Recent Advances in Nanomaterial-Assisted Combinational Sonodynamic Cancer Therapy

Ultrasound (US)-triggered sonodynamic therapy (SDT), as a promising noninvasive therapeutic modality, has received ever-increasing attention in recent years. Its specialized chemical agents, named sonosensitizers, are activated by low-intensity US to produce lethal reactive oxygen species (ROS) for oncotherapy. Compared with phototherapeutic strategies, SDT provides many noteworthy opportunities and benefits, such as deeper penetration depth, absence of phototoxicity, and fewer side effects. Nevertheless, previous studies have also demonstrated its intrinsic limitations. Thanks to the facile engineering nature of nanotechnology, numerous novel nanoplatforms are being applied in this emerging field to tackle these intrinsic barriers and achieve continuous innovations. In particular, the combination of SDT with other treatment strategies has demonstrated a superior efficacy in improving anticancer activity relative to that of monotherapies alone. Therefore, it is necessary to summarize the nanomaterial-assisted combinational sonodynamic cancer therapy applications. Herein, the design principles in achieving synergistic therapeutic effects based on nanomaterial engineering methods are highlighted. The ultimate goals are to stimulate the design of better-quality combined sonodynamic treatment schemes and provide innovative ideas for the perspectives of SDT in promoting its future transformation to clinical application.     

Inorganic Sonosensitizers for Sonodynamic Therapy in Cancer Treatment

The rapid development of nanomedicine and nanobiotechnology has allowed the emergence of various therapeutic modalities with excellent therapeutic efficiency and biosafety, among which, the sonodynamic therapy (SDT), a combination of low-intensity ultrasound and sonosensitizers, is emerging as a promising noninvasive treatment modality for cancer treatment due to its deeper penetration, good patient compliance, and minimal damage to normal tissue. The sonosensitizers are indispensable components in the SDT process because their structure and physicochemical properties are decisive for therapeutic efficacy. Compared to the conventional and mostly studied organic sonosensitizers, inorganic sonosensitizers (noble metal-based, transition metal-based, carbon-based, and silicon-based sonosensitizers) display excellent stability, controllable morphology, and multifunctionality, which greatly expand their application in SDT. In this review, the possible mechanisms of SDT including the cavitation effect and reactive oxygen species generation are briefly discussed. Then, the recent advances in inorganic sonosensitizers are systematically summarized and their formulations and antitumor effects, particularly highlighting the strategies for optimizing the therapeutic efficiency, are outlined. The challenges and future perspectives for developing state-of-the-art sonosensitizers are also discussed. It is expected that this review will shed some light on future screening of decent inorganic sonosensitizers for SDT.     

Enhanced Sonodynamic Cancer Therapy through Iron-Doping and Oxygen-Vacancy Engineering of Piezoelectric Bismuth Tungstate Nanosheets

Sonodynamic therapy (SDT) is regarded as a new-rising strategy for cancer treatment with low invasiveness and high tissue penetration, but the scarcity of high-efficiency sonosensitizers has seriously hindered its application. Herein, the iron-doped and oxygen-deficient bismuth tungstate nanosheets (BWO-Fe NSs) with piezotronic effect are synthesized for enhanced SDT. Due to the existence of oxygen defects introduced through Fe doping, the bandgap of BWO-Fe is significantly narrowed so that BWO-Fe can be more easily activated by exogenous ultrasound (US). The oxygen defects acting as the electron traps inhibit the recombination of US-induced electrons and holes. More importantly, the dynamically renewed piezoelectric potential facilitates the migration of electrons and holes to opposite side and causes energy band bending, which further promotes the production of reactive oxygen species. Furthermore, Fe doping endows BWO-Fe with Fenton reactivity, which converts hydrogen peroxide (H₂O₂) in tumor microenvironment into hydroxyl radicals (•OH), thereby amplifying the cellular oxidative damage and enhancing SDT. Both in vitro and in vivo experiments illustrate their high cytotoxicity and tumor suppression rate against refractory breast cancer in mice. This work may provide an alternative strategy to develop oxygen-deficient piezoelectric sonosensitizers for enhanced SDT via doping metal ions.     

