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.

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.

Quinoline-derived NNP-manganese complex catalyzed α-alkylation of ketones with primary alcohols.

An air-stable quinoline-derived NNP ligand chelated Mn catalyst was developed for the efficient α-alkylation of ketones with primary alcohols via a hydrogen auto-transfer methodology. The sole by-product formed is water, rendering the protocol atom efficient. A wide range of ketone and alcohol substrates were employed, providing the α-alkylated ketones with isolated yields up to 94%. This system was also efficient for the green synthesis of quinoline derivatives while using (2-aminophenyl)methanol as an alkylating reagent.

Integrated analysis of ceRNA-miRNA changes in paraquat-induced pulmonary epithelial-mesenchymal transition via high-throughput sequencing.

Recent studies have shown that epithelial-mesenchymal transition (EMT) plays an important role in paraquat (PQ)-induced tissue fibrosis, which is the main cause of death in patients with PQ poisoning. However, no effective treatment for pulmonary interstitial fibrosis caused by PQ poisoning exists. It is of great significance for us to find new therapeutic targets through bioinformatics in PQ-induced EMT. We conducted transcriptome sequencing to determine the expression profiles of 1210 messenger RNAs (mRNAs), 558 long noncoding RNAs, 28 microRNAs (miRNAs), including 18 known-miRNAs, 10 novel-miRNAs and 154 circular RNAs in the PQ-exposed EMT group mice. Using gene ontology and Kyoto Encyclopaedia of Genes and Genomes analyses, we identified the pathways associated with signal transduction, cancers, endocrine systems and immune systems were involved in PQ-induced EMT. Furthermore, we constructed long noncoding RNA-miRNA-mRNA interrelated networks and found that upregulated genes included Il22ra2, Mdm4, Slc35e2 and Angptl4, and downregulated genes included RGS2, Gabpb2, Acvr1, Prkd3, Sp100, Tlr12, Syt15 and Camk2d. Thirteen new potential competitive endogenous RNA targets were also identified for further treatment of PQ-induced pulmonary tissue fibrosis. Through further study of the pathway and networks, we may identify new molecular targets in PQ-induced pulmonary EMT.

Atmospheric chemistry of 2-nitrobenzaldehyde: Initiated by photo-excitation, OH-oxidation, and small TiO2 clusters adsorption catalysis.

The fate of 2-nitrobenzaldehyde (2-NBA) is of interest in atmospheric chemistry as it is a semi-volatile organic compound with high photosensitivity. This study presents a quantum chemical study of the gas-phase reactions of 2-NBA photo-excitation and OH-oxidation in the absence and presence of small TiO2 clusters. To further understand the unknown photolysis mechanism, the photo-reaction pathways of ground singlet state and the lying excited triplet state of 2-NBA were investigated including the initial and subsequent reactions of proton transfer, direct CO, NO2, and HCO elimination routes in the presence of O2 and NO. Meanwhile, the OH-mediated degradation of 2-NBA proceeded via five H-extraction and six OH-addition channels by indirect mechanism, which follows a succession of reaction steps initiated by the formation of weakly stable intermediate complexes. The H-extraction from the -CHO group was the dominant pathway with a negative activation energy of -1.22 kcal/mol. The calculated rate coefficients at 200-600 K were close to the experimental data in literature within 308-352 K, and the kinetic negative temperature independence was found in both experimental literature and computational results. Interestingly, 2-NBA was favored to be captured onto small TiO2 clusters via six adsorption configurations formed via various combination of three types of bonds of Ti···O, Ti···C, and O···H between the molecularly adsorbed 2-NBA and TiO2 clusters. Comparison indicted that the chemisorptions of aldehyde oxygen have largest energies. The results suggested adsorption conformations have a respectable impact on the catalysis barrier. This study is significant for understanding the atmospheric chemistry of 2-nitrobenzaldehyde.

Theoretical Study of the Hydroxyl-Radical-Initiated Degradation Mechanism, Kinetics, and Subsequent Evolution of Methyl and Ethyl Iodides in the Atmosphere.

