All-Nitrogen Energetic Material Cubic Gauche Polynitrogen: Plasma Synthesis and Thermal Performance.

Numerous theoretical calculations have demonstrated that polynitrogen with an extending polymeric network is an ultrahigh-energy all-nitrogen material. Typical samples, such as cubic gauche polynitrogen (cg-N), have been synthesized, but the thermal performance of polynitrogen has not been unambiguously determined. Herein, macroscopic samples of polynitrogen were synthesized utilizing a coated substrate, and their thermal decomposition behavior was investigated. Polynitrogen with carbon nanotubes was produced using a plasma-enhanced chemical vapor deposition method and characterized using infrared, Raman, X-ray diffraction X-ray photoelectron spectroscopy and transmission electron microscope. The results showed that the structure of the deposited polynitrogen was consistent with that of cg-N and the amount of deposition product obtained with coated substrates increased significantly. Differential scanning calorimetry (DSC) at various heating rates and TG-DSC-FTIR-MS analyses were performed. The thermal decomposition temperature of cg-N was determined to be 429 °C. The apparent activation energy (Ea) of cg-N calculated by the Kissinger and Ozawa equations was 84.7 kJ/mol and 91.9 kJ/mol, respectively, with a pre-exponential constant (lnAk) of 12.8 min-1. In this study, cg-N was demonstrated to be an all-nitrogen material with good thermal stability and application potential to high-energy-density materials.

Research on obstacle avoidance algorithm for unmanned ground vehicle based on multi-sensor information fusion.

With the wide application of unmanned ground vehicles (UGV) in a complex environment, the research on the obstacle avoidance system has gradually become an important research part in the field of the UGV system. Aiming at the complex working environment, a sensor detection system mounted on UGV is designed and the kinematic estimation model of UGV is studied. In order to meet the obstacle avoidance requirements of UGVs in a complex environment, a fuzzy neural network obstacle avoidance algorithm based on multi-sensor information fusion is designed in this paper. MATLAB is used to simulate the obstacle avoidance algorithm. By comparing and analyzing the simulation path of UGV's obstacle avoidance motion under the navigation control of fuzzy controller and fuzzy neural network algorithm, the superiority of the proposed fuzzy neural network algorithm was verified. Finally, the superiority and reliability of the obstacle avoidance algorithm are verified through the obstacle avoidance experiment on the UGV experimental platform.

Effects of an industrial passive assistive exoskeleton on muscle activity, oxygen consumption and subjective responses during lifting tasks.

The purpose of this study was to evaluate the effects of an industrial passive assisted exoskeleton (IPAE) with simulated lifting tasks on muscle activity, oxygen consumption, perceived level of exertion, local perceived pressure, and systemic usability. Eight workers were required to complete two lifting tasks with and without the IPAE, that were single lifting tasks (repeated 5 times) and 15 min repeated lifting tasks respectively. Both of the tasks required subjects to remove a toolbox from the ground to the waist height. The test results showed that IPAE significantly reduced the muscle activity of the lumbar erector spinae, thoracic erector spinae, middle deltoid and labrum-biceps muscles; the reduction effect during the 15 min lifting task was reached 21%, 12%, 32% and 38% respectively. The exoskeleton did not cause significant differences in oxygen consumption and the perceived level of exertion, but local perceived pressure on the shoulders, thighs, wrists, and waist of the subjects could be produced. 50% of the subjects rated the usability of the equipment as acceptable. The results illustrate the good potential of the exoskeleton to reduce the muscle activity of the low back and upper arms. However, there is still a concern for the obvious contact pressure.

Insights into 2-Indolylmethanol-Involved Cycloadditions: Origins of Regioselectivity and Enantioselectivity.

