Inflammation-Responsive Mesoporous Silica Nanoparticles with Synergistic Anti-inflammatory and Joint Protection Effects for Rheumatoid Arthritis Treatment.

PURPOSE: Joint destruction is a major burden and an unsolved problem in rheumatoid arthritis (RA) patients. We designed an intra-articular mesoporous silica nanosystem (MSN-TP@PDA-GlcN) with anti-inflammatory and joint protection effects. The nanosystem was synthesized by encapsulating triptolide (TP) in mesoporous silica nanoparticles and coating it with pH-sensitive polydopamine (PDA) and glucosamine (GlcN) grafting on the PDA. The nano-drug delivery system with anti-inflammatory and joint protection effects should have good potency against RA. METHODS: A template method was used to synthesize mesoporous silica (MSN). MSN-TP@PDA-GlcN was synthesized via MSN loading with TP, coating with PDA and grafting of GlcN on PDA. The drug release behavior was tested. A cellular inflammatory model and a rat RA model were used to evaluate the effects on RA. In vivo imaging and microdialysis (MD) system were used to analyze the sustained release and pharmacokinetics in RA rats. RESULTS: TMSN-TP@PDA-GlcN was stable, had good biocompatibility, and exhibited sustained release of drugs in acidic environments. It had excellent anti-inflammatory effects in vitro and in vivo. It also effectively repaired joint destruction in vivo without causing any tissue toxicity. In vivo imaging and pharmacokinetics experiments showed that the nanosystem prolonged the residence time, lowered the Cmax value and enhanced the relative bioavailability of TP. CONCLUSIONS: These results demonstrated that MSN-TP@PDA-GlcN sustained the release of drugs in inflammatory joints and produced effective anti-inflammatory and joint protection effects on RA. This study provides a new strategy for the treatment of RA.

Relationship between left ventricular mechanical synchrony and left ventricular systolic function: a CZT-SPECT analysis.

BACKGROUND: CZT-SPECT has good agreement in the evaluation of mechanical synchronization compared with conventional SPECT. The aim of this study was to evaluate the correlation between left ventricular mechanical contraction synchrony and left ventricular systolic function by gated myocardial perfusion imaging (GMPI) using cadmium-zine-telluride (CZT) single photon emission computed tomography (SPECT). METHODS: This retrospective study involved 371 patients (239 males and 132 females, mean age 61.06 ± 11.78 years old) who underwent GMPI at the Nuclear Medicine Department of Shanxi Cardiovascular Hospital from January 2020 to August 2020. Systolic synchrony parameters and left ventricular systolic function parameters were calculated via Emory Cardiac Toolbox, including PP, PSD, PHB, HS, HK, EDV, ESV, and LVEF. Based on LVEF value, patients were divided into the severe reduction group (group 1, 127 cases, EF < 35%), moderate reduction group (group 2, 47 cases, 35% ≤ EF < 45%), mild reduction group (group 3, 50 cases, 45% ≤ EF < 50%) and normal group (group 4, 147 cases, EF ≥ 50%). Differences in PP, PSD, PHB, HS and HK among the four groups were compared using one-way ANOVA. Differences between two groups were compared using LSD-t test. The correlation among functional and mechanical contraction synchrony factors were analyzed using Pearson test. RESULTS: PP, PSD, PHB, HS and HK were significantly different among the four groups (F = 5.20, 188.72, 202.88, 171.05, 101.36, P < 0.001). Pairwise comparison tests showed significant differences in PSD and PHB in each two groups, and HS and HK in each two groups except for group 2 and 3 (t = 0.28 and 0.39, both P > 0.001). PP was significantly higher in group 1, relative to group 3 (t = 2.43, P < 0.001) and group 4 (t = 3.67, P < 0.001). Pearson correlation analysis revealed that LVEF negatively correlates with PP, PSD, PHB (r = 0.194, - 0.790, - 0.799, all P < 0.001). HS and HK showed positive correlation for LVEF (r = 0.778 and 0.795, P < 0.001), PSD, PHB and ESV were had good positive correlation (r = 0.778, 0.795, P < 0.001), PSD, PHB and EDV had good positive correlation (r = 0.722, 0.732, P < 0.001). However, PP had poor correlation with EDV (r = 0.095, P > 0.001). HS and HK were negatively correlated with EDV and ESV (r = - 0.700 to - 0.594, P < 0.001). CONCLUSION: CZT SPECT GMPI provided left ventricular mechanical contraction synchrony parameters that correlated well with left ventricular systolic function. Worse left ventricular mechanical contraction synchrony lead to decreased LVEF, making the systolic synchrony parameters valuable in the prediction of left ventricular systolic function.