The degradation and transformation of iodinated alkanes are crucial in the iodine chemical cycle in the marine boundary layer. In this study, MP2 and CCSD(T) methods were adopted to study the atmospheric transformation mechanism and degradation kinetic properties of CH3 I and CH3 CH2 I mediated by ⋅OH radical. The results show that there are three reaction mechanisms including H-abstraction, I-substitution and I-abstraction. The H-abstraction channel producing ⋅CH2 I and CH3 C ⋅ HI radicals are the main degradation pathways of CH3 I and CH3 CH2 I, respectively. By means of the variational transition state theory and small curvature tunnel correction method, the rate constants and branching ratios of each reaction are calculated in the temperature range of 200-600 K. The results show that the tunneling effect contributes more to the reaction at low temperatures. Theoretical reaction rate constants of CH3 I and CH3 CH2 I with ⋅OH are calculated to be 1.42×10-13 and 4.44×10-13  cm3 molecule-1 s-1 at T=298 K, respectively, which are in good agreement with the experimental values. The atmospheric lifetimes of CH3 I and CH3 CH2 I are evaluated to be 81.51 and 26.07 day, respectively. The subsequent evolution mechanism of ⋅CH2 I and CH3 C ⋅ HI in the presence of O2 , NO and HO2 indicates that HCHO, CH3 CHO, and I-atom are the main transformation end-products. This study provides a theoretical basis for insight into the diurnal conversion and environmental implications of iodinated alkanes.

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.

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.

Roles of Amides on the Formation of Atmospheric HONO and the Nucleation of Nitric Acid Hydrates.

Nitrous acid (HONO) is hazardous to the human respiratory system, and the hydrolysis of NO2 is the source of HONO. Hence, the investigation on the removal and transformation of HONO is urgently established. The effects of amide on the mechanism and kinetics of the formation of HONO with acetamide, formamide, methylformamide, urea, and its clusters of the catalyst were studied theoretically. The results show that amide and its small clusters reduce the energy barrier, the substituent improves the catalytic efficiency, and the catalytic effect order is dimer > monohydrate > monomer. Meanwhile, the clusters composed of nitric acid (HNO3), amides, and 1-6 water molecules were investigated in the amide-assisted nitrogen dioxide (NO2) hydrolysis reaction after HONO decomposes by combining the system sampling technique and density functional theory. The study on thermodynamics, intermolecular forces, optics properties of the clusters, as well as the influence of humidity, temperature, atmospheric pressure, and altitude shows that amide molecules promote the clustering and enhance the optical properties. The substituent facilitates the clustering of amide and nitric acid hydrate and lowers the humidity sensitivity of the clusters. The findings will help to control the atmospheric aerosol particle and then reduce the harm of poisonous organic chemicals on human health.

Evaluation of peripapillary retinal nerve fiber layer thickness in intracranial atherosclerotic stenosis.

PURPOSE: To evaluate the peripapillary retinal nerve fiber layer thickness (pRNFL) in patients with intracranial atherosclerotic stenosis (ICAS). METHODS: A cross-sectional study was performed in a general hospital. The intracranial atherosclerotic stenosis was evaluated by digital subtraction angiography (DSA), computed tomography angiography (CTA) or magnetic resonance angiography (MRA). High-definition optical coherence tomography (HD-OCT) was used to evaluate the peripapillary retinal nerve fiber layer thickness. RESULTS: A total of 102 patients, including 59(57.8%) patients with ICAS and 43(42.2%) patients without ICAS, were finally analysed in the study. The peripapillary retinal nerve fiber layer thickness (pRNFL) was reduced significantly in the average, the superior and the inferior quadrants of the ipsilateral eyes and in the superior quadrant of the contralateral eyes in patients with ICAS compared with patients without ICAS. After multivariate analysis, only the superior pRNFL thickness in the ipsilateral eyes was significantly associated with ICAS (OR,0.968; 95% CI,0.946-0.991; p = 0.006). The area under receiver operator curve was 0.679 (95% CI,0.576-0.782) for it to identify the presence of ICAS. The cut-off value of the superior pRNFL was 109.5 µm, and the sensitivity and specificity were 50.8% and 83.7%, respectively. CONCLUSION: The superior pRNFL in the ipsilateral eye was significantly associated with ICAS in this study. Larger studies are needed to explore the relation between pRNFL and ICAS further.

Cleaning and Disinfecting Oval-Shaped Root Canals: Ex Vivo Evaluation of Three Rotary Instrumentation Systems with Passive Ultrasonic Irrigation.

