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Diabetes is an increasingly common disease that poses an immense challenge to public health. Hyperglycemia is also a common complication in clinical patients in the intensive care unit, increasing the rate of infection and mortality. The accurate and real-time prediction of blood glucose concentrations after each short-acting insulin injection has great clinical significance and is the basis of all intelligent blood glucose control systems. Most previous prediction methods require long-term continuous blood glucose records from specific patients to train the prediction models, resulting in these methods not being used in clinical practice. In this study, we construct 13 deep neural networks with different architectures to atomically predict blood glucose concentrations after arbitrary independent insulin injections without requiring continuous historical records of any patient. Using our proposed models, the best root mean square error of the prediction results reaches 15.82 mg/dL, and 99.5% of the predictions are clinically acceptable, which is more accurate than previously proposed blood glucose prediction methods. Through the re-validation of the models, we demonstrate the clinical practicability and universal accuracy of our proposed prediction method.
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Glicemia , Diabetes Mellitus Tipo 1 , Humanos , Insulina de Ação Curta , Automonitorização da Glicemia/métodos , Insulina/uso terapêuticoRESUMO
Importance: Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC. Objective: To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC. Design, Setting, and Participants: This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021. Interventions: Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks. Main Outcomes and Measures: The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events. Results: Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group. Conclusions and Relevance: Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT04063163.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Método Duplo-Cego , Etoposídeo/efeitos adversos , Feminino , Humanos , Inibidores de Checkpoint Imunológico , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1 , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/etiologiaRESUMO
Zn2SiO4, Zn2GeO4, and CdAl2O4 possess high electron density in their six-membered-ring nanotunnels, manganese from MnO2 was successfully doped into them, and green or blue phosphors were produced in air. It is nanotunnel A with high electron density that induces active sites for the reduction of MnIV. MnIV is captured and reduced to MnII on active sites by seizing two electrons from native defect VO× (VO× + Mn4+ â VO·· + Mn2+). CdB4O7:0.02Mn2+ was also synthesized from MnO2 or MnCO3 to confirm the role of nanotunnels. Such inorganic crystals with unique nanotunnel structure may bring more amazing performances in the field of materials in the future.
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A series of Sr2ZnWO6 phosphors co-doped with Eu(3+), Bi(3+) and Li(+) were prepared using the Pechini method. The samples were tested using X-ray diffraction and luminescence spectroscopy. The results show that the samples can be effectively excited by near-ultraviolet (UV) and UV light. The introduction of Bi(3+) and Li(+) significantly enhances the fluorescence emission of Sr2ZnWO6 :Eu(3+) and changes the light emitted by the phosphors from bluish-green to white. When excited at 371 nm, Sr(2-x-z)Zn(1-y)WO6:xEu(3+), yBi(3+), zLi(+) (x = 0.05, y = 0.05, z = 0.05, 0.1 and 0.15) samples emit high-performance white light. Intense red-orange emission is also observed when excited by UV light. The obtained phosphor is a potential white-emitting phosphor that could meet the needs of excitation sources with near-UV chips. In addition, this phosphor might have promising application as a red-orange emitting phosphor for white light-emitting diodes based on UV light-emitting diodes.
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Bismuto/química , Európio/química , Luz , Lítio/química , Substâncias Luminescentes/química , Estrôncio/química , Tungstênio/química , Zinco/química , Medições LuminescentesRESUMO
A novel single-component warm white light-emitting Sr(2)Ca(0.995)MoO(6): Sm(3+) (0.005) phosphor was synthesized by solid-state reaction. The photoluminescence excitation spectra ranging from 300 to 450 nm and 460 to 500 nm broadly are observed. Direct full-color warm white light [(x, y) = 0.3221, 0.3525] was realized in this single-phase phosphor with exposure to 380 nm UV light. When this phosphor is pumped by 466 nm radiation we obtained yellow emission with an intense red component, suggesting that this material is also competitive as a blue-pumped yellow phosphor. Thus two approaches to white light are realized simultaneously in Sm(3+) doped single-component phosphor for the first time. The quantum yield and the reliability of the as-synthesized phosphors for White LED applications were also investigated.