Mesenchymal Stem Cells Functionalized Sonodynamic Treatment for Improving Therapeutic Efficacy and Compliance of Orthotopic Oral Cancer

Despite multiple treatment options being available, many critical challenges are still ongoing in the treatment of oral squamous cell carcinoma (OSCC). Particularly, the major hurdle is to avoid facial disfigurement and oral function disability during treatment. Herein, nanoengineered mesenchymal stem cells (MSCs) are developed as a supersonosensitizer, named M/LPV/O₂, for improving nondestructive sonodynamic therapy (SDT) against OSCC along with good therapeutic compliance. M/LPV/O₂ is composed of an MSCs membrane functionalized liposomal formulation of oxygen-loading perfluorocarbon and sonosensitizer verteporfin (M/LPV/O₂), which can not only increase circulation and targeting efficacy but also supply oxygen to overcome tumor-hypoxia-associated resistance in SDT, resulting in enhanced therapeutic outcomes in vitro and in vivo. It is identified that M/LPV/O₂ effectively stimulates the generation of reactive oxygen species even in hypoxic conditions, and consequently tremendously induces cancer cell death. In addition, M/LPV/O₂ displays good tumor accumulation and penetration under ultrasound stimulation, and efficiently induces tumor inhibition and even abrogation, leading to prolonged survival of tumor-bearing mice. Importantly, M/LPV/O₂-based SDT exhibits minimal systemic adverse effects and successfully maintains oral functions with no facial tissue damage. Therefore, these studies provide a promising therapeutic strategy for OSCC, which has a potential to enhance life quality and compliance after treatment.     

Two-Dimensional FePS3 Nanosheets as an Integrative Sonosensitizer/Nanocatalyst for Efficient Nanodynamic Tumor Therapy

As the emerging modalities for tumor therapy, sonodynamic therapy (SDT) and chemodynamic therapy (CDT) can generate reactive oxygen species (ROS), typically inducing tumor cell apoptosis. However, the construction of more efficient sonosensitizers integrated with excellent Fenton/Fenton-like catalytic activity to improve the synergistic therapeutic effect of SDT and CDT is still highly challenging. In this study, 2D semiconductor FePS₃ nanosheets (NSs), as one of the metal phosphorus trichalcogenides for both sonosensitizer and Fenton catalyst, are successfully synthesized via an ultrasonic-assisted liquid phase exfoliation method from bulk FePS₃ and further modified with lipoic acid-polyethylene glycol (LA-PEG) to obtain FePS₃-PEG NSs with desirable biocompatibility. The in vitro and in vivo results demonstrate that the engineered FePS₃-PEG NSs induce the combinatorial SDT/CDT effect attributing to the enhanced ROS generation and significant glutathione depletion, which can conduct highly efficient and safe tumor inhibition and prolong the life span of tumor-bearing mice. This work provides the paradigm of semiconductor FePS₃ NSs as the integrative sonosensitizer/Fenton nanocatalyst for dual nanodynamic tumor therapy, paving the new way for exploring other 2D metal phosphorus trichalcogenides in biomedicine.     

压电半导体纳米材料在声动力疗法中的应用进展

随着纳米医学的发展, 利用纳米材料在外源超声波的刺激下催化产生过量的活性氧物种(Reactive Oxygen Species, ROS)以治疗疾病的方法, 被称为声动力疗法(Sonodynamic Therapy, SDT), 已引起人们的广泛关注。目前, 开发可用于SDT的高效声敏剂用于提高ROS产率, 仍然是当前研究和未来临床转化的最大挑战之一。近年来, 得益于压电电子学和压电光电子学的兴起, 基于压电半导体纳米材料的新型声敏剂在SDT中崭露头角, 显示出良好的应用前景。本文从压电半导体的结构出发, 介绍了压电半导体纳米材料应用于SDT的机理研究, 以及利用压电半导体纳米材料作为声敏剂在声动力学癌症治疗及相关抗菌性能方面所取得的研究进展。最后, 本文对该领域存在的问题以及未来的发展趋势进行了展望。     

