. Absorption of ultrasound by tissue is followed by rapid increases in local temperature. The increased blood flow to the tumor site elevates the temperature absorption coefficient compared with that in normal tissue. Therefore, during ultrasound irradiation, high energy can heat the targeted tissue, leading to coagulative necrosis, without obvious collateral damage. By using an improved mechanical oscillation method, Zhong et al. explored nanoscale N2O microbubbles, which could increase the temperature of the target area rapidly and induce necrosis of cancer cells when combined with ultrasound [18].

2.4 Antitumor immunity

SDT has the potential to induce immunogenic cell death and release tumor-associated antigens, thereby triggering antitumor immunity [19,20]. By combining self-assembled trifunctional peptides with difunctional sono-/photo-sensitizers, Liu et al. developed multifunctional peptide amphiphile-Rose Bengal (RB) nanocapsules, which could produce a considerable amount of ROS and were associated with targeted immune enhancement to the tumor [21]. By using 5‑aminolevulinic acid as the sonosensitizer, Peng et al. proved that SDT could inhibit tumor growth by effectively activating CD8+ T cells and inhibiting the activity of T regulatory cells [22]. Zhang et al. constructed low-molecular-weight hyaluronic acid (LMWHA)-mesoporous Prussian blue (MPB) nanoparticles (NPs) by synthesizing MPB NPs with LMWHA surface modification. The study showed that SDT with LMWHA-MPB NPs could remodel the phenotype of tumor-associated macrophages, promoting M2 to M1 transition as well as inhibiting the metastasis of 4T1 cells [23].

3 Targeting BC using SDT

SDT uses ultrasound waves to administer sonosensitizers to exert mechanical and photochemical actions, and it is an emerging treatment method in the field of anticancer therapy. The benefits of SDT in BC are not only due to thermal and mechanical effects generated by the physical properties of ultrasound but also due to the synergistic effect when combined with sensitizers, which triggers the subsequent accumulation of the drug at the targets and activation of sonochemical effects. Thus, SDT is toxic to cancer cells exhibiting different phenotypes. Therefore, investigators have studied the possible mechanism of interaction between SDT and BC tissue. Herein, we have summarized SDT-based therapies for BC (Table 1).

Table 1

Summary of SDT-based therapies for BC

Therapeutic modality Main biomaterials Target Authors Year Country/region Refs.
SDT C-RGD + HMME + PFH + AQ4N 4T1 cells Zhao et al. 2020 China [24]
SDT DVDMS + Exosome proteins + Homotypic proteins 4T1 cells Liu et al. 2019 China [25]
SDT HMONs-MnPpIX-PEG 4T1 cells Huang et al. 2017 China [26]
SDT RB MDA-MB-468 cells Tung et al. 2017 United States [27]
SDT HB MDA-MB-231 cells Jia et al. 2017 China [28]
SDT IR-780 4T1 cells Li et al. 2016 China [29]
SDT PEG-IR780-Ce6 MDA-MB-231 cells Han et al. 2021 China [30]
SDT + PDT DVDMS 4T1 cells Liu et al. 2016 China [31]
SDT + Chemotherapy MSN-DOX-Ce6 MDA-MB-2231 cells Xu et al. 2020 China [32]
SDT + Chemotherapy RB + PTX + DOX Michigan cancer foundation-7 (MCF-7) cells Logan et al. 2019 United Kingdom [33]
SDT + Chemotherapy Ce6/PFP/DTX/poly(lactic-co-glycolic acid) (PLGA) 4T1 cells Zhang et al. 2021 China [34]
SDT + Immunotherapy HMME/R837@Lip + Anti-PD-L1 4T1 cells Yue et al. 2019 China [35]
SDT + Immunotherapy TiO2@CaP + Anti-PD-L1 4T1 cells Tan et al. 2021 China [36]
SDT + Immunotherapy iCRET NPs + Anti-PD-L1 4T1 and 4T1-Luc cells Jeon et al. 2022 Korea [37]
SDT + other modality CCM-HMTNPs/HCQ MCF-7 cells Feng et al. 2019 China [38]
SDT + other modality 2DG MDA-MB-231 and MCF-7 cells Xie et al. 2018 China [39]
SDT + other modality L-Arg + TPP + nitric oxide (NO) MCF-7 cells Zuo et al. 2022 China [40]
SDT + other modality DOX + MTNs MCF-7/ADR cells Shi et al. 2018 China [41]
SDT + other modality C-doped TiO2 4T1 cells Yang et al. 2020 Taiwan [42]

