Graphene Quantum Dots Nanoantibiotic-Sensitized TiO2- x Heterojunctions for Sonodynamic-Nanocatalytic Therapy of Multidrug-Resistant Bacterial Infections.

The exploration of sonodynamic therapy (SDT) as a possible replacement for antibiotics by creating reactive oxygen species (ROS) is suggested as a non-drug-resistant theranostic method. However, the low-efficiency ROS generation and complex tumor microenvironment which can deplete ROS and promote tumor growth will cause the compromised antibacterial efficacy of SDT. Herein, through an oxygen vacancy engineering strategy, TiO2- x microspheres with an abundance of Ti3+ are synthesized using a straightforward reductant co-assembly approach. The narrow bandgaps and Ti3+/Ti4+-mediated multiple-enzyme catalytic activities of the obtained TiO2- x microspheres make them suitable for use as sonosensitizers and nanozymes. When graphene quantum dot (GQD) nanoantibiotics are deposited on TiO2- x microspheres, the resulting GQD/TiO2- x shows an increased production of ROS, which can be ascribed to the accelerated separation of electron-hole pairs, as well as the peroxidase-like catalytic activity mediated by Ti3+, and the depletion of glutathione mediated by Ti4+. Moreover, the catalytic activities of TiO2- x microspheres are amplified by the heterojunctions-accelerated carrier transfer. In addition, GQDs can inhibit Topo I, displaying strong antibacterial activity and further enhancing the antibacterial activity. Collectively, the combination of GQD/TiO2- x-mediated SDT/NCT with nanoantibiotics can result in a synergistic effect, allowing for multimodal antibacterial treatment that effectively promotes wound healing.

Graphene Quantum Dots Eradicate Resistant and Metastatic Cancer Cells by Enhanced Interfacial Inhibition.

Drug-resistant and metastatic cancer cells such as a small population of cancer stem cells (CSCs) play a crucial role in metastasis and relapse. Conventional small-molecule chemotherapeutics, however, are unable to eradicate drug-resistant CSCs owing to limited interface inhibitory effects. Herein, it is reported that enhanced interfacial inhibition leading to eradication of drug-resistant CSCs can be dramatically induced by self-insertion of bioactive graphene quantum dots (GQDs) into DNA major groove (MAG) sites in cancer cells. Since transcription factors regulate gene expression at the MAG site, MAG-targeted GQDs exert greatly enhanced interfacial inhibition, downregulating the expression of a collection of cancer stem genes such as ALDH1, Notch1, and Bmi1. Moreover, the nanoscale interface inhibition mechanism reverses cancer multidrug resistance (MDR) by inhibiting MDR1 gene expression when GQDs are used at a nontoxic concentration (1/4 × half-maximal inhibitory concentration (IC50)) as the MDR reverser. Given their high efficacy in interfacial inhibition, CSC-mediated migration, invasion, and metastasis of cancer cells can be substantially blocked by MAG-targeted GQDs, which can also be harnessed to sensitize clinical cytotoxic agents for improved efficacy in combination chemotherapy. These findings elucidate the inhibitory effects of the enhanced nano-bio interface at the MAG site on eradicating CSCs, thus preventing cancer metastasis and recurrence.

Single Atom Catalysts Remodel Tumor Microenvironment for Augmented Sonodynamic Immunotherapy.

The immunosuppressive tumor microenvironment (TME) is a huge hurdle in immunotherapy. Sono-immunotherapy is a new treatment modality that can reverse immunosuppressive TME, but the sonodynamic effects are compromised by overexpressed glutathione (GSH) and hypoxia in the TME. Herein, this work reports a new sono-immunotherapy strategy using Pdδ+ single atom catalysts to enhance positive sonodynamic responses to the immunosuppressive and sono-suppressive TME. To demonstrate this technique, this work employs rich and reductive Ti vacancies in Ti3-xC2Ty nanosheets to construct the atomically dispersed Pd-C3 single atom catalysts (SAC) with Pd content up to 2.5 wt% (PdSA/Ti3-xC2Ty). Compared with Pd nanoparticle loaded Ti3-xC2Ty, PdSA/Ti3-xC2Ty single-atom enzyme showed augmented sonodynamic effects that are ascribed to SAC facilitated electron-hole separation, rapid depletion of overexpressed GSH by ultrasound (US) excited holes, and catalytic decomposition of endogenous H2O2 for relieving hypoxia. Importantly, the sono-immunotherapy strategy can boost abscopal antitumor immune responses by driving maturation of dendritic cells and polarization of tumor-associated macrophages into the antitumoral M1 phenotype. Bilateral tumor models demonstrate the complete eradication of localized tumors and enhance metastatic regression. Th strategy highlights the potential of single-atom catalysts for robust sono-immunotherapy by remodeling the tumor microenvironment.