2D Piezoelectric BiVO4 Artificial Nanozyme with Adjustable Vanadium Vacancy for Ultrasound Enhanced Piezoelectric/Sonodynamic Therapy

Increasing the yield of reactive oxygen species (ROS) to enhance oxidative stress in cells is an eternal goal in cancer therapy. In this study, BiVO₄ artificial nanozyme is developed with adjustable vanadium vacancy for ultrasound (US) enhanced piezoelectric/sonodynamic therapy. Under US excitation, the vanadium vacancy-rich BiVO₄ nanosheets (abbreviated V_v-r BiVO₄ NSs) facilitate the generation of a large number of electrons to improve the ROS yield. Meanwhile, the mechanical strain imposed by US irradiation makes the V_v-r BiVO₄ NSs display a typical piezoelectric response, which tilts the conduction band to be more negative and the valance band more positive than the redox potentials of O₂/O₂^•− and H₂O/·OH, boosting the efficiency of ROS generation. Both density functional theory calculations and experiments confirm that the introduction of cationic vacancy can improve the sonodynamic effect. As expected, V_v-r BiVO₄ NSs have better peroxidase enzyme catalytic and glutathione depletion activities, resulting in increased intracellular oxidative stress. This triple amplification strategy of oxidative stress induced by US substantially inhibits the growth of cancer cells. The work may open an avenue to achieve a synergetic therapy by introducing cationic vacancy, broadening the biomedical use of piezoelectric materials.     

Engineering Dynamic Defect of CeIII/CeIV-Based Metal-Organic Framework through Ultrasound-Triggered Au Electron Trapper for Sonodynamic Therapy of Osteomyelitis

Defect engineering is an important way to tune the catalytic properties of metal-organic framework (MOF), yet precise control of defects is difficult to achieve. Herein, a cerium-based MOF (CeTCPP) is decorated with Au nanoparticles. Under ultrasound irradiation, Au nanoparticles can precisely turn 1/3 of the pristine Ce³⁺ nodes into Ce⁴⁺. With the stable existence of Ce⁴⁺, the coordination of Ce nodes changed, causing the structural irregularity in CeTCPP-Au, so that the electron-hole recombination is obviously hindered, facilitating the generation of reactive oxygen species. Therefore, under 20 min of ultrasound irradiation, the CeTCPP-Au showed superior antibacterial efficacy of over 99% against Staphylococcus aureus and Escherichia coli with good biocompatibility, which is further used for effective therapy of osteomyelitis. Overall, this work provides a dynamic defect formation strategy of MOF through the electron trapping of Au nanoparticles, which also sheds light on sonodynamic therapy in curing deep-seated lesions.     

Micro/Nanoparticle‐Augmented Sonodynamic Therapy (SDT): Breaking the Depth Shallow of Photoactivation

The fast development of photoactivation for cancer treatment provides an efficient photo‐therapeutic strategy for cancer treatment, but traditional photodynamic or photothermal therapy suffers from the critical issue of low in vivo penetration depth of tissues. As a non‐invasive therapeutic modality, sonodynamic therapy (SDT) can break the depth barrier of photoactivation because ultrasound has an intrinsically high tissue‐penetration performance. Micro/nanoparticles can efficiently augment the SDT efficiency based on nanobiotechnology. The state‐of‐art of the representative achievements on micro/nanoparticle‐enhanced SDT is summarized, and specific functions of micro/nanoparticles for SDT are discussed, from the different viewpoints of ultrasound medicine, material science and nanobiotechnology. Emphasis is put on the relationship of structure/composition‐SDT performance of micro/nanoparticle‐based sonosensitizers. Three types of micro/nanoparticle‐augmented SDT are discussed, including organic and inorganic sonosensitizers and micro/nanoparticle‐based but sonosensitizer‐free strategies to enhance the SDT outcome. SDT‐based synergistic cancer therapy augmented by micro/nanoparticles and their biosafety are also included. Some urgent critical issues and potential developments of micro/nanoparticle‐augmented SDT for efficient cancer treatment are addressed. It is highly expected that micro/nanoparticle‐augmented SDT will be quickly developed as a new and efficient therapeutic modality which will find practical applications in cancer treatment. At the same time, fundamental disciplines regarding materials science, chemistry, medicine and nanotechnology will be advanced.     

