The protective effects of Axitinib on blood-brain barrier dysfunction and ischemia-reperfusion injury in acute ischemic stroke.

BACKGROUND AND PURPOSE: The pathophysiological features of acute ischemic stroke (AIS) often involve dysfunction of the blood-brain barrier (BBB), characterized by the degradation of tight junction proteins (Tjs) leading to increased permeability. This dysfunction can exacerbate cerebral injury and contribute to severe complications. The permeability of the BBB fluctuates during different stages of AIS and is influenced by various factors. Developing effective therapies to restore BBB function remains a significant challenge in AIS treatment. High levels of vascular endothelial growth factor (VEGF) in the early stages of AIS have been shown to worsen BBB breakdown and stroke progression. Our study aimed to investigate the protective effects of the VEGF receptor inhibitor Axitinib on BBB dysfunction and cerebral ischemia/reperfusion-induced injury. METHODS: BEnd3 cell exposed to oxygen-glucose deprivation (OGD) model was constructed to estimate pharmacological activity of Axitinib (400 ng/ml) on anti-apoptosis and pathological barrier function recovery. In vivo, rats were subjected to a 1 h transient middle cerebral artery occlusion and 23 h reperfusion (tMCAO/R) to investigate the permeability of BBB and cerebral tissue damage. Axitinib was administered through the tail vein at the beginning of reperfusion. BBB integrity was assessed by Evans blue leakage and the expression levels of Tjs claudin-5 and occludin. RESULTS: Our research revealed that co-incubation with Axitinib enhanced the cell viability of OGD-insulted bEnd3 cells, decreased LDH leakage rate, and suppressed the expression of apoptosis-related proteins cytochrome C and Bax. Axitinib also mitigated the damage to Tjs and facilitated the restoration of transepithelial electrical resistance in OGD-insulted bEnd.3 cells. In vivo, Axitinib administration reduced intracerebral Evans blue leakage and up-regulated the expression of Tjs in the penumbra brain tissue in tMCAO/R rats. Notably, 10 mg/kg Axitinib exerted a significant anti-ischemic effect by decreasing cerebral infarct volume and brain edema volume, improving neurological function, and reducing pro-inflammatory cytokines IL-6 and TNF-α in the brain. CONCLUSIONS: Our study highlights Axitinib as a potent protectant of blood-brain barrier function, capable of promoting pathological blood-brain barrier recovery through VEGF inhibition and increased expression of tight junction proteins in AIS. This suggests that VEGF antagonism within the first 24 h post-stroke could be a novel therapeutic approach to enhance blood-brain barrier function and mitigate ischemia-reperfusion injury.

Functionalized lipid nanoparticles modulate the blood-brain barrier and eliminate α-synuclein to repair dopamine neurons.

The challenge in the clinical treatment of Parkinson's disease lies in the lack of disease-modifying therapies that can halt or slow down the progression. Peptide drugs, such as exenatide (Exe), with potential disease-modifying efficacy, have difficulty in crossing the blood-brain barrier (BBB) due to their large molecular weight. Herein, we fabricate multi-functionalized lipid nanoparticles (LNP) Lpc-BoSA/CSO with BBB targeting, permeability-increasing and responsive release functions. Borneol is chemically bonded with stearic acid and, as one of the components of Lpc-BoSA/CSO, is used to increase BBB permeability. Immunofluorescence results of brain tissue of 15-month-old C57BL/6 mice show that Lpc-BoSA/CSO disperses across the BBB into brain parenchyma, and the amount is 4.21 times greater than that of conventional LNP. Motor symptoms of mice in Lpc-BoSA/CSO-Exe group are significantly improved, and the content of dopamine is 1.85 times (substantia nigra compacta) and 1.49 times (striatum) that of PD mice. α-Synuclein expression and Lewy bodies deposition are reduced to 51.85% and 44.72% of PD mice, respectively. Immunohistochemical mechanism studies show AKT expression in Lpc-BoSA/CSO-Exe is 4.23 times that of PD mice and GSK-3ß expression is reduced to 18.41%. Lpc-BoSA/CSO-Exe could reduce the production of α-synuclein and Lewy bodies through AKT/GSK-3ß pathway, and effectively prevent the progressive deterioration of Parkinson's disease. In summary, Lpc-BoSA/CSO-Exe increases the entry of exenatide into brain and promotes its clinical application for Parkinson's disease therapy.