Activation of Piezo1 increases the sensitivity of breast cancer to hyperthermia therapy.

Photothermal therapy (PTT) of nanomaterials is an emerging novel therapeutic strategy for breast cancer. However, there exists an urgent need for appropriate strategies to enhance the antitumor efficacy of PTT and minimize damage to surrounding normal tissues. Piezo1 might be a promising novel photothermal therapeutic target for breast cancer. This study aims to explore the potential role of Piezo1 activation in the hyperthermia therapy of breast cancer cells and investigate the underlying mechanisms. Results showed that the specific agonist of Piezo1 ion channel (Yoda1) aggravated the cell death of breast cancer cells triggered by heat stress in vitro. Reactive oxygen species (ROS) production was significantly increased following heat stress, and Yoda1 exacerbated the rise in ROS release. GSK2795039, an inhibitor of NADPH oxidase 2 (NOX2), reversed the Yoda1-mediated aggravation of cellular injury and ROS generation after heat stress. The in vivo experiments demonstrate the well photothermal conversion efficiency of TiCN under the 1,064 nm laser irradiation, and Yoda1 increases the sensitivity of breast tumors to PTT in the presence of TiCN. Our study reveals that Piezo1 activation might serve as a photothermal sensitizer for PTT, which may develop as a promising therapeutic strategy for breast cancer.

Tumour microenvironment-responded Fe-doped carbon dots-sensitized cubic Cu2O for Z-scheme heterojunction-enhanced sono-chemodynamic synergistic tumor therapy.

The efficacy of electron-hole separation in a single sonosensitizer and the complexities of the tumor microenvironment (TME) present significant challenges to the effectiveness of sonodynamic therapy (SDT). Designing efficient sonosensitizers to enhance electron-hole separation and alleviate TME resistance is crucial yet challenging. Herein, we introduce a novel Z-scheme heterojunctions (HJs) sonosensitizer using Fe-doped carbon dots (CDs) as auxiliary semiconductors to sensitize cubic Cu2O (Fe-CDs@Cu2O) for the first time. Fe-CDs@Cu2O demonstrated enhanced SDT effects due to improved electron-hole separation. Additionally, the introduction of Fe ions in CDs synergistically enhances Fenton-like reactions with Cu ions in Cu2O, resulting in enhanced chemodynamic therapy (CDT) effects. Moreover, Fe-CDs@Cu2O exhibited rapid glutathione (GSH) depletion, effectively mitigating TME resistance. With high rates of 1O2 and OH generated by Fe-CDs@Cu2O, coupled with strong GSH depletion, single drug injection and ultrasound (US) irradiation effectively eliminate tumors. This innovative heterojunction sonosensitizer offers a promising pathway for clinical anti-tumor treatment.

An NIR-II-photoresponsive CoSnO3 nanozyme for mild photothermally augmented nanocatalytic cancer therapy.

The main challenges of nanozyme-based tumor catalytic therapy (NCT) lie in the unsatisfactory catalytic activity accompanied by a complex tumor microenvironment (TME). A few nanozymes have been designed to possess both enzyme-like catalytic activities and photothermal properties; however, the previously reported nanozymes mainly utilize the inefficient and unsafe NIR-I laser, which has a low maximum permissible exposure limit and a limited penetration depth. Herein, we report for the first time an all-in-one strategy to realize mild NIR-II photothermally amplified NCT by synthesizing amorphous CoSnO3 nanocubes with efficient triple enzyme-like catalytic activities and photothermal conversion properties. The presence of Co2+ and Sn4+ endows CoSnO3 nanocubes with the triple enzyme-like catalytic activities, not only achieving enhanced reactive oxygen species (ROS) generation through the Co2+-mediated peroxidase-like catalytic reaction to generate ˙OH and Sn4+-mediated depletion of overexpressed GSH, but also realizing the catalytic decomposition of endogenous H2O2 for relieving tumor hypoxia. More importantly, the obtained CoSnO3 nanocubes with a high photothermal conversion efficiency of 82.1% at 1064 nm could achieve mild hyperthermia (43 °C), which further improves the triple enzyme-like catalytic activities of the CoSnO3 nanozyme. The synergetic therapeutic efficacy of the NIR-II-responsive CoSnO3 nanozyme through mild NIR-II PTT-enhanced NCT could realize all-in-one multimodal tumor therapy to completely eliminate tumors without recurrence. This study will open a new avenue to explore NIR-II-photoresponsive nanozymes for efficient tumor therapy.