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Luz , Substâncias Luminescentes/química , Análise Espectral , Temperatura , Difração de Raios XRESUMO
In recent years, photodynamic therapy (PDT) or chemodynamic therapy (CDT) based on the antimicrobial property or anti-biofilm property of reactive oxygen species (ROS) have been widely recognized for their low susceptibility to microbial resistance. However, due to the complication of the three-dimensional structure of the biofilm at the wound site and the high quenching rate of common ROS, the treatment with traditional ROS could not achieve satisfactory wound healing effects. Here, Na2S2O8@ZIF-67/GOx nanoparticles (NZG NPs) were prepared as a new high-toxic ROS nanogenerator for application of biofilm-infecting wound healing with the assistance of glucose oxidase (GOx) for amplified CDT and immune activation. When the NZG NPs entered the biofilm, Co-based metal organic frame (ZIF-67) ruptured in the acidic microenvironment, which induced the release of GOx and the production of gluconic acid and H2O2, further promoting the decrease of pH of the biofilm microenvironment and in turn accelerating the cleavage of ZIF-67 and the release of Na2S2O8. Then, S2O82- could gradually transformed into high-toxic sulfate radical (SO4-), part of which further produced OH in situ with H2O, thereby inhibiting the proliferation of bacteria and biofilms. Interestingly, these two types of ROS not only caused direct damage to the biofilm, but also activated the immune system of the wound site as well as the body more effectively, which also played an indirect role in promoting biofilm destruction and wound healing. In vitro and in vivo results showed that, as a new high-toxic ROS nanogenerator, the NZG NPs supply amplified chemodynamic therapy and immune activation to destroy biofilms, but also achieve effective wound healing without causing bacterial tolerance, which provides a new strategy for the development of biofilm-infecting wound healing.
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Anti-Infecciosos , Estruturas Metalorgânicas , Estruturas Metalorgânicas/farmacologia , Glucose Oxidase , Peróxido de Hidrogênio/farmacologia , Cicatrização , Anti-Infecciosos/farmacologia , Íons/farmacologiaRESUMO
Antibiotics show unsuccessful application in biofilm destruction, which induce chronic infections and emergence of antibiotic resistant bacteria. Photodynamic therapy (PDT) and photothermal therapy (PTT), as widely accepted antimicrobial tools of phototherapy, could effectively activate the immune system and promote the proliferation of wound tissue, thus becoming the most promising therapeutic strategy to replace antibiotics and avoid drug-resistant strains. However, there is no consensus on whether antibacterial and wound healing achieved by PDT/PTT depend not only on the cytotoxic effect of the treatment itself, but also on the activation of host immune system. In this study, CaSiO3-ClO2@PDA-ICG nanoparticles (CCPI NPs) were designed as PDT/PTT antimicrobial model material. With the comparison of healing effect between wide-type mice and severely immunodeficient (C-NKG) mice, the dependence of PDT/PTT-induced microbial apoptosis and wound healing on immune activation and macrophage phenotype transformation was explored and verified. Furthermore, the induced phenotypic transformation of macrophages during PDT/PTT treatment was demonstrated to play crucial role in the improvement of epithelial-mesenchymal transformation (EMT). In summary, this study represents great significance for further identifying the role of immune system activation in antibacterial phototherapy and developing new treatment strategies for biofilm-infected wound healing. STATEMENT OF SIGNIFICANCE: A PDT/PTT combination therapy model nanoparticle was established for biofilm-infected wounds. Both microbial apoptosis and wound healing achieved by PDT/PTT combination therapy were highly dependent on the activated immune system, especially the M2 macrophage phenotype. PDT/PTT could promote the polarization of monocytes to the phenotype of M2 macrophages, which promotes EMT behavior of the tissue at the edge of the wound through the secretion of TGF-ß1, thus accelerating wound healing.