Hypoxia and Singlet Oxygen Dual-Responsive Micelles for Photodynamic and Chemotherapy Therapy Featured with Enhanced Cellular Uptake and Triggered Cargo Delivery.

Introduction: Combination therapy provides better outcomes than a single therapy and becomes an efficient strategy for cancer treatment. In this study, we designed a hypoxia- and singlet oxygen-responsive polymeric micelles which contain azo and nitroimidazole groups for enhanced cellular uptake, repaid cargo release, and codelivery of photosensitizer Ce6 and hypoxia-activated prodrug tirapazamine TPZ (DHM-Ce6@TPZ), which could be used for combining Ce6-mediated photodynamic therapy (PDT) and PDT-activated chemotherapy to enhance the therapy effect of cancer. Methods: The hypoxia- and singlet oxygen-responsive polymeric micelles DHM-Ce6@TPZ were prepared by film hydration method. The morphology, physicochemical properties, stimuli responsiveness, in vitro singlet oxygen production, cellular uptake, and cell viability were evaluated. In addition, the in vivo therapeutic effects of the micelles were verified using a tumor xenograft mice model. Results: The resulting dual-responsive micelles not only increased the concentration of intracellular photosensitizer and TPZ, but also facilitated photosensitizer and TPZ release for enhanced integration of photodynamic and chemotherapy therapy. As a photosensitizer, Ce6 induced PDT by generating toxic singlet reactive oxygen species (ROS), resulting in a hypoxic tumor environment to activate the prodrug TPZ to achieve efficient chemotherapy, thereby evoking a synergistic photodynamic and chemotherapy therapeutic effect. The cascade synergistic therapeutic effect of DHM-Ce6@TPZ was effectively evaluated both in vitro and in vivo to inhibit tumor growth in a breast cancer mice model. Conclusion: The designed multifunctional micellar nano platform could be a convenient and powerful vehicle for the efficient co-delivery of photosensitizers and chemical drugs for enhanced synergistic photodynamic and chemotherapy therapeutic effect of cancer.

Data mining and spatio-temporal characteristics of urban road traffic emissions: A case study in Shijiazhuang, China.

Accurate estimation of traffic emissions and analysis of spatio-temporal distribution on urban roads play a crucial role in the development of low-carbon transportation system. Traditionally, a region's emission characteristics have been studied using numerous emission models with GPS-based spatio-temporal data. Due to the heavy data processing needs of GPS-based data, emission characteristics for a large region have been studied by dividing the region into a limited number of smaller areas or units. Additionally, GPS data are based on a few vehicles in the traffic which does not fully reflect road conditions. This paper proposed an approach that can be used to study and calculate the spatio-temporal emission pattern of a region at a roadway section level by using Baidu's online traffic data and COPERT model. The proposed method can be used to estimate road-level emission patterns while avoiding the impact of redundant data in large datasets, making the dataset more reliable, applicable, and scalable. The proposed approach has been demonstrated through a study of spatio-temporal emission patterns in the Qiaoxi district within city of Shijiazhuang, China. Online data crawling technology was used to obtain data on urban road traffic speed and driving distance. The linear reference technology was used to construct a two-layer road network model to conduct the coupling and matching of traffic data with the road network data. The COPERT model was implemented to calculate the average traffic emissions on each road in the road network, and a traffic emission intensity index was proposed to quantify the CO, VOC, NOx and CO2 emissions on urban roads in the study area. The analysis results show that the traffic emission intensity of the expressway, trunk road, secondary road, and branch road is high during the morning peak (7 AM-9 AM) and evening peak (5 PM-7 PM). The sections with higher traffic emission intensity are mainly concentrated on the main roads and secondary roads such as Jiefang South Street, Shitong Road and Xinhua Road. Nearly one-third of 2nd Ring and 3rd Ring roads also have relatively high emission intensity. The research results provide new ideas for estimating traffic emissions in urban road networks and analyzing the spatio-temporal distribution of traffic emissions. The research results can also provide a decision-making basis for traffic management departments to formulate energy-saving and emission-reduction measures and promote the development of urban green and low-carbon transportation.

Metal-Organic Framework for Hypoxia/ROS/pH Triple-Responsive Cargo Release.