A Sonoresponsive and NIR-II-Photoresponsive Nanozyme for Heterojunction-Enhanced "Three-in-One" Multimodal Oncotherapy.

Although low-cost nanozymes with excellent stability have demonstrated the potential to be highly beneficial for nanocatalytic therapy (NCT), their unsatisfactory catalytic activity accompanied by intricate tumor microenvironment (TME) significantly hinders the therapeutic effect of NCT. Herein, for the first time, a heterojunction (HJ)-fabricated sonoresponsive and NIR-II-photoresponsive nanozyme is reported by assembling carbon dots (CDs) onto TiCN nanosheets. The narrow bandgap and mixed valences of Ti3+ and Ti4+ endow TiCN with the capability to generate reactive oxygen species (ROS) when exposed to ultrasound (US), as well as the dual enzyme-like activities of peroxidase and glutathione peroxidase. Moreover, the catalytic activities and sonodynamic properties of the TiCN nanosheets are boosted by the formation of HJs owing to the increased speed of carrier transfer and the enhanced electron-hole separation. More importantly, the introduction of CDs with excellent NIR-II photothermal properties could achieve mild hyperthermia (43 °C) and thereby further improve the NCT and sonodynamic therapy (SDT) performances of CD/TiCN. The synergetic therapeutic efficacy of CD/TiCN through mild hyperthermia-amplified NCT and SDT could realize "three-in-one" multimodal oncotherapy to completely eliminate tumors without recurrence. This study opens a new avenue for exploring sonoresponsive and NIR-II-photoresponsive nanozymes for efficient tumor therapy based on semiconductor HJs.

A Two-Generation Reproductive Toxicity Study of Cerium Nitrate in Sprague-Dawley Rats.

A two-generation reproductive toxicity study was performed to evaluate the effects of cerium nitrate on the development of the parent, offspring, and third generation of Sprague-Dawley (SD) rats. A total of 240 SD rats (30 rats/sex/group) were randomly divided into four dosage groups according to body weight: 0 mg/kg, 30 mg/kg, 90 mg/kg, and 270 mg/kg. The rats were administered different dosages of cerium nitrate by oral gavage. There were no observed changes related to cerium nitrate in body weight, food consumption, sperm survival rate, motility, mating rate, conception rate, abortion rate, uterine plus fetal weight, uterine weight, corpus luteum number, implantation rate, live fetus number (rate), stillbirth number (rate), absorbed fetus number (rate), appearance, visceral, and skeletal in rats of each generation dosage group. In addition, the pathological findings showed no significant lesions associated with cerium nitrate toxicity in all tissues and organs, including reproductive organs. In conclusion, the present study showed that long-term oral gavage of cerium nitrate at 30 mg/kg, 90 mg/kg, and 270 mg/kg had no significant effect on reproduction and the developmental ability of their offspring in rats. The no-observed-adverse-effect level (NOAEL) of cerium nitrate in SD rats was higher than 270 mg/kg.

In Situ Synthesis of Ru/TiO2- x @TiCN Ternary Heterojunctions for Enhanced Sonodynamic and Nanocatalytic Cancer Therapy.