Background and Objectives: Successful root canal treatment depends on the thorough removal of biofilms through chemomechanical preparation. This study aimed to investigate and compare the cleaning and disinfecting efficiency of oval-shaped root canals using XP-endo Shaper (XPS), ProTaper Next (PTN), and HyFlex CM (HCM) in combination with passive ultrasonic irrigation (PUI). Materials and Methods: Ninety extracted teeth were contaminated and randomly divided into three groups: XPS, PTN, and HCM. Each group was assigned to three subgroups: subgroup A (sterile saline), subgroup B (3% sodium hypochlorite and 17% ethylenediaminetetraacetic acid), and subgroup C (3% sodium hypochlorite, 17% ethylenediaminetetraacetic acid, and PUI). Bacterial sampling was conducted both from baseline samples and samples after chemomechanical preparation. Scanning electron microscopy (SEM) was used to evaluate the residue bacterial biofilms, hard tissue debris, and smear layers on the buccolingual walls of oval-shaped root canals. Results: When combined with sterile saline, XPS demonstrated a higher reduction of bacterial counts and was more effective in eradicating Enterococcus faecalis in the middle third of the canals compared to the other instruments (p < 0.05). Additionally, when used with antimicrobial irrigants, XPS was more effective in disinfecting the coronal third of the canals than the other instruments (p < 0.05). Furthermore, XPS reduced hard tissue debris more effectively in the middle third of canals than in the apical third (p < 0.05). Conclusions: XPS outperforms PTN and HCM in disinfecting oval-shaped root canals. Despite the fact that combining XPS and PUI improves cleaning and disinfecting, removing hard tissue debris from the critical apical area remains challenging.

Biomolecule-Compatible Dehydrogenative Chan-Lam Coupling of Free Sulfilimines.

Inspired by the discovery of a S═N bond in the collagen IV network and its essential role in stabilizing basement membranes, sulfilimines have drawn much attention in the fields of chemistry and biology. However, their further uptake is hindered by the lack of mild, efficient, and environmentally benign protocols by which sulfilimines can be constructed under biomolecule-compatible conditions. Here, we report a terminal oxidant-free copper-catalyzed dehydrogenative Chan-Lam coupling of free diaryl sulfilimines with arylboronic acids with excellent chemoselectivity and broad substrate compatibility. The mild reaction conditions and biomolecule-compatible nature allow the employment of this protocol in the late-stage functionalization of complex peptides, and more importantly, as an effective bioconjugation method as showcased in a model protein. A combined experimental and computational mechanistic investigation reveals that an inner-sphere electron-transfer process circumvents the sacrificial oxidant employed in traditional Chan-Lam coupling reactions. An energetically viable concerted pathway was located wherein a copper hydride facilitates hydrogen-atom abstraction from the isopropanol solvent to produce dihydrogen via a four-membered transition state.

Sensitivity of the Transport of Plastic Nanoparticles to Typical Phosphates Associated with Ionic Strength and Solution pH.

The influence of phosphates on the transport of plastic particles in porous media is environmentally relevant due to their ubiquitous coexistence in the subsurface environment. This study investigated the transport of plastic nanoparticles (PNPs) via column experiments, paired with Derjaguin-Landau-Verwey-Overbeek calculations and numerical simulations. The trends of PNP transport vary with increasing concentrations of NaH2PO4 and Na2HPO4 due to the coupled effects of increased electrostatic repulsion, the competition for retention sites, and the compression of the double layer. Higher pH tends to increase PNP transport due to the enhanced deprotonation of surfaces. The release of retained PNPs under reduced IS and increased pH is limited because most of the PNPs were irreversibly captured in deep primary minima. The presence of physicochemical heterogeneities on solid surfaces can reduce PNP transport and increase the sensitivity of the transport to IS. Furthermore, variations in the hydrogen bonding when the two phosphates act as proton donors will result in different influences on PNP transport at the same IS. This study highlights the sensitivity of PNP transport to phosphates associated with the solution chemistries (e.g., IS and pH) and is helpful for better understanding the fate of PNPs and other colloidal contaminants in the subsurface environment.

Nano-Drug Delivery Systems Based on Different Targeting Mechanisms in the Targeted Therapy of Colorectal Cancer.

Colorectal cancer (CRC) is a usual digestive tract malignancy and the third main cause of cancer death around the world, with a high occurrence rate and mortality rate. Conventional therapies for CRC have certain side effects and restrictions. However, the exciting thing is that with the rapid development of nanotechnology, nanoparticles have gradually become more valuable drug delivery systems than traditional therapies because of their capacity to control drug release and target CRC. This also promotes the application of nano-drug targeted delivery systems in the therapy of CRC. Moreover, to make nanoparticles have a better colon targeting effect, many approaches have been used, including nanoparticles targeting CRC and in response to environmental signals. In this review, we focus on various targeting mechanisms of CRC-targeted nanoparticles and their latest research progress in the last three years, hoping to give researchers some inspiration on the design of CRC-targeted nanoparticles.

A Hypoxia-Sensitive Drug Delivery System Constructed by Nitroimidazole and its Application in the Treatment of Hepatocellular Carcinoma.