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Fotoquimioterapia , Camundongos , Animais , Terapia Fototérmica , Macrófagos , Antibacterianos , CicatrizaçãoRESUMO
Ferric phosphate (FePOs) nanoenzymes can express peroxidase (POD) activity under the dual stimulation of an acidic environment and high H2O2 concentrations. In living organisms, this generates reactive oxygen species (ROS) in sites of lesion infection, and thus FePOs nanoenzymes can act as antimicrobial agents. Here, CeO2 and ZnO2 were immobilized in a scallop-type FePOs nanoenzyme material loaded with a photosensitizer, indocyanine green, to synthesize a multifunctional cascade nanoparticle system (FePOs-CeO2-ZnO2-ICG, FCZI NPs). H2O2 concentrations could be adjusted through the ZnO2 self-activation response to the slightly acidic environment in biofilms, further promoting the release of ROS from the POD-like reaction of FePOs, achieving amplification of oxidative stress, DNA and cell membrane damage, and exploiting the photodynamic/photothermal effects of indocyanine green to enhance the antibiofilm effects. CeO2 can remove redundant ROS by switching from Ce4+ to Ce3+ valence, enhancing its ability to fight chronic inflammation and oxidative stress and thus promoting the regeneration of tissues around infection. By maintaining the redox balance of normal cells, increasing ROS at the infection site, eliminating redundant ROS, and protecting normal tissues from damage, the synthesized system maximizes the elimination of biofilms and treatment at the infection site. Therefore, this work may pave the way for the application of biocompatible nanoenzymes.
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Nanopartículas , Fotoquimioterapia , Óxido de Zinco , Espécies Reativas de Oxigênio/metabolismo , Verde de Indocianina/farmacologia , Óxido de Zinco/farmacologia , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo , Antibacterianos/farmacologia , Concentração de Íons de HidrogênioRESUMO
Application of Combined photodynamic therapy (PDT) and photothermal therapy (PTT) has become one of the most promising strategy to replace antibiotics and avoid the epidemic of drug-resistant strains during wound healing. However, high amount of reactive oxygen species (ROS) and high temperature cause severe stress response to normal tissues, leading to potential risks of wound healing. Herein, a three-dimension chitosan hydrogel melanin-glycine-C60 nanoparticles (MGC NPs) were prepared to realized effective anti-bacterial activity, immune activation and macrophage autophagy promotion in three-dimensional wound space without triggering stress response. MGC NP is a composite polymer material composed of natural melanin polymer, oligopeptide and carbon-based material, which showed excellent biological safety. By regulating the peptide length between melanin and C60 and nanoparticle content, a high ROS/heat environment at the upper wound site and a low ROS/heat environment at the lower region adjacent to the wound tissue were established to obtain a three-dimension hydrogel with precise PDT and PTT efficiency in different regions. Highly effective PDT/PTT was used to kill microorganisms in upper region, thus providing a barrier to reduce microbial infection. Mild PDT/PTT in lower region promoted the polarization of M1 macrophage to M2 macrophage and activated autophagy of M2 macrophages, regulating the immune microenvironment and promoting wound repair. In conclusion, the novel three-dimensional PDT/PTT therapy based on natural macromolecules proposed in this study accelerates wound healing through dual pathways on the premise of avoiding wound stress response, which is of great significance for the development of clinical strategies for phototherapy.
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Quitosana , Nanopartículas , Fotoquimioterapia , Quitosana/farmacologia , Melaninas/farmacologia , Hidrogéis/farmacologia , Espécies Reativas de Oxigênio/farmacologia , Nanopartículas/química , Macrófagos , Cicatrização , Antibacterianos/farmacologiaRESUMO
Owing to the severe photogenerated carriers recombination and low oxidation ability, the photocatalytic performance of pristine CsPbBr3 is still unsatisfactory. Herein, melamine foam supported S-scheme WO3/CsPbBr3 heterojunction is successfully synthesized by electrostatic self-assembly. Because of the appropriate energy level positions, an S-scheme charge migration route between CsPbBr3 and WO3 is constructed. Under solar light irradiation, melamine foam assisted WO3/CsPbBr3 exhibits significantly enhanced photocatalytic CO2 reduction performance under liquid H2O medium, and the electron consumption rate (Relectron) reaches to 1225.50 µmol.g-1.h-1, which is 1.49- and 13.7-fold of CsPbBr3 and WO3, respectively, ascribing to the boosted charges transfer and the strengthened redox ability. Furthermore, S-scheme WO3/CsPbBr3 heterojunction also exhibits strong durability, with no noticeable reduction of product yields after four 8-h cycles.
