Telemedicine in Improving Glycemic Control Among Children and Adolescents With Type 1 Diabetes Mellitus: Systematic Review and Meta-Analysis.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is the most common chronic autoimmune disease among children and adolescents. Telemedicine has been widely used in the field of chronic disease management and can benefit patients with T1DM. However, existing studies lack high-level evidence related to the effectiveness of telemedicine for glycemic control in children and adolescents with T1DM. OBJECTIVE: This study aims to systematically review the evidence on the effectiveness of telemedicine interventions compared with usual care on glycemic control among children and adolescents with T1DM. METHODS: In this systematic review and meta-analysis, we searched PubMed, Cochrane Library, Embase, Web of Science (all databases), and CINAHL Complete from database inception to May 2023. We included randomized controlled trials (RCTs) that evaluated the effectiveness of a telemedicine intervention on glycemic control in children and adolescents with T1DM. In total, 2 independent reviewers performed the study selection and data extraction. Study quality was assessed using the Cochrane Risk of Bias 2 tool. Our primary outcome was glycated hemoglobin (HbA1c) levels. Secondary outcomes were quality of life, self-monitoring of blood glucose, the incidence of hypoglycemia, and cost-effectiveness. A random-effects model was used for this meta-analysis. RESULTS: Overall, 20 RCTs (1704 participants from 12 countries) were included in the meta-analysis. Only 5% (1/20) of the studies were at high risk of bias. Compared to usual care, telemedicine was found to reduce HbA1c levels by 0.22 (95% CI -0.33 to -0.10; P<.001; I2=35%). There was an improvement in self-monitoring of blood glucose (mean difference [MD] 0.54, 95% CI -0.72 to 1.80; P=.40; I2=67.8%) and the incidence of hypoglycemia (MD -0.15, 95% CI -0.57 to 0.27; P=.49; I2=70.7%), although this was not statistically significant. Moreover, telemedicine had no convincing effect on the Diabetes Quality of Life for Youth score (impact of diabetes: P=.59; worries about diabetes: P=.71; satisfaction with diabetes: P=.68), but there was a statistically significant improvement in non-youth-specific quality of life (MD -0.24, 95% CI -0.45 to -0.02; P=.04; I2=0%). Subgroup analyses revealed that the effect of telemedicine on HbA1c levels appeared to be greater in studies involving children (MD -0.41, 95% CI -0.62 to -0.20; P<.001), studies that lasted <6 months (MD -0.32, 95% CI -0.48 to -0.17; P<.001), studies where providers used smartphone apps to communicate with patients (MD -0.37, 95% CI -0.53 to -0.21; P<.001), and studies with medication dose adjustment (MD -0.25, 95% CI -0.37 to -0.12; P<.001). CONCLUSIONS: Telemedicine can reduce HbA1c levels and improve quality of life in children and adolescents with T1DM. Telemedicine should be regarded as a useful supplement to usual care to control HbA1c levels and a potentially cost-effective mode. Meanwhile, researchers should develop higher-quality RCTs using large samples that focus on hard clinical outcomes, cost-effectiveness, and quality of life.

Multifunctional ZnO@DOX/ICG-LMHP Nanoparticles for Synergistic Multimodal Antitumor Activity.

Multifunctional nanoparticles are of significant importance for synergistic multimodal antitumor activity. Herein, zinc oxide (ZnO) was used as pH-sensitive nanoparticles for loading the chemotherapy agent doxorubicin (DOX) and the photosensitizer agent indocyanine green (ICG), and biocompatible low-molecular-weight heparin (LMHP) was used as the gatekeepers for synergistic photothermal therapy/photodynamic therapy/chemotherapy/immunotherapy. ZnO was decomposed into cytotoxic Zn2+ ions, leading to a tumor-specific release of ICG and DOX. ZnO simultaneously produced oxygen (O2) and reactive oxygen species (ROS) for photodynamic therapy (PDT). The released ICG under laser irradiation produced ROS for PDT and raised the tumor temperature for photothermal therapy (PTT). The released DOX directly caused tumor cell death for chemotherapy. Both DOX and ICG also induced immunogenic cell death (ICD) for immunotherapy. The in vivo and in vitro results presented a superior inhibition of tumor progression, metastasis and recurrence. Therefore, this study could provide an efficient approach for designing multifunctional nanoparticles for synergistic multimodal antitumor therapy.