Albeit nanozymes-based tumor catalytic therapy (NCT) relies on endogenous chemical reactions that could achieve tumor microenvironment (TME)-specialized reactive oxygen species (ROS) production, the unsatisfactory catalytic activity of nanozymes accompanied by complex TME poses a barrier to the therapeutic effect of NCT. Herein, a one-step in situ synthesis strategy is reported to construct ternary Ru/TiO2- x @TiCN heterojunctions through oxidative conversion of TiCN nanosheets (NSs) to TiO2- x NSs and reductive deposition of Ru3+ to Ru nanoparticles. The narrow bandgap and existence of heterojunctions enhance the ultrasound-activated ROS generation of Ru/TiO2- x @TiCN because of the accelerated electron transfer and inhibits electron-hole pair recombination. The augmented ROS production efficiency is achieved by Ru/TiO2- x @TiCN with triple enzyme-like activities, which amplifies the ROS levels in a cascade manner through the catalytic decomposition of endogenous H2 O2 to relieve hypoxia and heterojunction-mediated NCT, as well as depletion of overexpressed glutathione. The satisfactory therapeutic effects of Ru/TiO2- x @TiCN heterojunctions are achieved through synergetic sonodynamic therapy and NCT, which achieve the complete elimination of tumors without recurrence. This strategy highlights the potential of in situ synthesis of semiconductor heterojunctions as enhanced sonosensitizers and nanozymes for efficient tumor therapy.

N-Heterocycle Modified Graphene Quantum Dots as Topoisomerase Targeted Nanoantibiotics for Combating Microbial Infections.

Developing next-generation antibiotics to eliminate multidrug-resistant (MDR) bacteria/fungi and stubborn biofilms is challenging, because of the excessive use of currently available antibiotics. Herein, the fabrication of anti-infection graphene quantum dots (GQDs) is reported, as a new class of topoisomerase (Topo) targeting nanoantibiotics, by modification of rich N-heterocycles (pyridinic N) at edge sites. The membrane-penetrating, nucleus-localizing, DNA-binding GQDs not only damage the cell walls/membranes of bacteria or fungi, but also inhibit DNA-binding proteins, such as Topo I, thereby affecting DNA replication, transcription, and recombination. The obtained GQDs exhibit excellent broad-spectrum antimicrobial activity against non-MDR bacteria, MDR bacteria, endospores, and fungi. Beyond combating planktonic microorganisms, GQDs inhibit the formation of biofilms and can kill live bacteria inside biofilms. RNA-seq further demonstrates the upregulation of riboflavin biosynthesis genes, DNA repair related genes, and transport proteins related genes in methicillin-resistant S. aureus (MRSA) in response to the stress induced by GQDs. In vivo animal experiments indicate that the biocompatible GQDs promote wound healing in MRSA or C. albicans-infected skin wound models. Thus, GQDs may be a promising antibacterial and antifungal candidate for clinical applications in treating infected wounds and eliminating already-formed biofilms.

Subchronic toxicity study of ferric oxide nanoparticles through intragastric administration: A 94-d, repeated dose study in Sprague Dawley rats.

In this study, the toxicity of ferric oxide nanoparticles (Fe2O3 NPs) administered through gavage to Sprague Dawley (SD) rats for 94 d, consecutively and the recovery after Fe2O3 NPs withdrawal for 30 d were evaluated. The vehicle control group, low-, medium-, and high-dose groups were administered with the vehicle (0.5% sodium carboxymethyl cellulose [CMC-Na]), 125, 250, and 500 mg/kg of Fe2O3 NPs, respectively, administered every morning for 94 d. There was no significant difference in the body weight, food intake, hematological, blood biochemical, and urine indices of SD rats in each administration group and the control group (P > 0.05). There was no significant difference in organ weight, organ indices, and the coefficient of the visceral brain between the SD rats in the different dosage groups and the SD rats in the vehicle control group (P > 0.05). Histopathological observations showed that there was no correlation between the pathological lesions of the organs observed in this study and the dose of Fe2O3 NPs (P > 0.05). The no-observed-adverse-effect level (NOAEL) dose of Fe2O3 NPs was initially determined to be 500 mg/kg administered to SD rats through oral gavage for 94 d, consecutively, followed by recovery after Fe2O3 NPs withdrawal for 30 d.

Evaluation of subchronic toxicity of the compound of diphenhydramine hydrochloride and caffeine after 28 days of repeated oral administration in Sprague-Dawley rats and beagle dogs.