To gain insights into 2-indolylmethanol-involved reactions and to understand the origins of regioselectivity and enantioselectivity, theoretical investigations on the reaction mechanisms of three representative cycloadditions of 2-indolylmethanols have been carried out. In Ir-catalyzed regioselective (3 + 3) cycloaddition, it was found that the great difference between the energy barriers of the first initiating steps of the two pathways played a key role in determining the observed high regioselectivity and the C3-nucleophilicity of 2-indolylmethanol in this reaction. In chiral phosphoric acid (CPA)-catalyzed regioselective and enantioselective (3 + 3) and (3 + 4) cycloadditions, it was discovered that the great difference between the energy barriers of the transition states corresponding to the (R)- and (S)-configurations led to the observed high enantioselectivity of the products. In the presence of CPA, the C3-nucleophilicity of 2-indolylmethanol increased, resulting in exclusive regioselectivity. It was discovered that the electronic nature is not a decisive factor for the observed C3-regioselectivity in the delocalized cation of 2-indolylmethanol, and the steric factor should play a crucial role in the observed C3-regioselectivity. This study offers insights into the mechanisms of 2-indolylmethanol-involved reactions, which will give an in-depth understanding of the chemistry of 2-indolylmethanols and advance the development of this research field.

Co-delivery of VEGF siRNA and Etoposide for Enhanced Anti-angiogenesis and Anti-proliferation Effect via Multi-functional Nanoparticles for Orthotopic Non-Small Cell Lung Cancer Treatment.

Targeting tumor angiogenesis pathway via VEGF siRNA (siVEGF) has shown great potential in treating highly malignant and metastatic non-small cell lung cancer (NSCLC). However, anti-angiogenic monotherapy lacked sufficient antitumor efficacy which suffered from malignant tumor proliferation. Therefore, the combined application of siVEGF and chemotherapeutic agents for simultaneous targeting of tumor proliferation and angiogenesis has been a research hotspot to explore a promising NSCLC therapy regimen. Methods: We designed, for the first time, a rational therapy strategy via intelligently co-delivering siVEGF and chemotherapeutics etoposide (ETO) by multi-functional nanoparticles (NPs) directed against the orthotopic NSCLC. These NPs consisted of cationic liposomes loaded with siVEGF and ETO and then coated with versatile polymer PEGylated histidine-grafted chitosan-lipoic acid (PHCL). We then comprehensively evaluated the anti-angiogenic and anti-proliferation efficiency in the in vitro tumor cell model and in bioluminescent orthotopic lung tumor bearing mice model. Results: The NPs co-delivering siVEGF and ETO exhibited tailor-made surface charge reversal features in mimicking tumor extracellular environment with improved internal tumor penetration capacity and higher cellular internalization. Furthermore, these NPs with flexible particles size triggered by intracellular acidic environment and redox environment showed pinpointed and sharp intracellular cargo release guaranteeing adequate active drug concentration in tumor cells. Enhanced VEGF gene expression silencing efficacy and improved tumor cell anti-proliferation effect were demonstrated in vitro. In addition, the PHCL layer improved the stability of these NPs in neutral environment allowing enhanced orthotopic lung tumor targeting efficiency in vivo. The combined therapy by siVEGF and ETO co-delivered NPs for orthotopic NSCLC simultaneously inhibited tumor proliferation and tumor angiogenesis resulting in more significant suppression of tumor growth and metastasis than monotherapy. Conclusion: Combined application of siVEGF and ETO by the multi-functional NPs with excellent and on-demand properties exhibited the desired antitumor effect on the orthotopic lung tumor. Our work has significant potential in promoting combined anti-angiogenesis therapy and chemotherapy regimen for clinical NSCLC treatment.

Doxorubicin and siRNA-PD-L1 co-delivery with T7 modified ROS-sensitive nanoparticles for tumor chemoimmunotherapy.