A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRASG12C Inhibitor.

AMG510, as the first approved inhibitor for KRASG12C mutation, has shown promising efficacy in nonsmall-cell lung cancer and colorectal cancer harboring KRASG12C mutation. However, the moderate response rate and the rapid emergence of acquired resistance limit the therapeutic potential of AMG510, highlighting the need for the development of combination strategies. Here, we observed the suppression of RAS-MAPK signaling induced by AMG510 was prolonged and enhanced by SOS1 knockdown. Thus, we design, synthesize, and characterize a potent and specific SOS1 degrader 23. Compound 23 showed efficient SOS1 degradation in KRAS-driven cancer cells and achieved significant antiproliferative potency. Importantly, the combination of 23 with AMG510 suppressed RAS signaling feedback activation, showing synergistic effects against KRASG12C mutant cells in vitro and in vivo. Our findings demonstrated that KRASG12C inhibition plus SOS1 degradation as a potential therapeutic strategy to improve antitumor response and overcome acquired resistance to KRASG12C inhibitor.

Discovery of Novel 2,3-Dihydro-1H-indene-5-sulfonamide NLRP3 Inflammasome Inhibitors Targeting Colon as a Potential Therapy for Colitis.

The NLRP3 inflammasome is a multiprotein complex that plays a crucial role in the pathophysiology of multiple inflammation-related diseases. In this study, we designed and synthesized a series of novel 2,3-dihydro-1H-indene-5-sulfonamide analogues as NLRP3 inflammasome inhibitors, and then identified compound 15z as a potent and specific inhibitor (IC50: 0.13 µM) with low toxicity. Mechanistic studies indicate that 15z binds directly to NLRP3 protein (KD: 102.7 nM), blocking the assembly and activation of the NLRP3 inflammasome and effectively inhibiting cell pyroptosis. Given the notable distribution of 15z in the colon, the DSS-induced colitis model was employed to evaluate its in vivo effectiveness. 15z significantly impacted NLRP3 inflammasome activation and relieved inflammatory bowel disease symptoms in this model. Acute and subacute toxicity studies suggested that 15z has a favorable safety profile. Our results indicate that 15z has great potential to be further developed as a candidate for the treatment of inflammatory bowel disease.

Novel Sulfonylurea-Based NLRP3 Inflammasome Inhibitor for Efficient Treatment of Nonalcoholic Steatohepatitis, Endotoxic Shock, and Colitis.

The NLRP3 inflammasome is a critical component of innate immunity involved in the pathophysiology of various inflammatory diseases. In this study, we designed and synthesized a series of NLRP3 inflammasome inhibitors based on MCC950. Specifically, we optimized the furan moiety, which is considered to be potentially associated with drug-induced liver injury. The representative inhibitor N14, 4-(2-(dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonamide, not only maintains the NLRP3 inhibitory activity of MCC950 with IC50 of 25 nM but also demonstrates improved tolerability in human hepatic cells line and mouse primary hepatocytes. In addition, N14 exhibits superior pharmacokinetic properties, with an oral bioavailability of 85.2%. In vivo studies demonstrate that N14 is more effective than MCC950 in multiple NLRP3-related animal model diseases, including nonalcoholic steatohepatitis, lethal septic shock, and colitis. Our research has provided a lead compound that directly targets the NLRP3 inflammasome and can be developed as a novel therapeutic candidate for NLRP3-driven diseases.

Discovery of BWA-522, a First-in-Class and Orally Bioavailable PROTAC Degrader of the Androgen Receptor Targeting N-Terminal Domain for the Treatment of Prostate Cancer.