3.1 Ultrasound combined with classic sono-/photo-sensitizers in BC treatment

SDT consists of the following three key factors: sonosensitizer, O2, and ultrasound. Sonosensitizers are partially derived from photosensitizers, and they enhance the anti-cancer effects of ultrasound energy. Currently, sonosensitizers can be divided into organic and inorganic nanosensitizers according to their biological function and chemical structure. Organic sonosensitizers include compounds such as porphyrin and diisocyanate phthalate, whereas inorganic sonosensitizers include materials like nano-titanium dioxide, mesoporous silica nanoparticles (MSNs), and manganese dioxide (MnO2). These materials have been extensively investigated in the treatment of BC in vivo and in vitro.

As an endogenous sensitizer, protoporphyrin (PPIX) can produce oxygen-active substances that induce oxidative damage in the surrounding mitochondria, cell membrane, and other organelles or biomolecules under ultrasonic induction. It is widely used in SDT. In vitro studies have shown that the sonosensitizing effects of PPIX were enhanced at a lower frequency, with the increased production of ROS, and they also amplified the ultrasonic cavitation effect [43,44].

Hematoporphyrin monomethyl ether (HMME) is a novel sonosensitizer encapsulated within a lipid bilayer. It consists of two monomer porphyrins, which contribute to strong photosensitization, highly selective uptake by tumors, strong photodynamic effect, and low toxicity, without any mutagenic or teratogenic effects. Zhao et al. have designed an HMME-loaded liposome that can amplify the sonochemical effects on BC [24]. Recent studies have shown that HMME enhanced cytotoxicity by promoting ROS production [45]. Excessive ROS can damage lipids, proteins, and DNA, thereby leading to mitochondrial dysfunction, ion imbalance, and loss of membrane integrity. An in vivo study has shown that NPs containing HMME combined with SDT exerted a synergistic antitumor effect by inducing extreme hypoxia in the tumor microenvironment [24].

Sinoporphyrin sodium (DVDMS), a derivative of porphyrin, has shown great potential for use in SDT and PDT as a newly discovered sensitizer. DVDMS is a porphyrin photosensitizer isolated from Photofrin II. Compared with Photofrin II, DVDMS offers advantages, such as high water solubility, good targeting, and low skin sensitivity [46]. Recent studies on BC have shown that DVDMS can be strongly activated by a combination of light and ultrasound [47]. Liu et al. reported that DVDMS-sono-photodynamic therapy (SPDT) had a stronger cytotoxic effect in vitro than SDT or PDT alone, as shown by (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltertrazolium bromide tetrazolium) and clone formation experiments. In vivo, DVDMS-SPDT significantly inhibited the growth of tumor volume and tumor weight [31]. The anticancer effect of DVDMS-SPDT may be mediated via oxidative stress. Overproduction of ROS may play a crucial role in SDT-induced cell death, cavitation effect, and altered membrane permeability, as well as in enhancing the efficacy of combination therapy.

Further, Liu et al. have designed a nanosensitizer (EXO-DVDMS) to load DVDMS onto the exosomes of tumor cells of the same origin [25] (Figure 2). Exosomes have been developed as delivery carriers for anticancer chemotherapeutic drugs, as well as diagnostic markers for various malignant tumors [48,49,50]. Compared with free DVDMS, EXO-DVDMS showed higher cytotoxicity. Exosomes protected DVDMS from the impact of low pH conditions until they were delivered to the target tumor therapy area, which provides a new option for the application of porphyrins in precision medicine for cancer.