Ultrasmall Oxygen‐Deficient Bimetallic Oxide MnWOX Nanoparticles for Depletion of Endogenous GSH and Enhanced Sonodynamic Cancer Therapy

Sonodynamic therapy (SDT) triggered by ultrasound (US) has attracted increasing attention owing to its abilities to overcome critical limitations including low tissue‐penetration depth and phototoxicity in photodynamic therapy. Herein, the design of a new type of sonosensitizer is revealed, namely, ultrasmall oxygen‐deficient bimetallic oxide MnWO_X nanoparticles, for multimodal imaging‐guided enhanced SDT against cancer. As‐made MnWO_X nanoparticles with poly(ethylene glycol) (PEG) modification show high physiological stability and biocompatibility. Interestingly, such MnWO_X‐PEG nanoparticles exhibit highly efficient US‐triggered production of ¹O₂ and ?OH, higher than that of previously reported sonosensitizers (e.g., protoporphyrin IX and titanium dioxide), because the oxygen‐deficient structure of MnWO_X serves as an electron trap site to prevent electron–hole recombination. The glutathione depletion capability of MnWO_X‐PEG can also further favor SDT‐triggered cancer cell killing. With efficient tumor homing as illustrated by computer tomography and magnetic resonance imaging, MnWO_X‐PEG enables effective destruction of mouse tumors under US stimulation. After accomplishing its therapeutic functions, MnWO_X‐PEG can be metabolized by the mouse body without any long‐term toxicity. Herein, a new type of sono‐sensitizing agent with high SDT efficacy, multimodal imaging functions, and rapid clearance is presented, an agent which is promising for noninvasive SDT cancer treatment.     

Perovskite-Type Manganese Vanadate Sonosensitizers with Biodegradability for Enhanced Sonodynamic Therapy of Cancer

Sonodynamic therapy (SDT) has attracted intensive attention, but is still hindered by low sonosensitization and non-biodegradability of the traditional sonosensitizers. Herein, perovskite-type manganese vanadate (MnVO₃) sonosensitizers integrating high reactive oxide species (ROS) production efficiency and appropriate bio-degradability are developed for enhanced SDT. Taking advantage of the intrinsic properties of perovskites such as narrow bandgap and substantial oxygen vacancies, MnVO₃ shows a facile ultrasound (US)-triggered electrons-holes separation and restrained recombination, thus enhancing the ROS quantum yield in SDT. Furthermore, MnVO₃ exhibits a considerable chemodynamic therapy (CDT) effect under the acidic condition probably owing to the presence of manganese and vanadium ions. Due to the presence of high-valent vanadium, MnVO₃ can also eliminate glutathione (GSH) within the tumor microenvironment, which synergistically amplifies the efficacy of SDT and CDT. Importantly, the perovskite structure bestows MnVO₃ with superior biodegradability, which alleviates the long-term presence of residues in metabolic organs after therapeutic actions. Based on these characteristics, US-assisted MnVO₃ achieves an excellent antitumor outcome along with low systemic toxicity. Overall, perovskite-type MnVO₃ may be promising sonosensitizers for highly efficient and safe treatment of cancer. The work attempts to explore the potential utility of perovskites in the design of degradable sonosensitizers.     