We report small molecular PROTAC compounds targeting the androgen receptor N-terminal domain (AR-NTD), which were obtained by tethering AR-NTD antagonists and different classes of E3 ligase ligands through chemical linkers. A representative compound, BWA-522, effectively induces degradation of both AR-FL and AR-V7 and is more potent than the corresponding antagonist against prostate cancer (PC) cells in vitro. We have shown that the degradation of AR-FL and AR-V7 proteins by BWA-522 can suppress the expression of AR downstream proteins and induce PC cell apoptosis. BWA-522 achieves 40.5% oral bioavailability in mice and 69.3% in beagle dogs. In a LNCaP xenograft model study, BWA-522 was also proved to be an efficacious PROTAC degrader, resulting in 76% tumor growth inhibition after oral administration of a dose of 60 mg/kg. This study indicates that BWA-522 is a promising AR-NTD PROTAC for the treatment of AR-FL- and AR-V7-dependent tumors.

High-sensitivity NaYF4:Yb3+/Ho3+/Tm3+ phosphors for optical temperature sensing based on thermally coupled and non-thermally coupled energy levels.

Non-contact optical temperature sensors are highly sought after by researchers due to their satisfactory temperature resolution (δ(T) < 0.1 °C), high relative thermal sensitivity (Sr > 1% °C-1), fast temporal response (t < 0.1 s), and long-term optical stability. In this study, NaYF4:Yb3+/Ho3+/Tm3+ upconversion nanoparticles were prepared by a solvothermal method, and their crystal structure, microscopic morphology, and luminescence mechanism, together with the temperature sensing properties of the specimens, were investigated. Under 980 nm laser excitation, the specimens exhibited strong upconversion luminescence, and the emission peaks corresponded to the characteristic energy level jumps of Ho3+ and Tm3+, respectively. The temperature-dependent luminescence spectra of the samples were investigated based on the fluorescence intensity ratio (FIR) technique over a temperature gradient of 295-495 K. The samples are based on thermally coupled energy levels (TCLs: 1G4(1,2) → 3H6(Tm3+)) and non-thermally coupled energy levels (NTCLs: 3F3 → 3H6(Tm3+) and 5F3 → 5I8(Ho3+), 3F3 → 3H6(Tm3+) and 1G4 → 3H6(Tm3+), 3F3 → 3H6(Tm3+) and 5F5 → 5I8(Ho3+), 3F3 → 3H6(Tm3+) and 5F4 → 5I8(Ho3+)) for temperature sensing performance. The maximum absolute sensitivity (Sa), relative sensitivity (Sr), and minimum temperature resolution δ(T) were found to be 0.0126 K-1 (495 K), 1.7966% K-1 (345 K), and 0.0167 K, respectively, which are better than those of most sensing materials, and the simultaneous action of multiple coupling energy levels can further improve the temperature precision. This study indicates that the sample has a good value for optical temperature measurement and also provides new ideas for the exploration of other high-quality optical temperature sensing materials.

Transmissive Digital Coding Metasurfaces for Polarization-Dependent Dual-Mode Quad Orbital Angular Momentum Beams.

In wireless communication systems, a multibeam can be used to increase the number of spatial channels by space-division multiplexing. Furthermore, the multimode is used to enhance the channel capacity by mode-division multiplexing. However, few of the previously reported methods cannot achieve independent controls of orbital angular momentum (OAM) states by transmissive metasurfaces in both space-division and mode-division multiplexing simultaneously. To expand the wireless communication channel, a multilayer transmissive digital coding metasurface with a single emitting source is demonstrated for quad-OAM beam generation with a dual mode. By changing the geometry of the cross dipole for a unit cell, the polarization-dependent 3-bit phase responses are obtained to flexibly manipulate the multi-OAM beams with different modes in preset directions simultaneously. Two types of metasurfaces are designed and fabricated to realize four OAM beams with two topological charges in different directions by encoding the phase sequence in x- and y-directions, which is validated by both theoretical analyses and experimental results. This scheme of transmissive digital coding metasurface provides a simple way to the multiplexing, multichannel, and multiplatform communication and imaging systems.