M-MDSCs mediated trans-BBB drug delivery for suppression of glioblastoma recurrence post-standard treatment.

We found that immunosuppressive monocytic-myeloid-derived suppressor cells (M-MDSCs) were more likely to be recruited by glioblastoma (GBM) through adhesion molecules on GBM-associated endothelial cells upregulated post-chemoradiotherapy. These cells are continuously generated during tumor progression, entering tumors and expressing PD-L1 at a high level, allowing GBM to exhaust T cells and evade attack from the immune system, thereby facilitating GBM relapse. αLy-6C-LAMP is composed of (i) drug cores with slightly negative charges condensed by cationic protamine and plasmids encoding PD-L1 trap protein, (ii) pre-formulated cationic liposomes targeted to Ly-6C for encapsulating the drug cores, and (iii) a layer of red blood cell membrane on the surface for effectuating long-circulation. αLy-6C-LAMP persistently targets peripheral, especially splenic, M-MDSCs and delivers secretory PD-L1 trap plasmids, leveraging M-MDSCs to transport the plasmids crossing the blood-brain barrier (BBB), thus expressing PD-L1 trap protein in tumors to inhibit PD-1/PD-L1 pathway. Our proposed drug delivery strategy involving intermediaries presents an efficient cross-BBB drug delivery concept that incorporates live-cell targeting and long-circulating nanotechnology to address GBM recurrence.

Functional Chitosan and Its Derivative-Related Drug Delivery Systems for Nano-Therapy: Recent Advances.

In the struggle against diseases, the development of nano-therapy has certainly been a tremendous progression owing to the various superiority, and chitosan is no doubt a kind of prominent biopolymer material with versatility for applications in disease treatments. For the rational construction of chitosan-related nano-biodevices, it is necessary to pay full attention to the material itself, where it is the material properties that guide the design criteria. Additionally, the well-matched preparation methods between material carriers and therapeutic agents draw much attention to the final construction since they seem to be more realistic. In detail, we present a comprehensive overview of recent advances in rational construction of chitosan-related nano-therapies with respect to material-property-oriented design criteria and preparation methods in the current review article, based on the foundation of continuous investigations. Based on this review, a portion of the various uses of chitosan-related nano-biodevices for biomedical applications are specifically discussed. Here, the strategies demonstrate the versatility of chitosan well, and the concept of being simple yet effective is well illustrated and vividly communicated. Altogether, a fresh concept concerning multi-functional chitosan and its derivative-related drug delivery systems for nano-therapy is proposed in this review, and this could be applied to other materials, which seems to be a novel angle.

Active Anchoring Stimuli-Responsive Nano-Craft to Relieve Pulmonary Vasoconstriction by Targeting Smooth Muscle Cell for Hypoxic Pulmonary Hypertension Treatment.

Recently, nanotechnology-based drug delivery platforms in treating pulmonary arterial hypertension (PAH) have gradually emerged. However, large mechanical stress and shear stress in blood vessels greatly affect the retention of nanopreparative materials at lesion sites, severely limiting nanotechnology-based drug delivery. Herein, a stimuli-responsive nanocraft is rationally designed by actively anchoring E-selectin overexpressed on pulmonary arterial endothelial cells (PAECs), under hypoxic conditions, allowing effective accumulation and retention of the drug at the lesion site. Briefly, a nitrobenzene group is incorporated into the framework of a nanocarrier, and then it is simultaneously linked with chitosan. Additionally, the surface of the nanocarrier with sialic acid (SA) and encapsulated the clinically used drug ambrisentan (Am), which enables the anchoring of E-selectin and subsequent drug delivery is modifed. This system facilitates intercellular transport to pulmonary artery smooth muscle cells (PASMCs) when targeting PAECs and specifically responds to a reductive hypoxic microenvironment with elevated nitroreductase in PASMCs. Moreover, compared with free Am, nanoencapsulation and SA-PEG2000-NH2 prolong the blood circulation time, achieving better therapeutic outcomes in preventing vascular remodeling and reversing systolic dysfunction. The originality and contribution of this work reveal the promising value of this pulmonary arterial anchoring stimuli-responsive nanocraft as a novel therapeutic strategy for satisfactory PAH treatment.

NIR-Triggered Thermosensitive Nanoreactors for Dual-Guard Mechanism-Mediated Precise and Controllable Cancer Chemo-Phototherapy.

