Piezocatalytic Tumor Therapy by Ultrasound-Triggered and BaTiO3-Mediated Piezoelectricity

Ultrasound theranostics features non-invasiveness, minor energy attenuation, and high tissue-penetrating capability, and is playing ever-important roles in the diagnosis and therapy of diseases in clinics. Herein, ultrasound is employed as a microscopic pressure resource to generate reactive oxygen species (ROS) for piezocatalytic tumor therapy under catalytic mediation by piezoelectric tetragonal BaTiO₃ (T-BTO). Under the ultrasonic vibration, the electrons and holes are unpaired and they are separated by the piezoelectricity, resulting in the establishment of a strong built-in electric field, which subsequently catalyzes the generation of ROS such as toxic hydroxyl (^•OH) and superoxide radicals (^•O₂⁻) in situ for tumor eradication. This modality shows intriguing advantages over typical sonoluminescence-activated sonodynamic therapy, such as more stable sensitizers and dynamical control of redox reaction outcomes. Furthermore, according to the finite element modeling simulation, the built-in electric field is capable of modulating the band alignment to make the toxic ROS generation energetically favorable. Both detailed in vitro cellular level evaluation and in vivo tumor xenograft assessment have demonstrated that an injectable T-BTO-nanoparticles-embedded thermosensitive hydrogel will substantially induce ultrasound irradiation-triggered cytotoxicity and piezocatalytic tumor eradication, accompanied by high therapeutic biosafety in vivo.     

Nanoparticle Regrowth Enhances Photoacoustic Signals of Semiconducting Macromolecular Probe for In Vivo Imaging

Smart molecular probes that emit deep‐tissue penetrating photoacoustic (PA) signals responsive to the target of interest are imperative to understand disease pathology and develop innovative therapeutics. This study reports a self‐assembly approach to develop semiconducting macromolecular activatable probe for in vivo imaging of reactive oxygen species (ROS). This probe comprises a near‐infrared absorbing phthalocyanine core and four poly(ethylene glycol) (PEG) arms linked by ROS‐responsive self‐immolative segments. Such an amphiphilic macromolecular structure allows it to undergo an ROS‐specific cleavage process to release hydrophilic PEG and enhance the hydrophobicity of the nanosystem. Consequently, the residual phthalocyanine component self‐assembles and regrows into large nanoparticles, leading to ROS‐enhanced PA signals. The small size of the intact macromolecular probe is beneficial to penetrate into the tumor tissue of living mice, while the ROS‐activated regrowth of nanoparticles prolongs the retention along with enhanced PA signals, permitting imaging of ROS during chemotherapy. This study thus capitalizes on stimuli‐controlled self‐assembly of macromolecules in conjunction with enhanced heat transfer in large nanoparticles for the development of smart molecular probes for PA imaging.     

Semiconducting Polymer Nanoreporters for Near-Infrared Chemiluminescence Imaging of Immunoactivation

Real-time in vivo imaging of immunoactivation is critical for longitudinal evaluation of cancer immunotherapy, which, however, is rarely demonstrated. This study reports semiconducting polymer nanoreporters (SPNRs) with superoxide anion (O₂^•−)-activatable chemiluminescence signals for in vivo imaging of immunoactivation during cancer immunotherapy. SPNRs are designed to comprise an SP and a caged chemiluminescence phenoxy-dioxetane substrate, which respectively serve as the chemiluminescence acceptor and donor to enable intraparticle chemiluminescence resonance energy transfer. SPNRs are intrinsically fluorescent but only become chemiluminescent upon activation by O₂^•−. Representing the first O₂^•−-activatable near-infrared chemiluminescent reporter, SPNR3 sensitively differentiates higher O₂^•− levels in immune cells from other cells including cancer and normal cells. Following systemic administration, SPNR3 passively accumulates into tumors in living mice and activates the chemiluminescence signals responding to the concentration of O₂^•− in the tumor microenvironment. Moreover, the enhancement of in vivo chemiluminescence signal after cancer immunotherapy is correlated with increased population of T cells in the tumor, proving its feasibility in tracking of T cell activation. Thus, SPNRs represent the first kind of chemiluminescent reporters competent for in vivo imaging of immunoactivation.     