Figure 2 
                  Endogenous nanosonosensitizers enhance SDT efficacy. Reproduced with permission [25]. Copyright 2019, the author(s).
Figure 2

Endogenous nanosonosensitizers enhance SDT efficacy. Reproduced with permission [25]. Copyright 2019, the author(s).

However, these organic sonosensitizers show poor chemical and biological stability and tumor accumulation, which limit the efficacy of SDT. Several organic and inorganic drug delivery systems have been synthesized to enhance the permeability and accumulation in tumors via enhanced permeability and retention. MSNs have attracted widespread research attention in the field of biomedicine, owing to their adjustable mesoporous nanostructure, large specific surface area, and high pore volume. Huang et al. reported an NP acoustosensitizer based on the structure and composition of mesoporous organic silicon dioxide and porphyrin (Figure 3), which significantly enhanced the efficiency of SDT. When exposed to external ultrasound, toxic ROS production was observed, resulting in apoptosis and suppression of growth of cancer cells in vitro and in vivo [26].

Figure 3 
                  Schematic illustration of the synthesis of HMONs-MnPpIX-PEG (a–c) and the mechanism of HMONs-MnPpIX-PEG binding to SDT (d). Reproduced with permission [26]. Copyright 2016, American Chemical Society.
Figure 3

Schematic illustration of the synthesis of HMONs-MnPpIX-PEG (a–c) and the mechanism of HMONs-MnPpIX-PEG binding to SDT (d). Reproduced with permission [26]. Copyright 2016, American Chemical Society.

RB, a known photosensitizer, is a chemical compound used as a stain. Studies have shown that RB can significantly amplify cell damage induced by ultrasound energy [51]. Its lethal effect on cells under ultrasound appears to be related to active oxygen scavenging and complete loss of membrane integrity. Tung et al. believed that its main toxic effect is not ROS synthesis but destabilization of the outer cell membrane [27]. Their study demonstrated that a combination of RB4 and low-intensity ultrasound caused membrane rupture and growth inhibition. In addition, it has been proven to be selective for tumors and molecules, making its use safer and more effective.

Further, Jia et al. demonstrated that hypocrellin B (HB), a traditional Chinese medicine, can be used as a sonosensitizer, with obvious sonodynamic and apoptotic effects on BC cells [28]. However, further studies investigating the antitumor effects of HB-mediated SDT in animal models are needed. Li et al. and Han et al. have reported that indocyanine dye IR-780-mediated SDT significantly induced tumor cell apoptosis or necrosis and suppressed the BC growth in mice [29,30].

3.2 Therapeutic effects of ultrasound combined with antitumor drugs in BC

Although SDT has proven to be effective against malignant tumors in preclinical and clinical studies, the antitumor effect of SDT is not adequate to replace traditional therapies. Therefore, studies have been exploring ways to combine SDT with antitumor drugs to improve the antitumor activity.

Doxorubicin (DOX) is a common antitumor antibiotic that inhibits the biosynthesis of RNA and DNA. As a broad-spectrum anticancer chemotherapeutic agent, it exerts a wide range of biochemical effects on the body and has strong cytotoxic effects on tumor cells. Different molecular subtypes of BC exhibit different drug sensitivities to DOX. In addition, chemotherapy is systemic, and the accumulation of DOX in tumor tissues is insufficient. Therefore, different strategies have been adopted to enhance DOX accumulation in breast tumors. Xu et al. synthesized mesoporous silicon microspheres (MSN-DOX-Ce6), a type of nanocomposite material, using chlorin E6 as the sonosensitizer and DOX [32]. During in vivo studies, tumor-bearing mice received MSN-DOX-Ce6 and ultrasound, which showed no significant increase in tumor volume when compared with other groups (control, DOX, and DOX + Ce6 + US). This indicated that the combination of DOX and ultrasound exhibited tremendous potential in cancer treatment.