Thermosensitive nanoparticles can be activated by externally applying heat, either through laser irradiation or magnetic fields, to trigger the release of drug payloads. This controlled release mechanism ensures that drugs are specifically released at the tumor site, maximizing their effectiveness while minimizing systemic toxicity and adverse effects. However, its efficacy is limited by the low concentration of drugs at action sites, which is caused by no specific target to tumor sties. Herein, hyaluronic acid (HA), a gooey, slippery substance with CD44-targeting ability, was conjugated with a thermosensitive polymer poly(acrylamide-co-acrylonitrile) to produce tumor-targeting and thermosensitive polymeric nanocarrier (HA-P) with an upper critical solution temperature (UCST) at 45 °C, which further coloaded chemo-drug doxorubicin (DOX) and photosensitizer Indocyanine green (ICG) to prepare thermosensitive nanoreactors HA-P/DOX&ICG. With photosensitizer ICG acting as the "temperature control element", HA-P/DOX&ICG nanoparticles can respond to temperature changes when receiving near-infrared irradiation and realize subsequent structure depolymerization for burst drug release when the ambient temperature was above 45 °C, achieving programmable and on-demand drug release for effective antitumor therapy. Tumor inhibition rate increased from 61.8 to 95.9% after laser irradiation. Furthermore, the prepared HA-P/DOX&ICG nanoparticles possess imaging properties, with ICG acting as a probe, enabling real-time monitoring of drug distribution and therapeutic response, facilitating precise treatment evaluation. These results provide enlightenment for the design of active tumor targeting and NIR-triggered programmable and on-demand drug release of thermosensitive nanoreactors for tumor therapy.

Fabrication of Dual-Functional Bacterial-Cellulose-Based Composite Anion Exchange Membranes with High Dimensional Stability and Ionic Conductivity.

Anion exchange membranes (AEMs) are increasingly becoming a popular research area due to their ability to function with nonprecious metals in electrochemical devices. Nevertheless, there is a challenge to simultaneously optimize the dimensional stability and ionic conductivity of AEMs due to the "trade-off" effect. Herein, we adopted a novel strategy of combining filling and cross-linking using functionalized bacterial cellulose (PBC) as a dual-functional porous support and brominated poly(phenylene oxide) (Br-PPO) as the cross-linking agent and filler. The PBC nanofiber framework together with cross-linking can provide a reliable mechanical support for the subsequent filled polymer, thus improving the mechanical properties and effectively limiting the size change of the final quaternized-PPO (QPPO)-filled PBC composite membrane. The composite membrane showed a very low swelling ratio of only 10.35%, even at a high water uptake (81.83% at 20 °C). Moreover, the existence of multiple -NR3+ groups in the cross-link bonds between BC and Br-PPO can provide extra OH- ion transport sites, contributing to the increase in ionic conductivity. The final membrane demonstrated a hydroxide ion conductivity of 62.58 mS cm-1, which was remarkably higher than that of the pure QPPO membrane by up to 235.93% (80 °C). The successful preparation of the PBC3/QPPO membrane provides an effective avenue to tackle the trade-off effect through a dual-functional strategy.

Glutathione Consumptive Dual-Sensitive Lipid-Composite Nanoparticles Induce Immunogenic Cell Death for Enhanced Breast Tumor Therapy.

Although chemotherapy remains the standard therapy for tumor treatment, serious side effects can occur because of nontargeted distribution and damage to healthy tissues. Hollow mesoporous silica nanoparticles (HMSNs) modified with lipids offer potential as delivery systems to improve therapeutic outcomes and reduce adverse effects. Herein, we synthesized HMSNs with integrated disulfide bonds (HMSN) for loading with the chemotherapeutic agent oxaliplatin (OXP) which were then covered with the synthesized hypoxia-sensitive lipid (Lip) on the surface to prepare the dual-sensitive lipid-composite nanoparticles (HMSN-OXP-Lip). The empty lipid-composite nanoparticles (HMSN-Lip) would consume glutathione (GSH) in cells because of the reduction of disulfide bonds in HMSN and would also inhibit GSH production because of NADPH depletion driven by Lip cleavage. These actions contribute to increased levels of ROS that induce the immunogenic cell death (ICD) effect. Simultaneously, HMSN-Lip would disintegrate in the presence of high concentrations of GSH. The lipid in HMSN-OXP-Lip could evade payload leakage during blood circulation and accelerate the release of the OXP in the tumor region in the hypoxic microenvironment, which could significantly induce the ICD effect to activate an immune response for an enhanced therapeutic effect. The tumor inhibitory rate of HMSN-OXP-Lip was almost twice that of free OXP, and no apparent side effects were observed. This design provides a dual-sensitive and efficient strategy for tumor therapy by using lipid-composite nanoparticles that can undergo sensitive drug release and biodegradation.