Design, Synthesis, and Biological Evaluation of Androgen Receptor (AR) Antagonist-Heat Shock Protein 90 (Hsp90) Inhibitor Conjugates for Targeted Therapy of Castration-Resistant Prostate Cancer.

Androgen deprivation in cases of castration-resistant prostate cancer (CRPC) leads to adverse effects, including loss of muscle and bone mass and gain of subcutaneous fat. The tumor-specific suppression of androgen receptor (AR) signaling, while not global, may reduce side effects. We present a class of small-molecular conjugates consisting of an AR antagonist linked to a heat shock protein 90 (Hsp90) inhibitor. We demonstrate that the high accumulation of Hsp90 on the surface of CRPC cells allows uptake of conjugates and increases the enrichment of drugs in the tumor cells. After penetrating prostate cancer cells, the conjugates not only inhibit AR function by the antagonist component but also bind to Hsp90 and suppress the AR protein level. Compared to AR antagonists, these conjugates showed improved tumor-targeting ability and enhanced potency against Enzalutamide-resistant 22Rv1 cells.

Inhibition of Astrocytic Carbohydrate Sulfotransferase 15 Promotes Nerve Repair After Spinal Cord Injury via Mitigation of CSPG Mediated Axonal Inhibition.

Nerve tissue regeneration is a significant problem. After neural diseases and damage such as spinal cord injury (SCI), the accumulation of chondroitin sulfate proteoglycans (CSPG) comprising axonal inhibitory glycosaminoglycan chains in the microenvironment is a major barrier that obstructs nerve repair. Interfering with the production of glycosaminoglycans, especially the critical inhibitory chains, could be a potential therapeutic strategy for SCI, which is, however, poorly defined. This study identifies Chst15, the chondroitin sulfotransferase controlling the generation of axonal inhibitory chondroitin sulfate-E, as a therapeutic target of SCI. Using a recently reported small molecular Chst15 inhibitor, this study investigates the effects of Chst15 inhibition on astrocyte behaviors and the associated consequences of in vivo disruption of the inhibitory microenvironment. Deposition of CSPGs in the extracellular matrix and migration of astrocytes are both significantly impaired by Chst15 inhibition. Administration of the inhibitor in transected spinal cord tissues of rats effectively promotes motor functional restoration and nerve tissue regeneration by a mechanism related to the attenuation of inhibitory CSPGs, glial scar formation and inflammatory responses. This study highlights the role of Chst15 in the CSPG-mediated inhibition of neural recovery after SCI and proposes an effective neuroregenerative therapeutic strategy that uses Chst15 as a potential target.

Lethal activity of BRD4 PROTAC degrader QCA570 against bladder cancer cells.

Bladder cancer is the most common malignancy of the urinary system. Efforts to identify innovative and effective therapies for bladder cancer are urgently needed. Recent studies have identified the BRD4 protein as the critical factor in regulation of cell proliferation and apoptosis in bladder cancer, and it shows promising potential for pharmacologic treatment against bladder cancer. In this study, we have evaluated the biological function of QCA570, a novel BET degrader, on multiple bladder cancer cells and explore its underlying mechanisms. QCA570 potently induces degradation of BRD4 protein at nanomolar concentrations, with a DC50 of ∼ 1 nM. It decreases EZH2 and c-MYC levels by transcriptional suppression and protein degradation. Moreover, the degrader significantly induces cell apoptosis and cycle arrest and shows antiproliferation activity against bladder cancer cells. These findings support the potential efficacy of QCA570 on bladder cancer.

Whole-transcriptome analyses of sheep embryonic testicular cells infected with the bluetongue virus.