Hypoxia is an important pathological phenomenon, and it can induce many tumor microenvironment changes, such as accumulations of intracellular lactic acid, decrease of tumor microenvironment pH value, and regulate a series of physiological and pathological processes such as adhesion, metastasis, and immune escape. Hypoxic tumor cells act as a key target for treating tumor. In this research, we designed and prepared PEG-nitroimidazole grafts, PEG-NI, and FA-PEG-NI. We first explored their physical and chemical properties to serve as a drug carrier. Then, the hypoxia-sensitive properties such as particle size changes and drug release were investigated. Finally, the tumor targeting ability was studied in vitro and in vivo, and anti-tumor capacity was determined. Both grafts showed excellent property as a nanodrug carrier and showed favorable drug encapsulation ability of sorafenib with the help of the hydrophobic chain of 6-(BOC-amino) hexyl bromide. The micelles responded to the hypoxic tumor environment with chemical and spatial structure changes leading to sensitive and fast drug release. With the modification of folic acid, FA-PEG-NI gained tumor targeting ability in vivo. FA-PEG-NI graft proved a potential targeting drug delivery system in the treatment of hypoxic hepatocellular carcinoma.

Asenapine maleate inhibits angiotensin II-induced proliferation and activation of cardiac fibroblasts via the ROS/TGFß1/MAPK signaling pathway.

BACKGROUND: Cardiac fibrosis will increase wall stiffness and diastolic dysfunction, which will eventually lead to heart failure. Asenapine maleate (AM) is widely used in the treatment of schizophrenia. In the current study, we explored the potential mechanism underlying the role of AM in angiotensin II (Ang II)-induced cardiac fibrosis. METHODS: Cardiac fibroblasts (CFs) were stimulated using Ang II with or without AM. Cell proliferation was measured using the cell counting kit-8 assay and the Cell-Light EdU Apollo567 In Vitro Kit. The expression levels of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA) were detected using immunofluorescence or western blotting. At the protein level, the expression levels of the components of the transforming growth factor beta 1 (TGFß1)/mitogen-activated protein kinase (MAPK) signaling pathway were also detected. RESULTS: After Ang II stimulation, TGFß1, TGFß1 receptor, α-SMA, fibronectin (Fn), collagen type I (Col1), and collagen type III (Col3) mRNA levels increased; the TGFß1/MAPK signaling pathway was activated in CFs. After AM pretreatment, cell proliferation was inhibited, the numbers of PCNA -positive cells and the levels of cardiac fibrosis markers decreased. The activity of the TGFß1/MAPK signaling pathway was also inhibited. Therefore, AM can inhibit cardiac fibrosis by blocking the Ang II-induced activation through TGFß1/MAPK signaling pathway. CONCLUSIONS: This is the first report to demonstrate that AM can inhibit Ang II-induced cardiac fibrosis by down-regulating the TGFß1/MAPK signaling pathway. In this process, AM inhibited the proliferation and activation of CFs and reduced the levels of cardiac fibrosis markers. Thus, AM represents a potential treatment strategy for cardiac fibrosis.

All-Trans Retinoic Acid and Doxorubicin Delivery by Folic Acid Modified Polymeric Micelles for the Modulation of Pin1-Mediated DOX-Induced Breast Cancer Stemness and Metastasis.

Stemness and metastasis are the two main challenges in cancer therapy and are related to disease relapse post-treatment. They both have a strong correlation with chemoresistance and poor prognosis, ultimately leading to treatment failure. It has been reported that chemotherapy can induce stemness and metastasis in many cancer types, especially treatment with the chemotherapeutic agent doxorubicin (DOX) in breast cancer. A combination treatment is an efficient and elegant approach in cancer therapy through simultaneous delivery of two or more drugs with a delivery system for its synergistic effect, which is not an additive of two individual drugs. Herein, we report a combinatorial system with DOX and all-trans retinoic acid (ATRA) to address both of the above issues. As a common critical regulatory factor for oncogenic signal transduction pathways, Pin1 is a specific isomerase highly expressed within various tumor cells. ATRA, a newly identified Pin1 inhibitor, can abolish several oncogenic pathways by effectively inhibiting and degrading overexpressed Pin1. We successfully developed a folic acid (FA)-modified chitosan (CSO)-derived polymer (FA-CSOSA) and obtained FA-CSOSA/DOX and FA-CSOSA/ATRA drug-loaded micelles. FA modification can improve the uptake of the nanoparticles in tumor cells and tumor sites via folate receptor-mediated cell internalization. Compared to treatment with DOX alone, the combined treatment induced 4T1 cell apoptosis in a synergistic manner. Reduced stemness-related protein expression and inhibited metastasis were observed during treatment with FA-CSOSA/DOX and FA-CSOSA/ATRA and were found to be associated with Pin1. Further in vivo experiments showed that treatment with FA-CSOSA/DOX and FA-CSOSA/ATRA resulted in 85.5% tumor inhibition, which was 2.5-fold greater than that of cells treated with DOX·HCl alone. This work presents a new paradigm for addressing chemotherapy-induced side effects via degradation of Pin1 induced by tumor-targeted delivery of DOX and ATRA.