铜离子注入对半导体BaTiO3陶瓷PTCR特性的影响

应用阻抗谱，结合阻温特性测量分析铜离子注入（１１０ＫｅＶ，６×１０＾１５和１×１０＾１７ｉｏｎｓ／ｃｍ＾２）半导体ＢａＴｉＯ３陶瓷的ＰＴＣＲ特性。结果表明，注入剂量较低时，可以提高材料的ＰＴＣＲ效应。认为注入的铜离子以Ｃｕ＾２＋和Ｃｕ＾＋同时存在于ＢａＴｉＯ３材料晶界处并发生电子转移，起着电子陷阱作用。     

Self‐Assembled Semiconducting Polymer Nanoparticles for Ultrasensitive Near‐Infrared Afterglow Imaging of Metastatic Tumors

Detection of metastatic tumor tissues is crucial for cancer therapy; however, fluorescence agents that allow to do share the disadvantage of low signal‐to‐background ratio due to tissue autofluorescence. The development of amphiphilic poly(p‐phenylenevinylene) derivatives that can self‐assemble into the nanoagent (SPPVN) in biological solutions and emit near‐infrared afterglow luminescence after cessation of light irradiation for ultrasensitive imaging of metastatic tumors in living mice is herein reported. As compared with the counterpart nanoparticle (PPVP) prepared from the hydrophobic PPV derivate, SPPVN has smaller size, higher energy transfer efficiency, and brighter afterglow luminescence. Moreover, due to the higher PEG density of SPPVN relative to PPVP poly(ethylene glycol), SPPVN has a better accumulation in tumor. Such a high sensitivity and ideal biodistribution allow SPPVN to rapidly detect xenograft tumors with the size as small as 1 mm³ and tiny peritoneal metastatic tumors that are almost invisible to naked eye, which is not possible for PPVP. Moreover, the oxygen‐sensitive afterglow makes SPPVN potentially useful for in vivo imaging of oxygen levels. By virtue of enzymatic biodegradability and ideal in vivo clearance, these organic agents can serve as a platform for the construction of advanced afterglow imaging tools.     

Spatiotemporally Synchronous Oxygen Self-Supply and Reactive Oxygen Species Production on Z-Scheme Heterostructures for Hypoxic Tumor Therapy

Photodynamic therapy (PDT) efficacy has been severely limited by oxygen (O₂) deficiency in tumors and the electron–hole separation inefficiency in photosensitizers, especially the long-range diffusion of O₂ toward photosensitizers during the PDT process. Herein, novel bismuth sulfide (Bi₂S₃)@bismuth (Bi) Z-scheme heterostructured nanorods (NRs) are designed to realize the spatiotemporally synchronous O₂ self-supply and production of reactive oxygen species for hypoxic tumor therapy. Both narrow-bandgap Bi₂S₃ and Bi components can be excited by a near-infrared laser to generate abundant electrons and holes. The Z-scheme heterostructure endows Bi₂S₃@Bi NRs with an efficient electron–hole separation ability and potent redox potentials, where the hole on the valence band of Bi₂S₃ can react with water to supply O₂ for the electron on the conduction band of Bi to produce reactive oxygen species. The Bi₂S₃@Bi NRs overcome the major obstacles of conventional photosensitizers during the PDT process and exhibit a promising phototherapeutic effect, supplying a new strategy for hypoxic tumor elimination.     

Bioinspired Copper Single-Atom Catalysts for Tumor Parallel Catalytic Therapy

The oxidation of intracellular biomolecules by reactive oxygen species (ROS) forms the basis for ROS-based tumor therapy. However, the current therapeutic modalities cannot catalyze H₂O₂ and O₂ concurrently for ROS generation, thereby leading to unsatisfactory therapeutic efficacy. Herein, it is reported a bioinspired hollow N-doped carbon sphere doped with a single-atom copper species (Cu-HNCS) that can directly catalyze the decomposition of both oxygen and hydrogen peroxide to ROS, namely superoxide ion (O₂•⁻) and the hydroxyl radical (•OH), respectively, in an acidic tumor microenvironment for the oxidation of intracellular biomolecules without external energy input, thus resulting in an enhanced tumor growth inhibitory effect. Notably, the Fenton reaction turnover frequency of Cu species in Cu-HNCS is ≈5000 times higher than that of Fe in commercial Fe₃O₄ nanoparticles. Experimental results and density functional theory calculations reveal that the high catalytic activity of Cu-HNCS originates from the single-atom copper, and the calculation predicts a next-generation Fenton catalyst. This work provides an effective paradigm of tumor parallel catalytic therapy for considerably enhanced therapeutic efficacy.     