Metalloporphyrin Complex‐Based Nanosonosensitizers for Deep‐Tissue Tumor Theranostics by Noninvasive Sonodynamic Therapy

Metal complexes are widely used as anticancer drugs, while the severe side effects of traditional chemotherapy require new therapeutic modalities. Sonodynamic therapy (SDT) provides a significantly noninvasive ultrasound (US) treatment approach by activating sonosensitizers and initiating reactive oxygen species (ROS) to damage malignant tissues. In this work, three metal 4‐methylphenylporphyrin (TTP) complexes (MnTTP, ZnTTP, and TiOTTP) are synthesized and encapsulated with human serum albumin (HSA) to form novel nanosonosensitizers. These nanosonosensitizers generate abundant singlet oxygen (¹O₂) under US irradiation, and importantly show excellent US‐activatable abilities with deep‐tissue depths up to 11 cm. Compared to ZnTTP‐HSA and TiOTTP‐HSA, MnTTP‐HSA exhibits the strongest ROS‐activatable behavior due to the lowest highest occupied molecular orbital?lowest unoccupied molecular orbital gap energy by density functional theory. It is also effective for deep‐tissue photoacoustic/magnetic resonance dual‐modal imaging to trace the accumulation of nanoparticles in tumors. Moreover, MnTTP‐HSA intriguingly achieves high SDT efficiency for simultaneously suppressing the growth of bilateral tumors away from ultrasound source in mice. This work develops a deep‐tissue imaging‐guided SDT strategy through well‐defined metalloporphyrin nanocomplexes and paves a new way for highly efficient noninvasive SDT treatments of malignant tumors.     

Metal–Organic‐Framework‐Derived Carbon Nanostructure Augmented Sonodynamic Cancer Therapy

Sonodynamic therapy (SDT) can overcome the critical issue of depth‐penetration barrier of photo‐triggered therapeutic modalities. However, the discovery of sonosensitizers with high sonosensitization efficacy and good stability is still a significant challenge. In this study, the great potential of a metal–organic‐framework (MOF)‐derived carbon nanostructure that contains porphyrin‐like metal centers (PMCS) to act as an excellent sonosensitizer is identified. Excitingly, the superior sonosensitization effect of PMCS is believed to be closely linked to the porphyrin‐like macrocycle in MOF‐derived nanostructure in comparison to amorphous carbon nanospheres, due to their large highest occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital (LUMO) gap for high reactive oxygen species (ROS) production. The nanoparticle‐assisted cavitation process, including the visualized formation of the cavitation bubbles and microjets, is also first captured by high‐speed camera. High ROS production in PMCS under ultrasound is validated by electron spin resonance and dye measurement, followed by cellular destruction and high tumor inhibition efficiency (85%). This knowledge is important from the perspective of understanding the structure‐dependent SDT enhancement of a MOF‐derived carbon nanostructure.     

钛基生物医学材料瞬态电能表面改性初探

钛基生物医学材料广泛应用于人体硬组织的修复,但耐磨性较差,限制了其更广泛的应用.采用瞬态电能强化技术以石墨为电极对钛合金TC4进行表面改性,对比研究了在空气、氩气和氮气气氛下获得的强化层的性能,并对氮气中制备的强化层的生物相容性进行了评价.结果表明,强化改性层物相主要为TiC及石墨相,表面硬度有较大提高,摩擦学性能获得显著改善,改性层与基体相比仍具有优异的耐蚀性能;氩气和氮气气氛下获得的强化层表面裂纹比空气气氛下的少;氮气保护下可得到裂纹较少、具有一定粗糙度、耐磨、生物相容性好且与基体为冶金结合的强化层.     