Composite proton exchange membrane for fuel cells based on chitosan modified by acid-base amphoteric nanoparticles.

Currently, achieving a simultaneous improvement in proton conductivity and mechanical properties is a key challenge in using chitosan (CS) as a proton exchange membrane (PEM) substrate in direct methanol fuel cells (DMFCs). Herein, a novel nanofiller-zwitterionic molecule, (3-(3-aminopropyl) dimethylammonio) propane-1-sulfonate, ADPS)-modified polydopamine (PDA) (PDA-ADPS) was synthesized by the Michael addition reaction and was incorporated into a CS matrix to prepare CS/PDA-ADPS composite membranes. PDA-ADPS, which contains an acid-based ion pair can create new proton conduction channels in the composite membrane, improving proton conductivity. The proton conductivity of the CS/PDA-ADPS composite membrane was as high as 38.4 mS cm-1 at 80 °C. Moreover, due to the excellent compatibility and dispersibility of PDA-ADPS in the CS matrix, the obtained CS/PDA-ADPS composite membranes exhibited favorable mechanical properties. Such outstanding proton conductivity and mechanical properties guarantee good performance of the composite membranes in fuel cells. The peak power density of the CS/PDA-ADPS composite membranes was 30.2 mW cm-2 at 70 °C. This work provides a new strategy for fabricating high-performance CS based PEMs for DMFCs.

Combining Multifunctional Delivery System with Blood-Brain Barrier Reversible Opening Strategy for the Enhanced Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative illness characterized by intracellular tau-phosphorylation, ß-amyloid (Aß) plaques accumulation, neuroinflammation, and impaired behavioral ability. Owing to the lack of effective brain delivery approaches and the presence of the blood-brain barrier (BBB), current AD therapeutic endeavors are severely limited. Herein, a multifunctional delivery system (RVG-DDQ/PDP@siBACE1) is elaborately combined with a protein kinase B (AKT) agonist (SC79) for facilitating RVG-DDQ/PDP@siBACE1 to target and penetrate BBB, enter brain parenchyma, and further accumulate in AD brain lesion. Moreover, compared with the unitary dose of RVG-DDQ/PDP@siBACE1, this collaborative therapy strategy exhibits a distinctive synergistic function including scavenging reactive oxygen species (ROS), decreasing of Aß production, alleviating neuroinflammation by promoting the polarized microglia into the anti-inflammatory M2-like phenotype and significantly enhancing the cognitive functions of AD mice. More strikingly, according to these results, an innovative signaling pathway "lncRNA MALAT1/miR-181c/BCL2L11" is found that can mediate the neuronal apoptosis of AD. Taken together, combining the brain targeted delivery system with noninvasive BBB opening can provide a promising strategy and platform for targeting treatment of AD and other neurodegenerative diseases.

A tripartite game analysis of industrial structure upgrading and green development of regional economy: A case study of Shanxi Province, China.

In the contemporary context, both the upgrading of the industrial structure and the implementation of environmentally sustainable practices within the regional economy have emerged as central avenues for achieving quality development. This study examines the strategic behavior of local governments, capital, and people through the construction of a tripartite evolutionary game model. Subsequently, six different evolutionary stable strategy (ESS) are subjected to a comprehensive analysis. Finally, the parameters influencing the strategic decisions of each party are meticulously examined through simulation. The results of this study can be summarized as follows: First, it is shown that under appropriate conditions, all three entities support the scenario of stable development prospects associated with industrial structure upgrading (1, 1, 1). Second, the strategic choices made by capital and people depend on several factors, including existing profits, future benefits, and the costs associated with transformation. At the same time, local governments show a propensity to adopt incentive strategies. Ultimately, the research underscores the pronounced impact of future benefits, transformation costs, and the probability of success in industrial upgrading on all stakeholders, shaping their evolutionary trajectories and results. In particular, the probability of successful industrial structure upgrading exerts the greatest influence on evolutionary trajectories, while the possibility of government imposing carbon taxes and initial willingness primarily determine the evolutionary trajectory. This paper attempts to provide a new perspective on industrial structure upgrading and green development of the regional economy by combining evolutionary game theory and scenario analysis methods to promote the process of industrial structure upgrading and sustainable development.