Nanoparticulate antitumor photodynamic therapy (PDT) is suffering from a very short lifetime, limited diffusion distance of reactive oxygen species (ROS). Herein, a hypoxia/ROS/pH triple-responsive metal-organic framework (MOF) is designed to facilitate the on-demand release of photosensitizers and hence enhanced PDT efficacy. Tailored azo-containing imidazole ligand is coordinated with zinc to form MOF where photosensitizer (Chlorin e6/Ce6) is encapsulated. Azo can be reduced by overexpressed azoreductase in hypoxic tumor cells, resulting in depletion of glutathione (GSH) and thioredoxin (Trx) which are major antioxidants against ROS oxidative damage in PDT, resulting in rapid cargo release and additional efficacy amplification. The imidazole ionization causes a proton sponge effect to ensure the disintegration of the nanocarriers in acidic organelles, allowing the rapid release of Ce6 through lysosome escape. Under light irradiation, ROS produced by Ce6 may oxidize imidazole to urea, resulting in rapid cargo release. All of the triggers are expected to show interactive synergism. The pH- and hypoxia-responsiveness can improve the release rate of Ce6 for enhanced PDT therapy, whereas the consumption of oxygen by PDT may induce elevated hypoxia and hence in turn enhanced cargo release. This work highlights the role of triple-responsive nanocarriers for triggered photosensitizer release and improved antitumor PDT efficacy.

Vanadium Oxide Nanozymes with Multiple Enzyme-Mimic Activities for Tumor Catalytic Therapy.

Using tumors containing high concentrations of hydrogen peroxide to design nanozymes is a new and effective strategy, and vanadium-based nanomaterials receive increasing attention. In this paper, four kinds of vanadium oxide nanozymes with different valences of vanadium are synthesized by a simple method to verify the effect of valence on enzyme activity. Vanadium oxide nanozyme-III (Vnps-III) with a low valence of vanadium (V4+) exhibits good peroxidase (POD) and oxidase (OXD) activities, which can effectively produce reactive oxygen species (ROS) in the tumor microenvironment for tumor treatment. In addition, Vnps-III can also consume glutathione (GSH) to reduce ROS consumption. Vanadium oxide nanozyme-I (Vnps-I) containing a high valence of vanadium (V5+) has catalase (CAT) activity, which can catalyze hydrogen peroxide (H2O2) into oxygen (O2), which is beneficial to alleviate the hypoxic environment of solid tumors. Finally, a vanadium oxide nanozyme with both trienzyme simulation activity and GSH consumption ability was screened out by adjusting the ratio of V4+ to V5+ in vanadium oxide nanozymes. In cell and animal experiments, we successfully demonstrate that vanadium oxide nanozymes have excellent antitumor ability and high safety, which may bring great potential for clinical cancer treatment.

Construction of pH-sensitive targeted micelle system co-delivery with curcumin and dasatinib and evaluation of anti-liver cancer.

Nanomedicine delivery systems can achieve precise drug delivery and reduce toxic side effects compared with traditional drug delivery methods, but further development is still needed to eliminate obstacles such as multiple drug co-delivery, uncontrolled drug-release, and drug-resistance. Herein, we designed a dual drug-loaded nanosystem (THCD-NPs) that selectively transports and targets tumor cells for the treatment of liver cancer. In this drug delivery system, hyaluronic acid (HA)-conjugated curcumin (Cur) and d-α-tocopherol acid polyethylene glycolsuccinate (TPGS) were used as selective drug-carrying vehicles to deliver dasatinib (DAS) to cancer cells for combined administration. The mean size of the nanoparticles was approximately 66.14 ± 4.02 nm with good in vitro stability. The nanoparticles were pH sensitive and could accelerate drug release at low pH conditions. In vitro experiments showed that THCD-NPs were significantly cytotoxic to HepG2 cells and could be effectively taken up by these cells. Detailed investigations also demonstrated its pro-apoptotic activity. In vivo NIR fluorescence imaging showed that the nanoparticles could accumulate efficiently at the tumor site. Meanwhile, in vivo experiments showed that THCD-NPs significantly inhibited tumor growth and reduced the toxic side effects of free drugs in a mouse solid tumor model. In short, the nanoparticles we prepared provide a new idea for the treatment of liver cancer.

Curved corannulene dually targets mitochondria and endoplasmic reticulum, and initiates apoptosis via localized ROS induction upon light triggering.