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BACKGROUND: GLS-010 (zimberelimab) is a novel, fully human, anti-programmed death-1 monoclonal antibody that shows promising efficacy and safety in advanced solid tumors. This trial aimed to evaluate the efficacy and safety of GLS-010 (zimberelimab) in Chinese patients with relapsed or refractory classical Hodgkin lymphoma (r/r-cHL). METHODS: This phase II, single-arm, open-label, multicenter clinical trial was conducted at 24 centers in China and enrolled patients with r/r-cHL after two or more lines of therapy. The patients were administered intravenous GLS-010 (zimberelimab) (240 mg, once every 2 weeks) until progression, death, unacceptable toxicity, or consent withdrawal. The primary end-point was the objective response rate assessed by an independent radiology review committee (IRC). This study was registered (NCT03655483). RESULTS: Eighty-five patients were enrolled between August 2018 and August 2019. The median follow-up was 15.8 months. Seventy-seven patients (90.6%; 95% confidence interval [CI] 82.3-95.9) had an IRC-assessed objective response. The complete response rate was 32.9% (n = 28). The 12-month progression-free survival and overall survival rates were 78% (95% CI 67.5-85.6) and 99% (95% CI 91.9-99.8), respectively. Treatment-related adverse events (TRAEs) were observed in 92.9% of participants. Grade III or IV TRAEs occurred in 24 (28.2%) of the 85 participants. The most common grade III or IV TRAEs were abnormal hepatic function (5.9%), hyperuricemia (4.7%), decreased neutrophil count (3.5%), and increased weight (3.5%). Only one grade V AE, gastrointestinal infection, occurred. CONCLUSIONS: GLS-010 (zimberelimab) appears to be effective and safe for the treatment of Chinese patients with r/r-cHL. Long-term follow-up is required to confirm these clinical benefits.
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Anticorpos Monoclonais Humanizados , Doença de Hodgkin , Recidiva Local de Neoplasia , Anticorpos Monoclonais Humanizados/efeitos adversos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Intervalo Livre de Progressão , Resultado do TratamentoRESUMO
Weak acidity (6.5-6.9) and limited H2O2 level in the tumor microenvironment (TME) usually impact the therapeutic effect of chemodynamic therapy (CDT) for cancer. A Specific TME promotes the formation of an immunosuppressive microenvironment and results in high rate of recurrence and metastasis of cancer. Fe3O4@ZIF-8/GOx@MnO2 multi-layer core shell nanostructure was constructed as a hybrid nanozyme. After magnetic targeting of the tumor site, the outermost MnO2 shell catalyzed H2O2 in TME to produce O2 and was broken due to the reaction with glutathione. Due to the acid response, the ZIF-8 layer would crack and release glucose oxidase (GOx) and Fe3O4. The generated O2 was utilized by GOx in starvation therapy to consume glucose and produce H2O2 and gluconic acid. The Fenton reaction efficiency of Fe(II) was improved by the increased H2O2 concentration and the enhanced acidity in TME. At the same time, the intrinsic photothermal effect of Fe3O4 upon 808 nm laser irradiation promoted the activity of MnO2 and GOx as oxidase, and Fe(II) as catalase-like, and ablated the primary tumor. Moreover, the hybrid nanozyme can facilitate the transformation of M2-type macrophages to M1-type, and strong systemic antitumor immune effect was induced. A synergy of multiple therapeutic modes including starvation therapy, CDT, photothermal therapy (PTT), and immunotherapy can be realized in the hybrid nanozyme for tumor therapy.
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Glucose Oxidase , Neoplasias , Linhagem Celular Tumoral , Humanos , Peróxido de Hidrogênio , Compostos de Manganês , Neoplasias/terapia , Óxidos , Microambiente TumoralRESUMO
Glucose oxidase (GOx) is regarded as an ideal endogenous natural enzyme for tumor starvation therapy and photothermal therapy (PTT) is a promising strategy for the ablation of primary tumor. In this work, Cu-doped cobalt oxide and porous carbon nanocomposites (CuCo(O)@PCNs) were synthesized from double-layered ZIF-8@ZIF-67 and GOx was loaded in the porous carbon to form a CuCo(O)/GOx@PCNs hybrid nanozyme. CuCo(O) was characterized as the Cu0.3Co2.7O4 phase through X-ray diffraction analysis and it can react with H2O2 to generate O2 and alleviate tumor hypoxia, resulting in the recovered enzymatic activity of GOx and the enhanced starvation therapy. The porous nanocarbon can ablate the primary tumor because of its high photothermal conversion efficiency of 40.04%. The three-in-one functions of oxygen supply, glucose consumption, and photothermal conversion were realized in the ZIFs-derived CuCo(O)/GOx@PCNs nanozyme and the starvation therapy effect was improved by PTT and oxygen supplement. Furthermore, the inhibition effect of CuCo(O)/GOx@PCNs on metastatic tumor is similar to combined therapy of the nanozyme and the immune checkpoint-blocking antibody, α-PD-1. The related antitumor immune mechanism was studied through the analysis of immune-related proinflammatory cytokines and the activated T cells. This work may provide new ideas for the development and application of the ZIFs-derived hybrid nanozyme in tumor therapy and the CuCo(O)/GOx@PCNs nanozyme may be a promising alternative to immune checkpoint inhibitors.