This study was designed to evaluate the subchronic toxicity of the compound of diphenhydramine hydrochloride (DH) and caffeine in Sprague-Dawley (SD) rats and beagle dogs. A total of 180 SD rats (15/sex/group) were randomly divided into the compound low-, medium- and high-dose groups (51, 102, 204 mg/kg), DH group (60 mg/kg), caffeine group (144 mg/kg) and the vehicle control group. Sixty beagle dogs (5/sex/group) were randomly divided into the compound low-, medium- and high-dose groups (male: 14.20, 28.30, 56.60 mg/kg, female: 5.66, 14.20, 28.30 mg/kg), DH group (male: 16.60 mg/kg, female: 8.30 mg/kg), caffeine group (male: 40.00 mg/kg, female: 20.00 mg/kg) and the vehicle control group. Rats and dogs were given continuous oral administration for 28 days following a 28-day recovery period. The adverse effects of the compound on rats and beagle dogs mainly included anorexia and liver function impairment. Most adverse effects induced by administration were reversible. Under the experimental conditions, the no-observed-adverse-effect level (NOAEL) of the compound of DH and caffeine was 51 mg/kg/day for SD rats and 28.30 mg/kg/day (male) and 5.66 mg/kg/day (female) for beagle dogs.

Carbon Dot@MXene Nanozymes with Triple Enzyme-Mimic Activities for Mild NIR-II Photothermal-Amplified Nanocatalytic Therapy.

Nanozymes have shown promising potential in disease treatment owing to the advantages of low-cost, facile fabrication, and high stability. However, the highly complex tumor microenvironment (TME) and inherent low catalytic activity severely restrict the clinical applications of nanozymes. Herein, a novel mild hyperthermia-enhanced nanocatalytic therapy platform based on Z-scheme heterojunction nanozymes by depositing N-doped carbon dots (CDs) onto Nb2 C nanosheets is constructed. CD@Nb2 C nanozymes not only display outstanding photothermal effects in the safe and efficient NIR-II window but also possess triple enzyme-mimic activities to obtain amplified ROS levels. The triple enzyme-mimic activities and NIR-II photothermal properties of CD nanozymes are enhanced by the construction of Z-scheme heterojunctions owing to the accelerated carrier transfer process. More importantly, the introduction of mild hyperthermia can further improve the peroxidase-mimic and catalase-mimic activities as well as the glGSH depletion abilities of CD@Nb2 C nanozymes, thereby producing more ROS to efficiently inhibit tumor growth. The combined therapy effect of CD@Nb2 C nanozymes through mild NIR-II photothermal-enhanced nanocatalytic therapy can achieve complete tumor eradication. This work highlights the efficient tumor therapy potential of heterojunction nanozymes.

The reproductive toxicity of yttrium nitrate in a two-generation study in Sprague-Dawley rats.

OBJECTIVE: To evaluate the effects of yttrium nitrate on the development of the parent, offspring and third generation of Sprague-Dawley (SD) rats by using a two-generation reproductive toxicity test. METHODS: The SD rats were randomly divided into 0 mg/kg group, 10.0 mg/kg group, 30.0 mg/kg group and 90.0 mg/kg group according to the different doses of yttrium nitrate administration. The reproductive toxicity of parent, offspring and third generation SD rats were compared. RESULTS: The weight gains of F1a female rats and F2a female rats in the low-dose groups were significantly lower than those of the control groups (p < 0.05), the weight gains of F1a male rats in the medium-dose and high-dose groups were significantly lower than those of the control groups (p < 0.05), and the weight gains of F2a male rats in the low-dose, medium-dose and high-dose groups were significantly lower than those of the control groups (p < 0.05). In F0 male rats, the absolute weight and relative weight of the liver in the low-dose, middle-dose, and high-dose groups were significantly lower than those of the control group (p < 0.05). In F1b male rats, the absolute and relative weights of the liver in the medium-dose and high-dose groups were significantly lower than those of the control group (p < 0.05). In F2b male rats, the absolute and relative weights of the liver and spleen of the medium-dose and high-dose groups were significantly lower than those of the control group (p < 0.05). In F2a female rats, the absolute weight and relative weight of oviduct in the high-dose group were significantly lower than those in the control group (p < 0.05). The absolute and relative weights of lung, spleen, brain and uterus of F2b female rats in the high-dose group were higher than those of the control group (p < 0.05). But the pathological test results showed no hepatotoxicity. There was no statistically significant difference in sperm count and sperm motility between male rats in the yttrium nitrate administration groups and the control group (p > 0.05). There was no significant correlation between F0, F1a, F1b, F2a, F2b SD rats' reproductive organ lesions and the dose of yttrium nitrate. CONCLUSION: Yttrium nitrate at a dose of 90 mg/kg has no reproductive toxicity to two generations of SD rats, but 30.0 mg/kg dose of yttrium nitrate is toxic to the liver weight of male two generations of SD rats, but no hepatotoxicity.