Organelle-targeting agents are promising in both fundamental and applied biomedicine research, but such materials are very limited. As a curved 2D carbon material, corannulene (Cor) displays an uneven intramolecular electron distribution, producing a large dipole moment that can favor the electrostatic interaction. Based on the large negative mitochondrial membrane potential and the presence of a connection structure between mitochondria and endoplasmic reticulum (ER), we hypothesized that Cor could simultaneously target both mitochondria and ER. Such hypothesis was well validated by using the fluorescence tag-labelled Cor. The co-localization analysis in a model cell line (PC3) revealed a preferred accumulation of Cor in both organelles, as evidenced by a large Pearson correlation coefficient. The large dipole also empowered Cor the ability of controlled production of reactive oxygen species (ROS) upon light irradiation. This feature plus mitochondria targeting of Cor induced depletion of adenosine triphosphate (ATP) and caspase 9/3 activation. The triggered ROS generation in ER caused the calcium dumping in the cytosol, as revealed by a calcium-specific fluorescence probe. A significant degree of apoptosis was induced by Cor as a result of the interplay of dual mitochondria/ER targeting and triggered organelle-specific ROS delivery. This study demonstrated the subcellular targeting ability of Cor for potential ROS-based therapy, and implied that the dipole could be a valuable parameter for efficient design and tailored screening of organelle-targeting materials for various biomedical applications.

Electron-Accepting Micelles Deplete Reduced Nicotinamide Adenine Dinucleotide Phosphate and Impair Two Antioxidant Cascades for Ferroptosis-Induced Tumor Eradication.

Ferroptotic antitumor therapy has been compromised by various intracellular antioxidants, particularly glutathione and thioredoxin. Both are cofactors of glutathione peroxide 4 (GPX4) that act against oxidative stress via catalyzing the reduction of lipid peroxides. It was postulated that tailored polymer micelles could enhance ferroptotic antitumor efficacy via diminishing glutathione and thioredoxin under hypoxia. The aim was to engineer hypoxia-responsive micelles for selective enhancement of ferroptotic cell death in solid tumor. The polymer contains hydrophilic poly(ethylene glycol) (PEG) that is linked by azobenzene linker with nitroimidazole-conjugated polypeptide. The tailored polymer could self-assemble into nanoscale micelles to encapsulate RAS-selective lethal small molecule 3, a covalent GPX4 inhibitor. Under hypoxia, the azobenzene moiety enabled PEG shedding and enhanced micelles uptake in 4T1 cells. Likewise, the nitroimidazole moiety was reduced by the overexpressed nitroreductase with reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the cofactor, resulting in transient depletion of NADPH. This impaired both the glutathione and thioredoxin redox cycle, leading to diminished intracellular glutathione and thioredoxin. The selective potency of ferroptotic micelles in depleting NADPH, glutathione and thioredoxin was further verified in vivo in the 4T1 tumor xenograft mice model. This work highlights the role of hypoxia-responsive polymers in enhancing the potency of ferroptotic inducers against solid tumors without additional side effects to healthy organs.

Gated Mesoporous Silica Nanocarriers for Hypoxia-Responsive Cargo Release.

Mesoporous silica nanocarriers (MSNs) are appealing in terms of their large cavity surface area and high loading capacity, but they have been suffering from premature cargo release. Herein, we report a gated smart MSN that is sensitive to low oxygen concentration (i.e., hypoxia) via taking advantage of the superior electron-accepting ability of the azobenzene moiety. The azobenzene polymer was employed as the responsive gate-keeper that was deposited on the MSN surface, followed by coating with amphiphilic Pluronic F68 for steric stabilization. The obtained nanocarriers were less than 200 nm. The in vitro polymer degradation was spectrophotometrically witnessed via the employment of a reducing agent, namely, sodium dithionite, with a strong electron-donating ability. The hypoxia-responsive cargo release from the gated MSN was quantitatively demonstrated in breast cancer cells (MCF-7) using the fluorescence resonance energy transfer (FRET) technique where coumarin 6 and rhodamine B was selected as the FRET donor and acceptor, respectively. The FRET ratio was used as the index and decreased linearly over time under hypoxia, whereas it almost remained steady under normoxia. In addition, a model photosensitizer, namely, chlorin e6, was also loaded in the gated MSN whose toxicity under hypoxia was verified. This study developed a hypoxia-responsive MSN with the azobenzene polymer as the removable gate-keeper, which would expand the application of MSNs in pharmaceutical and biomedical areas since the low oxygen concentration is a unique trigger in many pathological conditions.