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Carbono/uso terapêutico , Cobalto/uso terapêutico , Cobre/uso terapêutico , Glucose Oxidase/uso terapêutico , Imidazóis/uso terapêutico , Estruturas Metalorgânicas/uso terapêutico , Neoplasias/terapia , Óxidos/uso terapêutico , Animais , Linhagem Celular Tumoral , Humanos , Imunoterapia , Camundongos , Terapia Fototérmica , Hipóxia TumoralRESUMO
A magnetically recyclable Ni/NiO/g-C3N4 photocatalyst with significantly enhanced H2 evolution efficiency was successfully synthesized by a simple ethanol-solvothermal treatment. The presence of electronegative g-C3N4 is found to be the key factor for Ni0 formation in ternary Ni/NiO/g-C3N4, which provides anchoring sites for Ni2+ absorption and assembling sites for Ni0 nanoparticle formation. The metallic Ni0, on one side, could act as an electron acceptor enhancing carrier separation and transfer efficiency, and on the other side, it could act as active sites for H2 evolution. The NiO forms a p-n heterojunction with g-C3N4, which also promotes carrier separation and transfer efficiency. The strong magnetic property of Ni/NiO/g-C3N4 allows a good recyclability of catalyst from aqueous solution. The optimal Ni/NiO/g-C3N4 showed a full-spectrum efficiency of 2310 µmol·h-1·g-1 for hydrogen evolution, which is 210 times higher than that of pure g-C3N4. This ethanol solvothermal strategy provides a facile and low-cost synthesis of metal/metal oxide/g-C3N4 for large-scale application.
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Neoadjuvant chemotherapy for the treatment of breast cancer can provide the option of surgery for patients with a large tumor mass or increase the rate of breast conservation. However, some patients are not sensitive to chemotherapeutic drugs, and therefore this may cause them to miss their optimal chance for surgery. Herein, photodynamic therapy (PDT) was chosen instead of chemotherapy as a neoadjuvant treatment for breast cancer because of its effectiveness against different cancer cells and the lack of side effects in normal tissues. Considering the hypoxic environment of tumors and the tissue penetration depth, a heterojunction Zn2GeO4:Mn2+/g-C3N4 was designed and combined with upconversion materials NaYF4:Yb3+, Tm3+ and hyaluronic acid to form a NaYF4:Yb3+, Tm3+/Zn2GeO4:Mn2+/g-C3N4@HA (UZC@HA) photosensitizer. After intratumoral administration using a thermosensitive hydrogel as a carrier, under a 980 nm laser, UZC@HA can generate holes and electrons to oxidize water to form a hydroxyl radical (ËOH) and react with O2 to produce the superoxide ion (ËO2-), respectively. The thermosensitive hydrogel not only supplies water, but also ensures the high loading capacity of UZC@HA. HA on the UZC can bind specifically with CD44R-overexpressing tumor cells and help the photosensitizer to target tumor sites. Thus, near infrared (NIR) mediated oxygen-independent PDT can be realized. After 12 d of treatment, the tumor mass was significantly reduced and no side effects in normal tissues were observed. Our work shows the potential of the NIR mediated heterojunction UZC@HA to act as a photosensitizer for neoadjuvant PDT in breast cancer and may open a new avenue for exploration of PDT and provide more options for breast cancer patients.