Introduction: bluetongue virus (BTV) infection triggers dramatic and complex changes in the host's transcriptional profile to favor its own survival and reproduction. However, there is no whole-transcriptome study of susceptible animal cells with BTV infection, which impedes the in-depth and systematical understanding of the comprehensive characterization of BTV-host interactome, as well as BTV infection and pathogenic mechanisms. Methods: to systematically understand these changes, we performed whole-transcriptome sequencing in BTV serotype 1 (BTV-1)-infected and mock-infected sheep embryonic testicular cells, and subsequently conducted bioinformatics differential analyses. Results: there were 1504 differentially expressed mRNAs, 78 differentially expressed microRNAs, 872 differentially expressed long non-coding RNAs, and 59 differentially expressed circular RNAs identified in total. Annotation from the Gene Ontology, enrichment from the Kyoto Encyclopedia of Genes and Genomes, and construction of competing endogenous RNA networks revealed differentially expressed RNAs primarily related to virus-sensing and signaling transduction pathways, antiviral and immune responses, inflammation, and development and metabolism related pathways. Furthermore, a protein-protein interaction network analysis found that BTV may contribute to abnormal spermatogenesis by reducing steroid biosynthesis. Finally, real-time quantitative PCR and western blotting results showed that the expression trends of differentially expressed RNAs were consistent with the whole-transcriptome sequencing data. Discussion: this study provides more insights of comprehensive characterization of BTV-host interactome, and BTV infection and pathogenic mechanisms.

Antitumor Activity of the Zinc Oxide Nanoparticles Coated with Low-Molecular-Weight Heparin and Doxorubicin Complex In Vitro and In Vivo.

Various metal oxide nanomaterials have been widely used as carriers to prepare pH-sensitive nanomedicines to respond to the acidic tumor microenvironment promoting antitumor efficiency. Herein, we used zinc oxide nanoparticles (ZnO NPs) as metal oxide nanomaterial coated with low-molecular-weight heparin (LMHP) and doxorubicin (DOX) complex (LMHP-DOX) to prepare ZnO-LD NPs for controllable pH-triggered DOX release on the targeted site. Our results indicated that the released DOX from ZnO-LD NPs was pH-sensitive. The oxygen produced by ZnO-LD NPs in H2O2 solution was observed in in vitro experiment. The ZnO-LD NPs entered into both PC-3M and 4T1 tumor cells via clathrin-mediated endocytosis and micropinocytosis pathway. The intracellular reactive oxygen species (ROS) generated by ZnO-LD NPs could significantly increase the caspase 3/7 level, leading to tumor cell apoptosis. The in vitro and in vivo antitumor activity was confirmed in PC-3M and 4T1 cell lines or tumor-bearing mice models. The in vivo and in vitro tumor images via second-order nonlinearity of ZnO-LD NPs indicated that ZnO-LD NPs could penetrate deep into the tumor tissues. Therefore, the ZnO-LD NPs developed in our study could provide an efficient approach for the preparation of pH-sensitive nano delivery systems suitable for tumor therapy and imaging.

Effect of Slurry Thickness on the Quality of Aluminized Coatings.

Diffusion aluminum coating is crucial to protect aero-engine turbine blades from high-temperature oxidation. Slurry aluminizing, as a commonly-used coating preparation technology, has variations in the process parameters that directly affect the quality of the coating. Therefore, this paper investigates the effect of slurry thickness on coating quality. Different forms of aluminized coatings were obtained by coating nine DZ22B nickel-based superalloy plates of the same size with different slurry thicknesses while keeping other parameters constant. These aluminized coatings were characterized using a scanning electron microscope (SEM) with an energy dispersive spectrometer (EDS), an X-ray diffractometer (XRD), and a surface gauge. The results show that the AlNi phase dominates the matrix of the aluminized coating, and the outer layer of the coating has white dotted precipitates of Cr. As the slurry thickness increases, the coating thickness increases, and the proportion of the outer layer in the overall coating increases. In contrast, the thickness of the interdiffusion layer does not change significantly. The thicker the slurry, the higher the Al content of the coating surface. A medium-thickness slurry can form a smooth aluminizing coating with a roughness Ra < 4.5 µm surface. The combined results show that a medium-thick slurry can produce a high-quality coating.

Multifunctional Coding-Feeding Metasurface Based on Phase Manipulation.