Paclitaxel (PTX), a natural anticancer drug, has been widely used for the clinical treatment of breast, ovarian, some head and neck cancers, and lung cancer. PTX can bind to microtubules, impair mitosis, and trigger cell apoptosis, thus effectively preventing proliferation of cancer cells and playing an anticancer role. Despite its favorable effect on various solid tumors, PTX-based chemotherapy is untargeted and associated with severe side effects. However, Logan et al. evaluated the possibility of a treatment that used ultrasound-targeted microvesicle destruction combined with PTX and DOX to develop chemotherapy–SDT for BC [33]. The study revealed that the number of cell colonies treated with PTX + US, Rb + US, or DOX + US was decreased by 7.3, 18.8, and 29.3%, respectively, compared with untreated cells, while the number of cell colonies treated with PTX, DOX, and Rb + US was decreased by 44.0%. The combination treatment group showed significant improvement in efficacy, probably due to the sonic effect that increased the uptake of these drugs and the overall cytotoxic effect. In both in vitro and in vivo studies, the efficacy of chemo-acoustic dynamic therapy mediated by O2MBs was superior to that of the standard PTX/DOX treatment. The chemo-acoustic dynamic therapy accentuated the decrease in tumor volume. In addition, all drugs in the combination treatment group (MBs, PTX, DOX, and RB) have been safely used in humans, laying the foundation for the clinical use of the combination.

In general, the combination of antitumor drugs and sonosensitizers can result in significant synergistic tumoricidal effects under ultrasonic irradiation. Currently, the development of microbubble technology has broadened the spectrum of chemotherapy drugs, which have been studied separately with ultrasound alone, ultrasound with microbubbles, and drug-carrying microbubbles. In 2021, Zhang et al. developed synergistic Ce6/PFP/DTX/PLGA (chlorin e6, perfluoropentane, docetaxel in a well-designed PLGA core–shell structure) NPs and reported that Ce6 could be activated by low-intensity focused ultrasound for ROS generation while releasing DTX, resulting in a synergistic therapeutic effect [34]. The synergistic activity of the combination of ultrasound and anticancer drugs blocks the growth of BC cells. Hence, SDT might be an appropriate option for patients with BC who respond poorly to surgery and chemotherapy.

3.3 SDT combined with immunotherapy

Combining SDT with immunotherapy is a promising method for improving the therapeutic effect and inhibiting metastasis. In addition to producing tumor antigens, SDT may also decrease host immune tolerance, thereby reversing immune tolerance to tumor antigens and stimulating the antitumor immune effect [52]. In 2019, Wang et al. combined SDT with immune-adjuvant-containing nanosonosensitizers and anti-PD-L1 (aPD-L1) antibody, which were capable of inhibiting the growth of primary tumors and triggering an effective systemic immune response (Figure 4). Further, the combination therapy generated long-term immunological memory and prevented tumor recurrence [35]. In 2021, Tan et al. [36] developed a nanosonosensitizer combined with aPD-L1 to effectively suppress the growth of the primary tumor. Moreover, it was able to induce an intense specific immune response to the tumor that suppressed nonirradiated preexisting distant tumors. In 2022, Jeon et al. also reported that SDT combined with immunotherapy more effectively inhibited tumor growth and metastasis by amplifying antitumor immunity [37].

Figure 4 
                  Schematic diagram of antitumor immune responses induced by combining SDT with immune-adjuvant-containing nano-sonosensitizers and immunotherapy. Reproduced with permission [35]. Copyright 2019, Nature Communications.
Figure 4

Schematic diagram of antitumor immune responses induced by combining SDT with immune-adjuvant-containing nano-sonosensitizers and immunotherapy. Reproduced with permission [35]. Copyright 2019, Nature Communications.

3.4 Potential new mechanisms of SDT for BC therapy

Novel SDT strategies and drugs have been developed during the past few decades. The mechanism of SDT is complex, and its cytotoxicity is largely associated with the cellular apoptotic response. Many researchers believe that ultrasound at the right wavelength can interact with the target tissue to activate the anticancer activity of a drug, physically damage cells, or induce a chemical cascade that kills cells.