Mechanistic insight into the singlet oxygen-triggered expansion of hypoxia-responsive polymeric micelles.

Nitroimidazole-bearing nanomedicine has been popular as a hypoxia-responsive platform for on-demand drug delivery. We report the singlet oxygen-responsive property of nitroimidazole-containing micelles and the corresponding reaction mechanism, which would pave the way for developing a dual hypoxia- and singlet oxygen-sensitive drug delivery nanoplatform based on a simple nitroimidazole moiety.

Alleviating the Liver Toxicity of Chemotherapy via pH-Responsive Hepatoprotective Prodrug Micelles.

Nanocarriers have been extensively utilized to enhance the anti-tumor performance of chemotherapy, but it is very challenging to eliminate the associated hepatotoxicity. This was due to the significant liver accumulation of cytotoxic drug-loaded nanocarriers as a consequence of systemic biodistribution. To address this, we report a novel type of nanocarrier that was made of hepatoprotective compound (oleanolic acid/OA) with a model drug (methotrexate/MTX) being physically encapsulated. OA was covalently connected with methoxy poly(ethylene glycol) (mPEG) via a hydrazone linker, generating amphiphilic mPEG-OA prodrug conjugate that could self-assemble into pH-responsive micelles (ca. 100 nm), wherein the MTX loading was ca. 5.1% (w/w). The micelles were stable at pH 7.4 with a critical micelle concentration of 10.5 µM. At the acidic endosome/lysosome microenvironment, the breakdown of hydrazone induced the micelle collapse and fast release of payloads (OA and MTX). OA also showed adjunctive anti-tumor effect with a low potency, which was proved in 4T1 cells. In the mouse 4T1 breasttumor model, MTX-loaded mPEG-OA micelles demonstrated superior capability regarding in vivo tumorgrowth inhibition because of the passive tumor targeting of nanocarriers. Unsurprisingly, MTX induced significant liver toxicity, which was evidenced by the increased liver mass and increased levels of alanine transaminase, aspartate transaminase, and lactate dehydrogenase in serum as well as in liver homogenate. MTX-induced hepatotoxicity was also accompanied with augmented oxidative stress, for example, the increase of the malondialdehyde level and the reduction of glutathione peroxidase and superoxide dismutase concentration in the liver. As expected, mPEG-OA micelles significantly reduced the liver toxicity induced by MTX because of the hepatoprotective action of OA, which was supported by the reversal of all the above biomarkers and qualitative histological analysis of liver tissue. This work offers an efficient approach for reducing the liver toxicity associated with chemotherapy, which can be applied to various antitumor drugs and hepatoprotective materials.

All-active antitumor micelles via triggered lipid peroxidation.

Traditional antitumor nanomedicines have been suffering from the poor tumor targeting (ca. 1%) by the enhanced permeability and retention (EPR) effect, and the low drug loading (<5%). It was postulated that engineering all-active nanoplatform could increase the therapeutic efficacy to enable the nanocarrier function as both vehicle and active ingredient. To achieve this, a photosensitizer, Ce6 was encapsulated within polymeric micelles with unsaturated fatty acids as the building blocks. Upon light irradiation, the singlet oxygen produced by Ce6 induced lipid peroxidation, resulting in the generation of both active free radicals and aldehydes. These supplementary radicals could exert cytotoxic effect for direct killing tumor cells. The aldehyde end-products induced significant cell cycle arrest at G2 phase in 4T1 cells. The peroxidation process also facilitated the on-demand disassembly of micelles and rapid release of Ce6 to maximize the therapeutic effect of singlet oxygen. These all-active micelles showed a significantly enhanced cytotoxicity with the half maximal inhibitory concentration (IC50) of 0.6 ±â€¯0.2 µg/mL in contrast to the control micelles at 3.4 ±â€¯0.5 µg/mL. The improved antitumor efficacy of the all-active micelles was also demonstrated in the 4T1 tumor-bearing mice in vivo. The current work provides a facile approach to enhance the antitumor efficacy of PDT nanomedicine using the biocompatible fatty acids, which can be applied to various antitumor drugs and unsaturated lipids.

When self-assembly meets topology: an enhanced micelle stability.

The topology of hydrophobic moieties can affect the stability of self-assembled micelles. Curved corannulene and flat perylene were selected as model hydrophobic molecules with poly(ethylene glycol) as the hydrophilic segment. The curvature can enhance the intermolecular π-π interaction, and hence the driving force of micelle formation.