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Neoplasias da Mama , Fotoquimioterapia , Neoplasias da Mama/tratamento farmacológico , Humanos , Hidrogéis/uso terapêutico , Terapia Neoadjuvante , Oxigênio , Fármacos Fotossensibilizantes/uso terapêutico , ZincoRESUMO
Dysfunction of the calcium balancing system and disruption of calcium distribution can induce abnormal intracellular calcium overload, further causing serious damage and even cell death, which provides a potential therapeutic approach for tumor treatment. Herein, a nano-platform, which includes UCNPs-Ce6@RuR@mSiO2 @PL-HA NPs (UCRSPH) and SA-CaO2 nanoparticles, is prepared for improving the tumor micro-environment (TME), Ca2+ signal disturbance as well as enhanced photodynamic tumor therapy (PDT). UCRSPH combined with SA-CaO2 can alter TME and relieve hypoxia of the tumor to realize self-reinforcing PDT under near-IR irradiation (980 nm). The ruthenium red (RuR) in the UCRSPH NPs can be released to the cytoplasm after endocytosis of the nanoparticles, target Ca2+ channel proteins on the endoplasmic reticulum and mitochondria, sarcoplasmic reticulum Ca2+ -ATPase (SERCA), and mitochondrial calcium uniporter (MCU). The combined participation of nanoparticles and RuR promotes Ca2+ imbalance and cytoplasmic calcium overload with the assistance of CaO2 , and provides tumor cells higher sensitivity to PDT. Furthermore, the nano-platform also provides fluorescence imaging and calcification computed tomography imaging for in vivo treatment guidance. In conclusion, this image-guided nano-platform show potential for highly specific, efficient combined therapy against tumor cells with minimal side-effects to normal cells by integrating TME improvement, self-reinforcing PDT, and Ca2+ signal disturbance.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Linhagem Celular Tumoral , Humanos , Hipóxia , Mitocôndrias , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/farmacologia , Microambiente TumoralRESUMO
Nitric oxide (NO) gas treatment offers a promising strategy for tumor therapy; however, its practical application is still limited due to its poor efficacy and biotoxicity which were caused by gas leakage during blood delivery. Herein, a nano-platform (CMH-OBN) composed of chlorin e6-melanin-hyaluronic acid nanoparticles (Ce6-MNP-HA, CMH) and oxidized bletilla striata polysaccharide microcapsules (Oxi-BSP) carrying NO donors was prepared for responsive and cascaded release of NO, reactive oxygen species (ROS) and its secondary metabolite reactive nitrogen species (RNS) in tumor sites. Melanin not only endowed CMH with good photothermal properties, but also helped Ce6 to produce a large number of ROS under near-infrared (NIR) irradiation. OBN microcapsules, which were sensitive to ROS, can release NO donors under the stimulation of ROS released by CMH nanoparticles under NIR irradiation and can further release NO in the tumor microenvironment (TME) with high expression of glutathione (GSH). NO could further up-regulate soluble guanylate cyclase-cyclic guanosine monophosphate (sGC-cGMP) signal pathways to relieve hypoxia, thus further enhancing the photodynamic therapy (PDT). Moreover, the cascaded release of ROS and NO could produce RNS with higher lethality, which could sequentially initiate the cellular apoptotic procedure and promote immunotherapy by activating T cells at the tumor sites. More interestingly, the CMH-OBN nano-platform could supply magnetic resonance imaging (MRI) and infrared photothermal imaging guidance for tumor therapy. In conclusion, the development of a CMH-OBN nano-platform provides a satisfactory demonstration by combining NO therapy with photothermal therapy (PTT), PDT and immunotherapy for the treatment of cancer.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Porfirinas , Linhagem Celular Tumoral , Humanos , Imunoterapia , Neoplasias/tratamento farmacológico , Óxido Nítrico , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêutico , Espécies Reativas de Oxigênio , Microambiente TumoralRESUMO
During rapid proliferation and metabolism, tumor cells show a high dependence on methionine. The deficiency of methionine exhibits significant inhibition on tumor growth, which provides a potential therapeutic target in tumor therapy. Herein, ClO2-loaded nanoparticles (fluvastatin sodium&metformin&bupivacaine&ClO2@CaSiO3@MnO2-arginine-glycine-aspatic acid (RGD) (MFBC@CMR) NPs) were prepared for synergistic chlorine treatment and methionine-depletion starvation therapy. After outer layer MnO2 was degraded in the high glutathione (GSH) tumor microenvironment (TME), MFBC@CMR NPs released metformin (Me) to target the mitochondria, thus interfering with the tricarboxylic acid (TCA) cycle and promoting the production of lactate. In addition, released fluvastatin sodium (Flu) by the NPs acted on monocarboxylic acid transporter 4 (MCT4) in the cell membrane to inhibit lactate leakage and induce a decrease of intracellular pH, further prompting the NPs to release chlorine dioxide (ClO2), which then oxidized methionine, inhibited tumor growth, and produced large numbers of Cl- in the cytoplasm. Cl- could enter mitochondria through the voltage-dependent anion channel (VDAC) channel, which was opened by bupivacaine (Bup). The disruption of Cl- homeostasis promotes mitochondrial damage and membrane potential decline, leading to the release of cytochrome C (Cyt-C) and apoptosis inducing factor (AIF) and further inducing cell apoptosis. To sum up, the pH-regulating and ClO2-loaded MFBC@CMR nanoplatform can achieve cascade chlorine treatment and methionine-depletion starvation therapy toward tumor cells, which is of great significance for improving the clinical tumor treatment effect.