Tumor cells avoid immunosurveillance during the tumorigenesis, metastasis and recurrence periods thanks to the overexpressed immunosuppressive molecules on their surface. For instance, the programmed cell death 1 ligand (PD-L1) binds with the T-cells' programmed cell death receptor 1 (PD-1) impairing the anti-tumor activity of the host T cells. In this study, a new reactive oxygen species (ROS) responsive nanoparticle (NP), modified with the HAIYPRH (T7) peptide, was developed for the co-delivery of siRNA-PD-L1 and doxorubicin (Dox). These NPs can block the inhibitory signal responding to T cells and enhance cytotoxicity of Dox against tumor cells. The T7 modification binds to the overexpressed transferrin receptor on tumor cells facilitating its cellular uptake. Dox rapid release is then triggered by the high tumor cells cytoplasmic concentration of ROS, leading to cell apoptosis. Our results demonstrated these NPs exhibited a T7-mediated cellular uptake and an intracellular ROS-triggered payloads release in vitro. They also suggested an improved in vivo 4T1 tumor targeting efficiency and chemoimmunotherapy. Most notably, the co-delivery system exhibited a significantly enhanced antitumor effect over Dox-only loaded NPs following prompting the proliferation of T cells by siRNA-PD-L1. In conclusion, these ROS-responsive NPs provided a promising strategy to combine siRNA-PD-L1 immunotherapy and Dox chemotherapy.

A Novel 3D in Vitro Tumor Model Based on Silk Fibroin/Chitosan Scaffolds To Mimic the Tumor Microenvironment.

Drug development involves various evaluation processes to ascertain drug effects and rigorous analysis of biological indicators during in vitro preclinical studies. Two-dimensional (2D) cell cultures are commonly used in numerous in vitro studies, which are poor facsimiles of the in vivo conditions. Recently, three-dimensional (3D) tumor models mimicking the tumor microenvironment and reducing the use of experimental animals have been developed generating great interest to appraise tumor response to treatment strategies in cancer therapy. In this study, silk fibroin (SF) protein and chitosan (CS), two natural biomaterials, were chosen to construct the scaffolds of 3D cell models. Human non-small cell lung cancer A549 cells in the SF/CS scaffolds were found to have a great tendency to gather and form tumor spheres. A549 cell spheres in the 3D scaffolds showed biological and morphological characteristics much closer to the in vivo tumors. Besides, the cells in 3D models displayed better invasion ability and drug resistance than 2D models. Additionally, differences in drug-resistant and immune-related protein levels were found, which indicated that 3D models might resemble the real-life situation. These findings suggested that these 3D tumor models composed of SF/CS are promising to provide a valuable biomaterial platform in the evaluation of anticancer drugs.

Programmed pH/reduction-responsive nanoparticles for efficient delivery of antitumor agents in vivo.

To bypass the biological barriers during the drug delivery process, it is desirable to develop smart nanoparticles (NPs) with flexible physical and chemical properties. In this study, a programmed NP delivery system with a pH-triggered detachable PEG layer and a lactobionic acid (Lac)-modified reduction-responsive core was developed to address the "PEG dilemma" and provide an on-demand intracellular release of doxorubicin (DOX). The positively charged DOX-loaded lactobionic acid-chitosan-lipoic acid (DOX/LCL) NPs were prepared and coated with a negatively charged dimethylmaleic acid-PEG-chitosan (PEG-CS-DA) layer to obtain a prolonged circulation time and improve the tumor-targeting effect. After reaching the tumor tissues through a targeted delivery effect, the surface charge of the PEG-CS-DA layer was reversed from negative to positive because of the trigger by the acidic microenvironment (pH 6.8), thus leading to the detachment of the PEG layer. The exposure of positive charges and the active targeting ligand enhanced cellular uptake and facilitated penetration into tumor tissues. Subsequently, the rapid release and diffusion of DOX into the nuclei was triggered by the intracellular high concentration of glutathione, thus leading to cell apoptosis. In conclusion, these programmed pH/reduction-responsive NPs provide a promising strategy for the delivery of antitumor agents in vivo. STATEMENT OF SIGNIFICANCE: In this study, novel programmed pH/reduction-responsive NPs were developed for the delivery of DOX in vivo. These NPs were coated with a negatively charged PEG layer to improve the serum stability and tumor target effect. The PEG layer detached because of the trigger by tumor acidic microenvironment (pH 6.8), thus leading to the exposure of positive charges and the active targeting ligand, which enhanced cellular uptake and facilitated penetration into tumor tissues. Subsequently, the rapid release of DOX was triggered by the intracellular high concentration of glutathione, thereby resulting in enhanced cytotoxicity. These programmed pH/reduction-responsive NPs provide a promising strategy for the delivery of antitumor agents in vivo.