Many therapeutic mechanisms of chemotherapeutic drugs are related to the induction of autophagy in tumor cells [53]. Autophagy refers to phagocytosis of cytoplasmic proteins or organelles, which fuses with lysosomes to form autophagy lysosomes. It is also involved in the occurrence, development, metastasis, and other processes of malignant tumors. Poor efficacy of chemotherapy or other conventional treatments is attributed to tumor cell insensitivity, which can be overcome by regulating autophagy. Feng et al. [38,54] reported that cytotoxicity of low-dose SDT (20 mg kg−1 hollow mesoporous titanium dioxide nanoparticles (HMTNPs), 1 W cm−2) was enhanced in MCF-7 cells via initiation of the autophagy inhibition response, which may be attributed to the formation of a large number of autophagy vesicles (Figure 5). The method inhibited mitochondrial and cell growth, thereby initiating autophagy to remove foreign bodies and damaged organelles.

Figure 5 
                  Treatment with CCM-HMTNPs/HCQ enhances SDT via the autophagy regulatory pathway (a–c). Reprinted (adapted) with permission [38]. Copyright 2019 American Chemical Society.
Figure 5

Treatment with CCM-HMTNPs/HCQ enhances SDT via the autophagy regulatory pathway (a–c). Reprinted (adapted) with permission [38]. Copyright 2019 American Chemical Society.

Cancer cells tend to metabolize glucose via glycolysis rather than oxidative phosphorylation, a phenomenon known as the Warburg effect. This abnormal glucose metabolism can evade the normal apoptotic process and enhance tumor cell proliferation and migration, which is a key factor in tumor aggressiveness [54]. Some antitumor drugs, such as 2-deoxyglucose (2DG) and dichloroacetic acid, inhibit tumor cell growth and promote tumor cell death by suppressing pathways mediated via the Warburg effect [55]. Xie et al. [39,47,55] investigated the combined efficacy of SDT and 2DG and reported that targeting mitochondria combined with aerobic glycolysis was more effective in BC than either treatment alone. In vitro and in vivo studies speculated that the SDT + 2DG combination may suppress tumors by increasing the ROS levels and switching from oxidative phosphorylation to glycolysis, thus aggravating energy deficiency [47]. In addition, the incorporation of low-intensity SDT compensated for the deficiency of 2DG due to its systemic toxicity and significantly enhanced its anticancer potential. The high efficiency of SDT was also promoted by NO (Figure 6) inhibition of mitochondrial aerobic respiration [40].

Figure 6 
                  HMTNPs target mitochondria with nitric oxide gas. Reprinted (adapted) with permission [40]. Copyright © 2022 Zuo et al.
Figure 6

HMTNPs target mitochondria with nitric oxide gas. Reprinted (adapted) with permission [40]. Copyright © 2022 Zuo et al.

PDT, proposed by Dougherty et al. [9], is a procedure based on the application of sensitizers and light to selectively induce cell death. Photothermal therapy (PTT) is an alternative therapeutic approach that uses electromagnetic radiation to kill malignant neoplasms. It relies on nanomaterials with high photothermal conversion efficiency, which may be a strategy to combat drug resistance in BC, and sensitivity of tumor tissue to drugs can be improved via ROS formation, thermal, mechanical, cavitation, and other effects [9,56,57]. Studies have found that therapies, such as PDT/PTT, combined with chemotherapy, radiotherapy, or immunotherapy based on different mechanisms significantly inhibited tumor growth and reduced tumor volume in BC [58,59,60,61]. The combination yielded a greater therapeutic effect than the single treatment option [31,62].

4 Conclusions and further perspectives

High rates of morbidity, malignancy, relapse, and metastasis pose immense challenges in BC treatment [5]. New and effective treatment strategies are urgently needed because of the limited clinical benefit associated with currently available therapies. The application of SDT in tumor treatment has attracted a great deal of attention in recent years. Despite significant advances, SDT has some intrinsic disadvantages. Although we have discussed a few possible mechanisms of SDT in this review, its underlying mechanism is still unknown.