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Antineoplásicos/farmacologia , Compostos Clorados/farmacologia , Metionina/deficiência , Óxidos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Metionina/análise , Metionina/metabolismo , Camundongos , Camundongos Endogâmicos , Imagem ÓpticaRESUMO
Tetracycline hydrochloride as an environmental pollutant is biologically toxic and highly difficult to degrade. To solve this problem, an efficient catalyst IO-TiO2-CdS composite with honeycomb-like three-dimensional (3D) inverse opal TiO2 (IO-TiO2) and cadmium sulphide (CdS) was synthesized and applied in the degradation of tetracycline hydrochloride in this paper. More than 99% of the tetracycline hydrochloride (30â mg/L) can be degraded by IO-TiO2-CdS (30â mg) within 20â min under visible light irradiation. Surprisingly, the naphthol rings can be opened and degraded to alkane with a minimum molecular weight of 60, which is the smallest fragment among all publications. The three-dimensional ordered macroporous (3DOM) structure of IO-TiO2 improves the utilization of light via the slow photon effect. Meanwhile, the addition of CdS enhances the degradation efficiency of tetracycline by broadening the range of absorption spectrum and improving the separation of charge carrier on the catalyst. In addition to the degradation of tetracycline hydrochloride, IO-TiO2-CdS also shows a good degradation efficiency of Rhodamine B (RhB). This work provides a promising approach to construct visible light response photocatalysts with non-noble metal for efficient degradation of wastewater pollutants.
Assuntos
Nanocompostos , Tetraciclina , Compostos de Cádmio , Luz , Sulfetos , Titânio , Águas ResiduáriasRESUMO
BACKGROUND: Previous studies have demonstrated the preclinical pharmacological and toxicological consistency, and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab (Avastin). This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first-line treatment of Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC). METHODS: Stage IIIB-IV NSCLC patients with evaluable lesions, good physical status, and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin (combined treatment) for 4-6 cycles, followed by maintenance monotherapy with LY01008 until disease progression, intolerable toxicity, or death. The primary endpoint was objective response rate (ORR) in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by independent radiological review committees (IRRC). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. This study was registered in ClinicalTrials.gov (NCT03533127). RESULTS: Between December 15th , 2017, and May 15th , 2019, a total of 649 patients were randomized to the LY01008 (n = 324) or Avastin (n = 325) group. As of September 25th , 2019 for primary endpoint analysis, 589 patients received ORR evaluation, with a median number of combined treatment cycles of 5 (range 1-6) and median duration of treatment of 3.0 (range 0.0-5.1) months. ORR of response-evaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%, respectively. The stratified ORR ratio was 0.91 (90% CI 0.80-1.04, within the prespecified equivalence margin of 0.75-1.33). Up to May 15th , 2020, with a median follow-up of 13.6 (range 0.8-28.4) months, no notable differences in DCR, median DoR, median PFS, median OS, and 1-year OS rate were observed between the LY01008 and Avastin groups. There were no clinically meaningful differences in safety and immunogenicity across treatment groups. CONCLUSIONS: LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non-squamous NSCLC. LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable, metastatic, or recurrent non-squamous NSCLC patients in the first-line setting.