Targeted Delivery of Doxorubicin via CD147-Mediated ROS/pH Dual-Sensitive Nanomicelles for the Efficient Therapy of Hepatocellular Carcinoma.

Low accumulation in tumor sites and slow intracellular drug release remain as the obstacles for nanoparticles to achieve effective delivery of chemotherapeutic drugs. In this study, multifunctional micelles were designed to deliver doxorubicin (Dox) to tumor sites to provide more efficient therapy against hepatic carcinoma. The micelles were based on pH-responsive carboxymethyl chitosan (CMCh) modified with a reactive oxygen species (ROS)-responsive segment phenylboronic acid pinacol ester (BAPE) and an active targeted ligand CD147 monoclonal antibody. The Dox-loaded micelles provided rapid and complete drug release in pH 5.3 incubation conditions with 1 mM H2O2. In addition, an in vitro cell uptake study revealed that CD147 modification significantly enhanced cellular internalization due to the high affinity to CD147 receptors, which are overexpressed on tumor cells. An in vivo study revealed that CD147-modified micellar formulations exhibited high accumulation in tumor sites and markedly enhanced antiproliferation effects with fewer side effects than other formulations. In conclusion, this CD147 receptor targeted delivery system with ROS/pH dual sensitivity provides a promising strategy for the treatment of hepatic carcinoma.

Nucleolin-Targeting AS1411-Aptamer-Modified Graft Polymeric Micelle with Dual pH/Redox Sensitivity Designed To Enhance Tumor Therapy through the Codelivery of Doxorubicin/TLR4 siRNA and Suppression of Invasion.

In this article, a novel graft polymeric micelle with targeting function ground on aptamer AS1411 was synthesized. The micelle was based on chitosan-ss-polyethylenimine-urocanic acid (CPU) with dual pH/redox sensitivity and targeting effects. This micelle was produced for codelivering Toll-like receptor 4 siRNA (TLR4-siRNA) and doxorubicin (Dox). In vitro investigation revealed the sustained gene and drug release from Dox-siRNA-loaded micelles under physiological conditions, and this codelivery nanosystem exhibited high dual pH/redox sensitivity, rapid intracellular drug release, and improved cytotoxicity against A549 cells in vitro. Furthermore, the micelles loaded with TLR4-siRNA inhibited the migration and invasion of A549. Excellent tumor penetrating efficacy was also noted in the A549 tumor spheroids and solid tumor slices. In vivo, multiple results demonstrated the excellent tumor-targeting ability of AS1411-chitosan-ss-polyethylenimine-urocanic acid (ACPU) micelle in tumor tissues. The micelles exhibited excellent antitumor efficacy and low toxicity in the systemic circulation in lung-tumor-bearing BALB/c mice. These results conclusively demonstrated the great potential of the new graft copolymer micelle with targeting function for the targeted and efficient codelivery of chemotherapeutic drugs and genes in cancer treatment.

Low-density lipoprotein-coupled micelles with reduction and pH dual sensitivity for intelligent co-delivery of paclitaxel and siRNA to breast tumor.