Near-infrared phosphorescent carbon dots for sonodynamic precision tumor therapy.

Theranostic sonosensitizers with combined sonodynamic and near infrared (NIR) imaging modes are required for imaging guided sonodynamic therapy (SDT). It is challenging, however, to realize a single material that is simultaneously endowed with both NIR emitting and sonodynamic activities. Herein, we report the design of a class of NIR-emitting sonosensitizers from a NIR phosphorescent carbon dot (CD) material with a narrow bandgap (1.62 eV) and long-lived excited triplet states (11.4 µs), two of which can enhance SDT as thermodynamically and dynamically favorable factors under low-intensity ultrasound irradiation, respectively. The NIR-phosphorescent CDs are identified as bipolar quantum dots containing both p- and n-type surface functionalization regions that can drive spatial separation of e--h+ pairs and fast transfer to reaction sites. Importantly, the cancer-specific targeting and high-level intratumor enrichment of the theranostic CDs are achieved by cancer cell membrane encapsulation for precision SDT with complete eradication of solid tumors by single injection and single irradiation. These results will open up a promising approach to engineer phosphorescent materials with long-lived triplet excited states for sonodynamic precision tumor therapy.

Graphitic-N-doped graphene quantum dots for photothermal eradication of multidrug-resistant bacteria in the second near-infrared window.

Developing efficient therapeutic strategies for combating bacterial infection remains a challenge owing to the indiscriminate utilization of antibiotics and the prevalence of multidrug-resistant (MDR) bacteria. Herein, highly graphitic-N-doped graphene quantum dots (N-GQDs) with efficient NIR-II photothermal conversion properties were synthesized for the first time for photothermal antibacterial therapy. The obtained N-GQDs exhibited strong NIR absorption ranging from 700 to 1200 nm, achieving high photothermal conversion efficiency of 77.8% and 50.4% at 808 and 1064 nm, respectively. Outstanding antibacterial and antibiofilm activities against MDR bacteria (methicillin-resistant Staphylococcus aureus, MRSA) were achieved by the N-GQDs in the presence of an 808 or 1064 nm laser. In vivo investigations verified that the generation of hyperthermia by N-GQDs plus a NIR-II laser can combat MDR bacterial infections and thus significantly accelerate wound healing. Our work provides a novel carbon-based nanomaterial as a photothermal antibacterial agent for efficiently avoiding bacterial resistance and fighting MDR bacterial infections.

Agaric-like cobalt diselenide supported by carbon nanofiber as an efficient catalyst for hydrogen evolution reaction.

We synthesized herein a novel 3D cathode constructed by growing cobalt diselenide in situ on the surface of carbon nanofiber for hydrogen evolution reaction. The cobalt diselenides with two typical morphologies (agaric-like and nanorod-like) were synthesized by precisely controlling reaction time and temperature in the same system. They show excellent electrocatalytic performance for hydrogen evolution reactions. Especially, the agaric-like diselenide cobalt electrode has the low overpotential (187 and 199 mV) to obtain the current density of 50 and 100 mA cm-2 with a small Tafel slope of 37 mV dec-1 in acidic medium. The excellent catalytic performance of the agaric-like cobalt diselenide can be attributed to its large specific surface area and fast electron transfer rate. More importantly, the agaric-like cobalt diselenide supported carbon nanofiber electrode has excellent long-term stability in electrolyte. The outstanding electrocatalytic performance and stability of agaric-like cobalt diselenide supported carbon nanofiber indicate that it is a promising electrocatalyst for hydrogen evolution reactions.

Platinum Crosslinked Carbon Dot@TiO2-x p-n Junctions for Relapse-Free Sonodynamic Tumor Eradication via High-Yield ROS and GSH Depletion.