Multiple functionalities on a shared aperture are crucial for metasurfaces (MSs) in many applications. In this paper, we propose a coding-feeding metasurface (CFMS) with the multiple functions of high-gain radiation, orbital angular momentum (OAM) generation, and radar cross-section (RCS) reduction based on phase manipulation. The unit cell of the CFMS is composed of a rectangular emission patch and two quasi-Minkowski patches for reflective phase manipulation, which are on a shared aperture. The high-gain radiation and multiple modes of ±1, ±2, and ±3 OAM generation were realized by rationally setting the elements and the phase of their excitation. The CFMS presents a broadband RCS reduction of 8 dB from 3.18 GHz to 7.56 GHz for y-polarization and dual-band RCS reduction for x-polarization based on phase interference. To validate the concept of the CFMS, a prototype was fabricated and measured. The results of the measurement agree well with the simulation. A CFMS with the advantages of light weight and low profile has potential application in detection and wireless communication systems for stealth aircraft.

Comparative Study on the Surface Remelting of Mo-Si-B Alloys with Laser and Electron Beam.

The Mo-12Si-8.5B alloy was surface-remelted by laser and electron beam, and the microstructure of its melt pool and substrate regions were analyzed by scanning electron microscopy (SEM), X-ray diffraction (XRD), and energy spectrometry (EDS) techniques. It was found that the composition of the surface phases in the Mo-12Si-8.5B alloy did not change by the high-energy beam surface remelting process, but the microstructure of the molten pool region was significantly different from that of the substrate region, and its phase distribution was more uniform. Dendrites appeared on the surface of the material under the action of both processes, and the Si- and B-rich phases were mainly gathered in the interdendritic region. In the melt pool of the laser-remelted specimens, the α-Mo phase was continuously distributed with an average dendrite length of 70 µm, while the α-Mo phase distribution in the melt pool of the electron beam remelted specimens were relatively concentrated, with a larger dendrite size and an average dendrite length of 120 µm. The dendrite size in the melt pool of the laser remelted material was smaller, and the distribution of the elements was relatively uniform. Using a laser beam as the heat source was more favorable for the next step of the additive manufacturing of the core parts of hypersonic vehicles.

Chitosan-Coated Selenium Nanoparticles Attenuate PRRSV Replication and ROS/JNK-Mediated Apoptosis in vitro.

Introduction: Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly prevalent and endemic swine pathogen that causes significant economic losses to the global swine industry. Selenium nanoparticles (SeNPs) have attracted increasing attention in the biomedical field, given their antiviral effects. This study aimed to investigate the inhibitory effect of chitosan-coated SeNPs (CS-SeNPs) on PRRSV replication. Methods: In this study, CS-SeNPs were synthesized by chemical reduction and characterized by assessing the morphology, size distribution, zeta potential, and element composition. Marc-145 cells were infected with r-PRRSV-EGFP (0.1 MOI) and inoculated with CS-SeNPs (10 µM). Subsequently, the concentrations of hydrogen peroxide (H2O2) and glutathione (GSH), and glutathione peroxidase (GSH-Px) activity were measured using specific commercial assay kits. ORF5 RNA expression, viral titer, and nucleocapsid (N) protein expression were assessed using qRT-PCR, TCID50, and Western blot. ROS generation, apoptosis rates, and JNK /caspase-3/PARP protein expression were evaluated using dihydroethidium staining, flow cytometry, and Western blot. Results: The results showed that CS-SeNPs treatment significantly suppressed oxidative stress induced by r-PRRSV-EGFP infection by increasing GSH-Px activity, promoting GSH production, and inhibiting H2O2 synthesis. CS-SeNPs treatment significantly inhibited ORF5 gene expression, viral titers, and N protein of r-PRRSV-EGFP at 24 and 48 hours post-infection (hpi) in Marc-145 cells. The increase in apoptosis rates induced by r-PRRSV-EGFP infection was significantly decreased by CS-SeNPs inoculation through inhibiting ROS generation, JNK phosphorylation levels, and cleavage of caspase-3 and PARP mainly at 48 hpi. Conclusion: These results demonstrated that CS-SeNPs suppress PRRSV-induced apoptosis in Marc-145 cells via the ROS/JNK signaling pathway, thereby inhibiting PRRSV replication, which suggested the potential antiviral activity of CS-SeNPs that deserves further investigation for clinical applications.