Intelligent Nanocomposites with Intrinsic Blood–Brain‐Barrier Crossing Ability Designed for Highly Specific MR Imaging and Sonodynamic Therapy of Glioblastoma

The blood–brain barrier (BBB) is the most important obstacle to improving the clinical outcomes of diagnosis and therapy of glioblastoma. Thus, the development of a novel nanoplatform that can efficiently traverse the BBB and achieve both precise diagnosis and therapy is of great importance. Herein, an intelligent nanoplatform based on holo‐transferrin (holo‐Tf) with in situ growth of MnO₂ nanocrystals is constructed via a reformative mild biomineralization process. Furthermore, protoporphyrin (ppIX), acting as a sonosensitizer, is then conjugated into holo‐Tf to obtain MnO₂@Tf‐ppIX nanoparticles (TMP). Because of the functional inheritance of holo‐Tf during fabrication, TMP can effectively traverse the BBB for highly specific magnetic resonance (MR) imaging of orthotopic glioblastoma. Clear suppression of tumor growth in a C6 tumor xenograft model is achieved via sonodynamic therapy. Importantly, the experiments also indicate that the TMP nanoplatform has satisfactory biocompatibility and biosafety, which favors potential clinical translation.     

医用钛合金超声-电化学抛光工艺

研究了一种对常用的医用钛合金(Ti-6Al-4V)试件进行表面光整加工的新工艺.在试验的基础上,将功率超声波与电化学作用相结合,利用功率超声波的能量特性并结合电化学抛光的特点,实现对常用钛合金试件的超声-电化学抛光处理.分析了功率超声波对电化学抛光过程的促进作用及电流密度对抛光效果的影响,获得了较为合理的工艺参数.结果表明,采用合理的超声-电化学抛光工艺参数,经2 min左右时间,试件表面粗糙度由 3.2 μm降至0.2 μm,这不仅可以改善试件的表面粗糙度,而且还可以增加表面氧化膜中钛的氧化物含量,进一步提高钛合金植入物的生物相容性和耐腐蚀性.     

生物医用多孔钛及钛合金激光快速成形研究进展

多孔钛及钛合金具有良好的生物相容性和与人骨更匹配的力学性能,是人体理想的替代材料,因此其制备技术及相关性能研究引起了广泛关注。激光快速成形是一项先进的制造技术,在制备生物多孔金属材料时具有独特的优势。介绍了激光快速成形的工作原理和技术特征,根据成形工艺特点简要回顾了4种代表性激光快速成形技术(选择性激光烧结、选择性激光熔化、激光近净成形和激光立体成形)的国内外发展现状,并重点论述了这几种技术在制备生物医用多孔钛及钛合金方面的最新研究进展,最后指出了今后在该领域的主要研究工作。     

Ultrasound-Activatable g-C3N4-Anchored Titania Heterojunction as an Intracellular Redox Homeostasis Perturbator for Augmented Oncotherapy

Energy band structure of inorganic nano-sonosensitizers is usually optimized by surface decoration with noble metals or metal oxide semiconductors, aiming to enhance interfacial charge transfer, augment spin-flip and promote radical generation. To avoid potential biohazards of metallic elements, herein, metal-free graphitic carbon nitride quantum dots (g-C₃N₄ QDs) are anchored onto hollow mesoporous TiO₂ nanostructure to formulate TiO₂@g-C₃N₄ heterojunction. The direct Z-scheme charge transfer significantly improves the separation/recombination dynamics of electron/hole (e⁻/h⁺) pairs upon ultrasound (US) stimulation, which promotes the yield of singlet oxygen (¹O₂) and hydroxyl radicals (·OH). The conjugated g-C₃N₄ QDs with peroxidase-mimic activity further react with the elevated endogenous H₂O₂ and aggravate oxidative stress. After loading prodrug romidepsin (RMD) in TiO₂@g-C₃N₄, stimulus-responsive drug delivery can be realized by US irradiation. The disulfide bridge of the released RMD tends to be reduced by glutathione (GSH) into a monocyclic dithiol, which arrests cell cycle in G2/M phase and evokes apoptosis through enhanced histone acetylation. Importantly, reactive oxygen species accumulation accompanied by GSH depletion is devoted to deleterious redox dyshomeostasis, leading to augmented systemic oncotherapy by eliciting antitumor immunity. Collectively, this paradigm provides useful insights in optimizing the performance of TiO₂-based nano-sonosensitizers for tackling critical diseases.