Recent advances in indole dimers and hybrids with antibacterial activity against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA), one of the major and most dangerous pathogens in humans, is a causative agent of severe pandemic of mainly skin and soft tissue and occasionally fatal infections. Therefore, it is imperative to develop potent and novel anti-MRSA agents. Indole derivatives could act against diverse enzymes and receptors in bacteria, occupying a salient place in the development of novel antibacterial agents. Dimerization and hybridization are common strategies to discover new drugs, and a number of indole dimers and hybrids possess potential antibacterial activity against a panel of clinically important pathogens including MRSA. Accordingly, indole dimers and hybrids are privileged scaffolds for the discovery of novel anti-MRSA agents. This review outlines the recent development of indole dimers and hybrids with a potential activity against MRSA, covering articles published between 2010 and 2020. The structure-activity relationship and the mechanism of action are also discussed to facilitate further rational design of more effective candidates.

Multi-directionally evaluating the formation mechanism of 1,4-dihydropyridine drug nanosuspensions through experimental validation and computer-aided drug design.

The poor aqueous solubility of 1,4-dihydropyridine drugs needs to be solved urgently to improve bioavailability. Nanotechnology can improve drug solubility and dissolution by reducing particle size, but usually, a specific polymer or surfactant is required for stabilization. In this study, Poloxamer-407(P-407) was screened as the optimal stabilize through energy simulation, molecular docking, and particle size. the morphological study, X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, Raman, in vitro dissolution test, and molecular simulation of interactions were utilized to explore the formation mechanisms of four 1,4-dihydropyridine drugs/P-407 nanosuspensions. The result shows that the optimized nanosuspensions had the particle size in the nano-size range and maintained the original crystal state. The in vitro dissolution rate of the nanosuspension was 3-4 times higher than the corresponding API and could reduce the restriction of drug dissolution in different pH environments. Raman spectroscopy, FTIR, and molecular docking simulations provided strong supporting evidence for the formation mechanism of 1,4-dihydropyridine drugs/P-407 nanosuspensions at the molecular level, which confirmed that the stable intermolecular hydrogen bond adsorption and hydrophobic interaction were formed between the drug and P-407. This research will provide practical concepts and technologies, which are helpful to develop nanosuspensions for the same class of drugs.

Exploring the influence factors and improvement strategies of drug polymorphic transformation combined kinetic and thermodynamic perspectives during the formation of nanosuspensions.

Nanosuspensions can effectively increase saturation solubility and improve the bioavailability of poorly water-soluble drugs attributed to high loading and surface-to-volume ratio. Wet media milling has been regarded as a scalable method to prepare nanosuspensions because of its simple operation and easy scale-up. In recent years, besides particle aggregation and Ostwald ripening, polymorphic transformation induced by processing has become a critical factor leading to the instability of nanosuspensions. Therefore, this review aims to discuss the influence factors comprehensively and put forward the corresponding improvement strategies of polymorphic transformation during the formation of nanosuspensions. In addition, this review also demonstrates the implication of molecular simulation in polymorphic transformation. The competition between shear-induced amorphization and thermally activated crystallization is the global mechanism of polymorphic transformation during media milling. The factors affecting the polymorphic transformation and corresponding improvement strategies are summarized from formulation and process parameters perspectives during the formation of nanosuspensions. The development of analytical techniques has promoted the qualitative and quantitative characterization of polymorphic transformation, and some techniques can in situ monitor dynamic transformation. The microhydrodynamic model can be referenced to study the stress intensities by analyzing formulation and process parameters during wet media milling. Molecular simulation can be used to explore the possible polymorphic transformation based on the crystal structure and energy. This review is helpful to improve the stability of nanosuspensions by regulating polymorphic transformation, providing quality assurance for nanosuspension-based products.HighlightsPolymorphic transformation depends on the intensity and temperature of milling.Stress intensities of milling can be elucidated and improved by microhydrodynamics.Higher stress intensities of milling perhaps be accompanied by higher temperatures.Molecular simulation used in polymorphs is based on crystal structure and energy.Molecular dynamics simulations can demonstrate the stability of amorphous forms.