Intervening in hnRNPA2B1-mediated exosomal transfer of tumor-suppressive miR-184-3p for tumor microenvironment regulation and cancer therapy.

BACKGROUND: Despite being a common malignant tumor, the molecular mechanism underlying the initiation and progression of triple-negative breast cancers (TNBCs) remain unclear. Tumor-associated macrophages (TAMs) are often polarized into a pro-tumor phenotype and are associated with a poor prognosis of TNBCs. Exosomes, important mediators of cell-cell communication, can be actively secreted by donor cells to reprogram recipient cells. The functions and molecular mechanisms of tumor cell-derived exosomes in TNBCs progression and TAMs reprogramming urgently need to be further explored. RESULTS: We demonstrated that tumor cell-derived exosomes enriched with miR-184-3p were taken up by macrophages to inhibit JNK signaling pathway by targeting EGR1, thereby inducing M2 polarization of macrophages and synergistically promoting tumor progression. Nanoparticles loaded with oncogene c-Myc inhibitor JQ1 could suppress the polarization process by reducing Rac1-related exosome uptake by macrophage. More importantly, it was found for the first time that tumor-suppressive miR-184-3p was actively sorted into exosomes by binding to RNA-binding protein heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), thus facilitating tumor cell proliferation and metastasis by relieving the inhibitory effect of miR-184-3p on Mastermind-like 1 (MAML1). Overexpressing miR-184-3p in tumor cells and simultaneously knocking down hnRNPA2B1 to block its secretion through exosomes could effectively inhibit tumor growth and metastasis. CONCLUSIONS: Our study revealed that hnRNPA2B1-mediated exosomal transfer of tumor-suppressive miR-184-3p from breast cancer cells to macrophages was an important mediator of TNBCs progression, providing new insights into TNBCs pathogenesis and therapeutic strategies.

Nanocarriers transport across the gastrointestinal barriers: The contribution to oral bioavailability via blood circulation and lymphatic pathway.

Oral administration is the preferred route of drug delivery in clinical practice due to its noninvasiveness, safety, convenience, and high patient compliance. The gastrointestinal tract (GIT) plays a crucial role in facilitating the targeted delivery of oral drugs. However, the GIT presents multiple barriers that impede drug absorption, including the gastric barrier in the stomach and the mucus and epithelial barriers in the intestine. In recent decades, nanotechnology has emerged as a promising approach for overcoming these challenges by utilizing nanocarrier-based drug delivery systems such as liposomes, micelles, polymeric nanoparticles, solid lipid nanoparticles, and inorganic nanoparticles. Encapsulating drugs within nanocarriers not only protects them from degradation but also enhances their transport and absorption across the GIT, ultimately improving oral bioavailability. The aim of this review is to elucidate the mechanisms underlying nanocarrier-mediated transportation across the GIT into systemic circulation via both the blood circulation and lymphatic pathway.

Photoswitchable and long-lived seven-membered cyclic singlet diradicals for the bioorthogonal photoclick reaction.

Annularly 1,3-localized singlet diradicals are energetic and homolytic intermediates, but commonly too short-lived for widespread utilization. Herein, we describe a direct observation of a long-lived and seven-membered singlet diradical, oxepine-3,6-dione-2,7-diyl (OXPID), via spectroscopic experiments and also theoretical evidence from computational studies, which is generated via photo-induced ring-expansion of 2,3-diaryl-1,4-naphthoquinone epoxide (DNQO). The photo-generated OXPID reverts to the thermally stable σ-bonded DNQO with t1/2 in the µs level, thus constituting a novel class of T-type molecular photoswitches with high light-energy conversion efficiency (η = 7.8-33%). Meanwhile, the OXPID is equilibrated to a seven-membered cyclic 1,3-dipole as an electronic tautomer that can be captured by ring-strained dipolarophiles with an ultrafast cycloaddition rate (k2CA up to 109 M-1 s-1). The T-type photoswitchable DNQO is then exploited to be a highly selective and recyclable photoclick reagent, enabling spatiotemporal-resolved bioorthogonal ligation on living cell membranes via a tailored DNQO-Cy3 probe.

"Targeted plus controlled" - Composite nano delivery system opens the tumor vascular and microenvironment normalization window for anti-tumor therapy.