A Biomimetic Polymer Magnetic Nanocarrier Polarizing Tumor‐Associated Macrophages for Potentiating Immunotherapy

The progress of antitumor immunotherapy is usually limited by tumor‐associated macrophages (TAMs) that account for the highest proportion of immunosuppressive cells in the tumor microenvironment, and the TAMs can also be reversed by modulating the M2‐like phenotype. Herein, a biomimetic polymer magnetic nanocarrier is developed with selectively targeting and polarizing TAMs for potentiating immunotherapy of breast cancer. This nanocarrier PLGA‐ION‐R837 @ M (PIR @ M) is achieved, first, by the fabrication of magnetic polymer nanoparticles (NPs) encapsulating Fe₃O₄ NPs and Toll‐like receptor 7 (TLR7) agonist imiquimod (R837) and, second, by the coating of the lipopolysaccharide (LPS)‐ treated macrophage membranes on the surface of the NPs for targeting TAMs. The intracellular uptake of the PIR @ M can greatly polarize TAMs from M2 to antitumor M1 phenotype with the synergy of Fe₃O₄ NPs and R837. The relevant mechanism of the polarization is deeply studied through analyzing the mRNA expression of the signaling pathways. Different from previous reports, the polarization is ascribed to the fact that Fe₃O₄ NPs mainly activate the IRF5 signaling pathway via iron ions instead of the reactive oxygen species‐induced NF‐κB signaling pathway. The anticancer effect can be effectively enhanced through potentiating immunotherapy by the polarization of the TAMs in the combination of Fe₃O₄ NPs and R837.     

Synergistic Enzyme-Mimetic Catalysis-Based Non-Thermal Sonocavitation and Sonodynamic Therapy for Efficient Hypoxia Relief and Cancer Ablation (Small 42/2023)

Non-invasive cancer treatment strategies that enable local non-thermal ablation, hypoxia relief, and reactive oxygen species (ROS) production to achieve transiently destroying tumor tissue and long-term killing tumor cells would greatly facilitate their clinical applications. However, continuously generating oxygen cavitation nuclei, reducing the transient cavitation sound intensity threshold, relieving hypoxia, and improving its controllability in the ablation area still remains a significant challenge. Here, in this work, an Mn-coordinated polyphthalocyanine sonocavitation agent (Mn-SCA) with large d-π-conjugated network and atomic Mn-N sites is identified for the non-thermal sonocavitation and sonodynamic therapy in the liver cancer ablation. In the tumor microenvironment, the catalytical generation of oxygen assists cavitation formation and generates microjets to ablate liver cancer tissue and relieve hypoxia, this work reports for the first time to utilize the enzymatic properties of Mn-SCA to lower the cavitation threshold in situ. Moreover, under pHIFU irradiation, high reactive oxygen species (ROS) production can be achieved. The two merits in liver cancer ablation are demonstrated by cell destruction and high tumor inhibition efficiency. This work will help deepen the understanding of cavitation ablation and the sonodynamic mechanisms related to the nanostructures and guide the design of sonocavitation agents with high ROS production for solid tumor ablation.     

Catalytically Selective Chemotherapy from Tumor‐Metabolic Generated Lactic Acid

Lactic acid (LA) is a powerful molecule as the metabolic driver in tumor microenvironments (TMEs). Inspired by its high intratumoral level (5–20 µmol g^?1), a novel treatment paradigm via the cascade release of H₂O₂ and ·OH from the LA generated by tumor metabolism is developed for catalytic and pH‐dependent selective tumor chemotherapy. By utilizing the acidity and overexpression of LA within the TME, the constructed lactate oxidase (LOD)‐immobilized Ce‐benzenetricarboxylic acid (Ce‐BTC) metal organic framework enables the intratumoral generation of ·OH via a cascade reaction: 1) the in situ catalytic release of H₂O₂ from LA by LOD, and 2) the catalytic production of ·OH from H₂O₂ by Ce‐BTC with peroxidase‐like activity. Highly toxic ·OH effectively induces tumor apoptosis/death. A new strategy for selective tumor chemotherapy is provided herein.     