Plasma Oscillatory Pressure Sintering of Mo-9Si-8B Alloy with ZrB2 Addition.

Oscillatory pressure sintering is a novel crystal refinement technology. The doping of different concentrations of ZrB2 under oscillatory sintering technology (9 Hz) is discussed here, focusing on its macroscopic mechanics and oxidation resistance. In particular, doping 2.5 wt% ZrB2 can effectively increase the hardness of the alloy, slightly increase the fracture toughness of the alloy and have an outstanding effect on the oxidation resistance of the alloy at 1300 °C, achieving the effect of reducing mass loss by 80.3%.

Intelligent Nanodelivery System-Generated 1 O2 Mediates Tumor Vessel Normalization by Activating Endothelial TRPV4-eNOS Signaling.

Tumor microenvironment (TME)-responsive intelligent photodynamic therapy (PDT) systems have attracted increasing interest in anticancer therapy, due to their potential to address significant and unsatisfactory therapeutic issues, such as limited tissue penetration, inevitable normal tissue damage, and excessive impaired vessels. Here, an H2 O2 -triggered intelligent LCL/ZnO PDT nanodelivery system is elaborately designed. LCL/ZnO can selectively regulate tumor-derived endothelial cells (TECs) and specifically kill tumor cells, by responding to different H2 O2 gradients in TECs and tumor cells. The LCL/ZnO is able to normalize tumor vessels, thereby resulting in decreased metastases, and ameliorating the immunosuppressive TME. Further analysis demonstrates that singlet oxygen (1 O2 )-activated transient receptor potential vanilloid-4-endothelial nitric oxide synthase signals generated in TECs by LCL/ZnO induce tumor vascular normalization, which is identified as a novel mechanism contributing to the increased ability of PDT to promote cancer therapy. In conclusion, designing an intelligent PDT nanodelivery system response to the TME, that includes both selective TECs regulation and specific tumor-killing, will facilitate the development of effective interventions for future clinical applications.

Antitumor Activity of α-Linolenic Acid-Paclitaxel Conjugate Nanoparticles: In vitro and in vivo.

PURPOSE: Small molecule modified antitumor drug conjugate nanoparticles have the advantages of high drug loading, simple synthesis and preparation, and better biocompatibility. Due to the large demand for exogenous α-linolenic acid (ALA) by tumor cells, we synthesized α-linolenic acid-paclitaxel conjugate (ALA-PTX) and prepared α-linolenic acid-paclitaxel conjugate nanoparticles (ALA-PTX NPs), in order to obtain better tumor cellular uptake and antitumor activity in vitro and in vivo. METHODS: We synthesized and characterized ALA-PTX, and then prepared and characterized ALA-PTX NPs. The cellular uptake, uptake pathways, intracellular behavior, in vitro and in vivo antitumor activity of ALA-PTX NPs were evaluated. RESULTS: The size of ALA-PTX NPs was approximately 110.7±1.7 nm. The drug loading was approximately 90% (w/w) with CrEL-free and organic solvent-free characteristics. The cellular uptake of ALA-PTX NPs was significantly higher than that of PTX injection by MCF-7, MCF-7/ADR and HepG2 cells. In these three cell lines, the cellular uptake of ALA-PTX NPs at 6h was approximately 1.5-2.6 times higher than that of PTX injection. ALA-PTX NPs were ingested through clathrin-mediated endocytosis, then transferred to lysosomes, and could dissolve in cells to play an antitumor activity. The in vitro and in vivo antitumor activity of ALA-PTX NPs was confirmed in MCF-7/ADR and HepG2 cell models and tumor-bearing nude mouse models. CONCLUSION: ALA-PTX NPs developed in our study could provide a new method for the preparation of nano-delivery systems suitable for antitumor therapy that could increase tumor cellular uptake and enhance antitumor activity.