The role of SDT is mainly related to sonosensitizers and ultrasonic conditions. However, sonosensitizers show limited ability to diffuse across specific biological barriers. Many sonosensitizers also have a limited clinical application due to their low chemical and biological stability and poor bioavailability for accumulation in tumor tissues. Optimization of organic and inorganic sonosensitizers may be a potential therapeutic strategy for enhancing the bioavailability and stability. Toward this end, redesigning or synthesizing the particle size and shape has been shown to promote stability and easy control in vivo. Shi et al. have reported a nanoscale drug delivery system in which DOX can be loaded into hollow mesoporous TiO2 (MTNs), which can reduce tumor drug resistance effectively and increase the concentration of O2 and drug in local tumor tissue to induce cell death [41]. C-doped TiO2 NPs have also been investigated as new sonosensitizers with improved antitumor effects of ROS on 4T1 BC cells [42]. Further, due to the O2 dependence of SDT, the hypoxic tumor microenvironment after SDT reduces the efficacy of combination therapy. Sonosensitizer materials promoting the production of O2, such as O2-loaded nanocarriers and catalase-like nanoenzymes, are toxic and have side effects. Therefore, it is necessary to develop multifunctional sonosensitizers that are safe and stable and exhibit high bioavailability to improve the antitumor effect and alleviate toxicity, with potential therapeutic applications in highly metastatic BC.

SDT may induce irreversible physical damage to the normal tissue surrounding the tumor because of the divergence of ultrasound. Optimization of ultrasound conditions, such as ultrasound intensity, irradiation time, and treatment cycle, is also a potential therapeutic strategy in SDT for BC. Tung et al. have reported that the use of low-intensity ultrasound and sound-excitable drugs can destroy the stability of the cell membrane and result in cell death [27]. However, their application needs further investigation in clinical trials.

The combinations of SDT/chemotherapy, SDT/immunotherapy, SDT/PDT, SDT/PTT, or other coordinated treatment methods provide new ideas for BC treatment [63,64].

In conclusion, SDT combined with multiple treatment approaches has broadened the scope of clinical applications in BC therapy and the prevention of its recurrence and metastasis. Further studies are needed to demonstrate the efficacy and safety of SDT in clinical use.


# These authors contributed equally to this work.


Acknowledgments

HZ, YC, and PL thank to financial support from Grant Nos. JCYJ20210324110211031, JCYJ20210324131402008, and KCXFZ20200201101048774, while XH, JZ, and ZH thank to financial support from Grant Nos. JCYJ20200109140212277, 2022A1515010986, and 81901767. LL, Y, GC, DS, and TZ thank to Grant Nos. JCYJ20180223181216494, 2022A1515010296, and JCYJ20180507183224565. All authors thank Shenzhen Key Medical Discipline Construction Fund No. SZXK051, Guangdong High-level hospital construction Fund No. GD2019260, and Sanming Project of Medicine in Shenzhen No. SZSM202111011.

  1. Author contributions: Z.H.Y.: investigation, data curation, and writing – original draft; C.Y.: investigation, data curation, and writing – original draft; L.P.: investigation and writing – original draft; H.X.X.: writing – review and editing; Z.J.Y.: supervision; H.Z.M.: methodology; L. Y, C. Y., and G.H.C.: manuscript modification; S.D.S.: funding acquisition and conceptualization; Z.T.T.: conceptualization and writing – review and editing. All the authors approved the final version of the manuscript.

  2. Conflict of interest: The authors have no conflict of interest to declare.

  3. Ethical approval: All animal procedures were approved by the Animal Care and Use Committee at Shenzhen PKU-HKUSTMedical Center (protocol number 2020-010) and are in accordance with the guidelines of the Animal Experiments of the National Institutes of Health.

  4. Data availability statement: All data generated or analyzed during this study are included in this published article [and its supplementary information files].

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Received: 2022-04-18
Revised: 2022-06-15
Accepted: 2022-06-24
Published Online: 2022-10-12

© 2022 Hai-ying Zhou et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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