锆钛酸铅纳米陶瓷粉体的水热合成技术

阐述了水热合成法制备锆钛酸铅纳米陶瓷粉多晶体的原理、工艺过程及其特点,重点分析了水热法制备锆钛酸铅纳米陶瓷粉多晶体的溶解/沉淀和原位合成两种形成机制,以及工艺过程中的影响因素,如反应的温度、碱度、时间、粉体的洗涤、干燥等影响因素。通过分析得出水热法制备锆钛酸铅纳米陶瓷粉多晶体适宜的工艺参数为:反应温度150～220℃,碱度pH7～11.5,反应时间2～4h,采用冷冻干燥法可获得分散性好、粒度均匀的锆钛酸铅纳米粉体。     

Thermal Annealing and Graphene Modification of Exfoliated Hydrogen Titanate Nanosheets for Enhanced Lithium-ion Intercalation Properties

Hydrogen titanate has been considered as a promising lithium intercalation material due to its unique layered structure. In the present work, we fabricate 2D graphene/hydrogen titanate hybrid nanosheets for application as anode materials in lithium-ion batteries. H2Ti307 nanosheets are synthesized by exfoliation of a layered precursor via interacting bulky tetrabutylammonium （TBA＋） cations, followed by ion exchange with Na＋ ions and washing with water. The as-prepared hydrogen titanate nanosheets are well-dispersed exhibiting ultra-thin thickness with a lateral size up to a few micrometers. The sample is then annealed at 450, 650 Rnd 850 ℃, to optimize its Li＋-intercalation property. Heating at 450 ℃ leads to well-crystallized hydrogen titanate with a trace amount of TiO2. Heating at 650 and 850 ℃ results in mixed sodium titanates, since some sodium ions in the interlayer structure cannot be washed away and become chemically bonded to [TiO6] octahedra at high temperatures. Electrochemical properties of all the four samples are then evaluated by charged/discharged for 100 electrochemical cycles at 0.01-2.5 V vs. Li＋/Li at a specific current of 170 mA g-1. The unannealed hydrogen titanate delivers the highest initial discharge capacity of 130.5 mA h g-l, higher than 124.6 mA h g-1 from hydrogen titanate annealed at 450 ℃, as well as 101.3 and 63.8 mA h g-1 from hydrogen titanate annealed at 650 and 850℃, respectively, due to the high surface area from well-dispersed unannealed nanosheets. However, after 100 electrochemical cycles, well-crystallized hydrogen titanate annealed at 450 ℃ retain the highest charge capacity of 115.2 mA h g-1, corresponding to a capacity retention of 92.5%, while unannealed hydrogen titanate exhibits a final capacity of 72.1 mA h g-1 and a capacity retention of only 55.2%. To further improve energy density of lithium-ion battery, graphene/hydrogen titanate hybrid nanosheets are fabricated by adding graphene nanosheets into hydrogen titanates. The initial charge cap     

Piezo-Activated Atomic-Thin Molybdenum Disulfide/MXene Nanoenzyme for Integrated and Efficient Tumor Therapy via Ultrasound-Triggered Schottky Electric Field

Monolayer molybdenum disulfide (MoS₂) nanoenzymes exhibit a piezoelectric polarization, which generates reactive oxygen species to inactivate tumors under ultrasonic strain. However, its therapeutic efficiency is far away from satisfactory, due to stackable MoS₂, quenching of piezo-generated charges, and monotherapy. Herein, chitosan-exfoliated monolayer MoS₂ (Ch-MS) is composited with atomic-thin MXene, Ti₃C₂ (TC), to self-assemble a multimodal nanoplatform, Ti₃C₂-Chitosan-MoS₂ (TC@Ch-MS), for tumor inactivation. TC@Ch-MS not only inherits piezoelectricity from monolayer MoS₂, but also maintains remarkable stability. Intrinsic metallic MXene combines with MoS₂ to construct an interfacial Schottky heterojunction, facilitating the separation of electron–hole pairs and endowing TC@Ch-MS increase-sensitivity magnetic resonance imaging responding. Schottky interface also leads to peroxidase mimetics with excellent catalytic performance toward H₂O₂ in the tumor microenvironment under mechanical vibration. TC@Ch-MS possesses the superior photothermal conversion efficiency than pristine TC under near-infrared ray illumination, attributed to its enhanced interlaminar conductivity. Meanwhile, TC@Ch-MS realizes optimized efficiency on tumor apoptosis with immunotherapy. Therefore, TC@Ch-MS achieves an integrated diagnosis and multimodal treatment nanoplatform, whereas the toxicity to normal tissue cells is negligible. This work may shed fresh light on optimizing the piezoelectric materials in biological applications, and also give prominence to the significance of intrinsic metallicity in MXene.