Sonodynamic therapy as a promising noninvasive modality is being developed for tumor therapy, but there is a lack of next-generation sonosensitizers that can generate full ROS at high yields and simultaneously deplete elevated levels of glutathione (GSH) in tumor cells. Semiconductor p-n junctions are engineered as high-efficacy sonosensitizers for sonodynamic tumor eradication using pyridine N-doped carbon dots (N-CDs) as a p-type semiconductor and oxygen-deficient TiO2-x nanosheets as a n-type semiconductor. The rate constants of 1 O2 and •OH generation by ultrasound-excited N-CD@TiO2-x p-n junctions are 4.3 and 4.5 times higher than those of TiO2 , respectively. A Z-scheme carrier migration mechanism in the p-n junction achieving the rapid spatial separation of the ultrasound-generated electron-hole pairs for enhanced full ROS production is proposed. GSH-cleavable, Pt-crosslinked, N-doped CD fluorescent probes to detect the presence of intracellular GSH are also constructed. A GSH-responsive, p-n junction platform (Pt/N-CD@TiO2-x ) with integrated GSH detection, GSH depletion, and enhanced sonodynamic performance is then assembled. Malignant tumors are completely eradicated without relapse via intravenous administration of low-dose Pt/N-CD@TiO2-x under ultrasound irradiation. This work substantiates the great potential of biocompatible, GSH-responsive p-n junctions as next-generation sonosensitizers via p-n junction-enhanced ROS generation and metal ion oxidation of intracellular GSH.

A Two-Generation Reproductive Toxicity Study of Lanthanum Nitrate in SD Rats.

In order to evaluate the effects of lanthanum nitrate on the development of the parent, offspring, and the third generation of Sprague-Dawley (SD) rats, a two-generation reproductive toxicity experiment, was conducted. Two hundred and forty specific pathogen-free (SPF) healthy SD rats were randomly divided into the control group, low-, medium-, and high-dose group, with 30 male and 30 female rats in each group. The rats in each group were given 0 mg/kg, 10.0 mg/kg, 30.0 mg/kg, and 90.0 mg/kg lanthanum nitrate by gavage, respectively. There was no statistically significant difference between the weight gain and food intake of rats in each group. High-dose lanthanum nitrate had no effect on rat implantation and no embryo toxicity. The absolute and relative liver weights of F1a and F1b male rats in the high-dose group were significantly decreased. The absolute liver and spleen weight of F1b female rats in the high-dose group decreased significantly, but the relative weight did not change significantly. Histopathological examination results showed that there were no significant differences in the effects of different doses of lanthanum nitrate on the uterus, ovaries, oviduct, testes and epididymis, and liver of SD rats. Under the experimental conditions, 90.0 mg/kg lanthanum nitrate had an effect on the liver weight of the SD rats, but there was no liver toxicity. The no visible harmful effect level (NOAEL) of lanthanum nitrate on SD rats' reproduction toxicity is 90 mg/kg.

W-Doped TiO2 Nanorods for Multimode Tumor Eradication in Osteosarcoma Models under Single Ultrasound Irradiation.

Sonosensitizers play crucial roles in the controlled production of reactive oxygen species (ROS) under ultrasound (US) irradiation with high tissue-penetration depth for noninvasive solid tumor therapy. It is desirable to fabricate structurally simple yet multifunctional sonosensitizers from ultrafine nanoparticles for ROS-based multimode therapy to overcome monomode limitations such as low ROS production yields and endogenous reductive glutathione (GSH) to ROS-based treatment resistance. We report the facile high-temperature solution synthesis of ultrafine W-doped TiO2 (W-TiO2) nanorods for exploration of their sonodynamic, chemodynamic, and GSH-depleting activities in sonodynamic-chemodynamic combination tumor therapy. We found that W5+ and W6+ ions doped in W-TiO2 nanorods play multiple roles in enhancing their ROS production. First, W doping narrows the band gap from 3.2 to 2.3 eV and introduces oxygen and Ti vacancies for enhancing their sonodynamic performance. Second, W5+ doping endows W-TiO2 nanorods with Fenton-like reaction activity to produce •OH from endogenous H2O2 in the tumor. Third, W6+ ions reduce endogenous GSH to glutathione disulfide (GSSG) and, in turn, form W5+ ions that further enhance their chemodynamic activity, which greatly modifies thae oxidation-reduction tumor microenvironment in the tumor. In vivo experiments display the excellent ability of W-TiO2 nanorods for enhanced tumor eradication in human osteosarcoma models under single US irradiation. Importantly, the ultrafine nanorod morphology facilitates rapid excretion from the body, displaying no significant systemic toxicity. Our work suggests that multivalent metal doping in ultrafine nanomaterials is an effective and simple strategy for the introduction of new functions for ROS-based multimode therapy.