Multidrug resistance (MDR) is a major obstacle for the clinical therapy of malignant human cancers. The discovery of RNA interference provides efficient gene silencing within tumor cells for reversing MDR. In this study, a new "binary polymer" low-density lipoprotein-N-succinyl chitosan-cystamine-urocanic acid (LDL-NSC-SS-UA) with dual pH/redox sensitivity and targeting effect was synthesized for the co-delivery of breast cancer resistance protein small interfering RNA (siRNA) and paclitaxel (PTX). In vivo, the co-delivering micelles can accumulate in tumor tissue via the enhanced permeability and retention effect and the specific recognition and combination of LDL and LDL receptor, which is overexpressed on the surface of tumor cell membranes. The siRNA-PTX-loaded micelles inhibited gene and drug release under physiological conditions while promoting fast release in an acid microenvironment or in the presence of glutathione. The micelles escaped from the lysosome through the proton sponge effect. Additionally, the micelles exhibited superior antitumor activity and downregulated the protein and mRNA expression levels of breast cancer resistance protein in MCF-7/Taxol cells. The biodistribution and antitumor studies proved that the siRNA-PTX-loaded micelles possessed prolonged circulation time with a remarkable tumor-targeting effect and effectively inhibited tumor growth. Therefore, the novel dual pH/redox-sensitive polymers co-delivering siRNA and PTX with excellent biocompatibility and effective reversal of MDR demonstrate a considerable potential in cancer therapy.

Enhanced Cellular Internalization and On-Demand Intracellular Release of Doxorubicin by Stepwise pH-/Reduction-Responsive Nanoparticles.

The efficient delivery of antitumor agents to tumor sites faces numerous obstacles, such as poor cellular uptake and slow intracellular drug release. In this regard, smart nanoparticles (NPs) that respond to the unique microenvironment of tumor tissues have been widely used for drug delivery. In this study, novel charge-reversal and reduction-responsive histidine-grafted chitosan-lipoic acid NPs (HCSL-NPs) were selected for efficient therapy of breast cancer by enhancing cell internalization and intracellular pH- and reduction-triggered doxorubicin (DOX) release. The surface charge of HCSL-NPs presented as negative at physiological pH and reversed to positive at the extracellular and intracellular pH of the tumor. In vitro release investigation revealed that DOX/HCSL-NPs demonstrated a sustained drug release under the physiological condition, whereas rapid DOX release was triggered by both endolysosome pH and high-concentration reducing glutathione (GSH). These NPs exhibited enhanced internalization at extracellular pH, rapid intracellular drug release, and improved cytotoxicity against 4T1 cells in vitro. Excellent tumor penetrating efficacy was also found in 4T1 tumor spheroids and solid tumor slices. In vivo experiments demonstrated that HCSL-NPs exhibited excellent tumor-targeting ability in tumor tissues as well as excellent antitumor efficacy and low systemic toxicity in breast tumor-bearing BALB/c mice. These results indicated that the novel charge-reversal and reduction-responsive HCSL-NPs have great potential for targeted and efficient delivery of chemotherapeutic drugs in cancer treatments.

[Preparation of freeze-dried long-circulation oridonin liposomes and their pharmacokinetics in rats].

OBJECTIVE: To prepare freeze-dried long-circulation oridonin liposomes with optimized parameters. METHODS: Ethanol injection method followed by freeze-drying was used to prepare the liposomes. Sephadex column was used to purify liposomes. Effects of formulation factors on entrapment efficiency of long-circulation oridonin liposomes were studied. The particle size, distribution and in vitro release were determined. Pharmacokinetics of oridonin liposomes in rats was determined by HPLC and the pharmacokinetic parameters calculated by Kinetica(TM) software were compared with conventional oridonin liposomes and solution. RESULTS: The optimized lipid formulation for long-circulation liposomes was composed of soy lecithin, cholesterol and DSPE-PEG 2000 with a ratio of 1:0.5:1.8(w/w). The ratio of drug to lipid was 1:6. Freeze-drying protectant was a mixture of glucose and mannitol (3:1). The entrapment efficiency (EE) of long-circulation oridonin liposomes was about 65%. The particle size of liposomes after hydrolyzation was 164 nm with good DPI. The liposomes showed a sustained drug release in vitro. Intravenous injected oridonin fitted with two-compartment pharmacokinetic model. The MRT of long-circulation liposomes was 2 times and 6 times and AUC was about 2 times and 3 times of conventional liposomes and oridonin solution, respectively. CONCLUSION: Freeze-dried liposomes with high EE have been obtained by the proposed approach. This long-circulation liposomes extend oridonin half time and significantly increase AUC in rats.