The bottleneck of traditional anti-tumor therapy is mainly limited by the abnormal microenvironment of tumors. Leaky vessels are difficult for drugs or immune cells to penetrate deep into tumors, but tumor cells can easily escape through which and metastasize to other organs. Reprogramming the tumor microenvironment is one of the main directions for anti-cancer research, among which, tumor vascular normalization has received increasing attention. However, how to control the dose and time of anti-angiogenic drugs for stable vascular normalizing effect limits it for further research. We developed a composite nano delivery system, P-V@MG, with double delivery function of pH-responsibility and sustained drug release. The PHMEMA shell improves amphiphilicity of nano delivery system and prolongs in vivo retention, and releases V@MG in the weakly acidic tumor microenvironment, which slowly release anti-angiogenic drugs, Vandetanib. We found that P-V@MG not only prolonged the normalization window of tumor vascular but also reprogram tumor microenvironment with increased perfusion, immune cells infiltration and relieved hypoxia, which further opened the pathway for other anti-cancer therapeutics. This synergy was proved by the improving anti-tumor efficiency by combination of P-V@MG with the doxorubicin hydrochloride in 4 T1 breast cancer model suggesting the desirable value of pro-vascular normalization nano delivery systems in the field of anti-tumor combination therapy.

Dual reinforced composite membranes from in-situ ionic crosslinked quaternized chitosan filled quaternized polyvinylidene fluoride nanofiber for alkaline direct methanol fuel cell.

The main obstacle of high-performance cationic functionalization chitosan (CS) as anion exchange membranes (AEMs) is the trade-off between mechanical stability and ionic conductivity. Here, in-situ ionic crosslinking between the deprotonated hydroxyl group and quaternary ammonium group under alkaline conditions was ingeniously applied to improve the mechanical stability of highly quaternized CS (HQCS) with high IEC (>2 mmol g-1). Meanwhile, to further reduce the swelling and enhance the hydroxide conductivity, a mechanically robust hydroxide ion conduction network, quaternized electrospun poly(vinylidene fluoride) (QPVDF) nanofiber, was subsequently used as the filling substrate of in-situ crosslinked HQCS to prepare dual reinforced thin AEMs. The introduction of a robust QPVDF nanofiber mat can not only greatly improve the mechanical properties and limit swelling, but also create facile ion transport channels. Notably, the HQCS/QPVDF-74.0 composite membrane demonstrates perfect dimensional stability, high mechanical performance and excellent alkaline stability, as well as superior ionic conductivity of 66.2 mS cm-1 at 80 °C. The thus assembled alkaline direct methanol fuel cell displays a maximum power density of 132.30 mW cm-2 using 5 M KOH and 3 M methanol as fuels at 80 °C with satisfactory durability.

GSH-Responsive Polymeric Micelles for Remodeling the Tumor Microenvironment to Improve Chemotherapy and Inhibit Metastasis in Breast Cancer.

The tumor microenvironment (TME) of breast cancer is hypoxic, which can promote tumor progression, including invasion and metastasis, and limit the efficacy of anti-tumor treatment. Nitric oxide (NO) can dilate blood vessels, effectively alleviate hypoxia, and regulate the TME, which has the potential to improve the anti-tumor therapeutic efficacy. Here, chitosan (CO) and octadecylamine (ODA) were linked by the disulfide bond, and the LinTT1 peptide was linked onto CO-SS-ODA for targeting tumor cells and endothelial cells in tumors. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) was connected to CO. Doxorubicin (DOX) was encapsulated, and GSH hierarchically responsive polymer micelles (TSCO-SS-ODA/DOX) were constructed for the treatment of breast cancer. The micelles had differently responsive drug release in different GSH concentrations. In endothelial cells, the micelles rapidly responded to release NO. In tumor cells, the disulfide bond rapidly broke and released DOX to effectively kill tumor cells. The disulfide bond was not sensitive to GSH concentration in endothelial cells, which had less release of DOX. The killing effect of the micelles to endothelial cells was much lower than that to tumor cells. The cell selective drug release of the drug delivery systems enabled safe and effective treatment of drugs. TSCO-SS-ODA/DOX, which had the excellent ability to target tumors, can alleviate tumor hypoxia, decrease the infiltration of M2 macrophages in tumors, increase the infiltration of M1 macrophages in tumors, and remodel the TME. Notably, TSCO-SS-ODA/DOX can significantly inhibit the growth of the primary tumor and effectively inhibit tumor metastasis. The drug delivery system provided a potential solution for effectively treating breast cancer.

Normalizing Tumor Blood Vessels to Improve Chemotherapy and Inhibit Breast Cancer Metastasis by Multifunctional Nanoparticles.

The abnormal tumor blood vessels with high leakage can promote tumor cells to infiltrate into the systemic circulation and increase the risk of tumor metastasis. In addition, chemotherapy may destroy tumor blood vessels and further aggravate metastasis. Normalizing tumor blood vessels can reduce vascular leakage and increase vascular integrity. The simultaneous administration of vascular normalization drugs and chemotherapy drugs may resist the blood vessels' destruction of chemotherapy. Here, multifunctional nanoparticles (CCM@LMSN/DOX&St), which combined chemotherapy with tumor blood vessel normalization, were prepared for the treatment of breast cancer. The results showed that CCM@LMSN/DOX&St-loaded sunitinib (St) promoted the expression of junction proteins Claudin-4 and VE-cadherin of endothelial cells, reversed the destruction of DOX to the endothelial cell layer, protected the integrity of the endothelial cell layer, and inhibited the migration of 4T1 tumor cells across the endothelial cell layer. In vivo experiments showed that CCM@LMSN/DOX&St effectively inhibited tumor growth in situ; what is exciting was that it also inhibited distal metastasis of breast cancer. CCM@LMSN/DOX&St encapsulated with St can normalize tumor blood vessels, reverse the damage of DOX to tumor blood vessels, increase the integrity of blood vessels, and prevent tumor cell invasion into blood vessels, which can inhibit breast cancer spontaneous metastasis and reduce chemotherapy-induced metastasis. This drug delivery platform effectively inhibited the progression of tumors and provided a promising solution for effective tumor treatment.

Chitosan-based nano-micelles for potential anti-tumor immunotherapy: Synergistic effect of cGAS-STING signaling pathway activation and tumor antigen absorption.

Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway is an essential DNA-sensing pathway to regulate the innate and adaptive immune response, which plays an important role in tumor immunotherapy. Although the STING agonists can be used, they are limited by their inability to target immune cells and systemic immunotoxicity, calling for novel strategies to accurately and effectively activate the cGAS-STING signaling pathway. Herein, mannose-modified stearic acid-grafted chitosan (M-CS-SA) micelles with the ability to activate the cGAS-STING signaling pathway and absorb tumor antigens were constructed. The chitosan-based nano-micelles showed valid dendritic cell (DCs) targeting and could escape from lysosomes leading to the activation of the cGAS-STING signaling pathway and the maturation of DCs. In addition, a combinatorial therapy was presented based on the programmed administration of oxaliplatin and M-CS-SA. M-CS-SA adsorbed tumor antigens released by chemotherapy to construct an autologous tumor vaccine and built a comprehensive antitumor immune response. In vivo, the combinatorial therapy achieved a tumor inhibition rate of 76.31 % at the oxaliplatin dose of 5 mg/kg and M-CS-SA dose of 15 mg/kg, and increased the CD3+ CD8+ T cell infiltration. This work demonstrated that M-CS-SA and its co-treatment with oxaliplatin showed great potential in tumor immunotherapy.

Research on the Mechanism of Low-Temperature Oxidation of Asphaltene.

Asphaltene extracted from heavy oil was oxidized by a mixture of propionic anhydride and hydrogen peroxide at a low temperature of 50 °C. Elemental analysis, infrared analysis, proton nuclear magnetic resonance analysis, and gas chromatograph/mass spectrometer analysis results indicated that oxygen addition, side chain cleavage, and condensation reactions mainly occurred in the oxidation process. The oxidation products were divided into 28% methanol solubles and 72% methanol insolubles. There were mainly fatty acids and fatty acid esters in the methanol solubles. There were also small amounts of aromatic compounds with low condensation in the methanol solubles, and the alkyl side chains were mostly short ones. The degree of aromatic ring condensation in the methanol insolubles was slightly higher than that of the pristine asphaltene. There were still some long unbroken chains in the methanol insolubles after the low-temperature reaction. The molecular dynamics simulation results show that the distribution of propionic anhydride around the asphaltene molecules can promote the oxidation of asphaltene. This low-temperature oxidation technology can be used to process asphaltenes to improve the profitability of heavy-oil-processing enterprises.