Glutathione (GSH) is an important antioxidant that maintains cellular redox homeostasis and significantly contributes to resistance against various chemotherapeutic agents. To address the challenge of GSH-mediated drug resistance in etoposide (ETS), we developed a facile synthetic method to prepare a biocompatible acid-responsive polycarbonate (PEG-PCA) containing cinnamaldehyde (CA), a potent GSH-depleting agent, as a side chain using nontoxic raw materials. This polymer self-assembled in aqueous solutions to form nanoparticles (ETS@PCA) that encapsulated ETS, enhancing its water solubility and enabling tumor-targeted delivery. In vitro studies demonstrated that ETS@PCA could respond to the acidic tumor microenvironment, releasing CA to rapidly deplete GSH levels. Consequently, ETS@PCA exhibited superior cytotoxicity compared to free ETS. Furthermore, in vivo experiments corroborated the enhanced tumor inhibitory effects of ETS@PCA.

Liposomal formulations of antibiotics for inhalation offer the potential for the delivery of high drug doses, controlled drug release kinetics in the lung, and an excellent safety profile. In this study, we evaluated the in vivo performance of a liposomal formulation for the poorly soluble, antituberculosis agent, bedaquiline. Bedaquiline was encapsulated within monodisperse liposomes of ∼70 nm at a relatively high drug concentration (∼3.6 mg/mL). Formulations with or without fucose residues, which bind to C-type lectin receptors and mediate a preferential binding to macrophage mannose receptor, were prepared, and efficacy was assessed in an in vivo C3HeB/FeJ mouse model of tuberculosis infection (H37Rv strain). Seven intranasal instillations of 5 mg/kg bedaquiline formulations administered every second day resulted in a significant reduction in lung burden (∼0.4-0.6 Δlog10 CFU), although no differences between fucosylated and nonfucosylated formulations were observed. A pharmacokinetic study in healthy, noninfected Balb/c mice demonstrated that intranasal administration of a single dose of 2.5 mg/kg bedaquiline liposomal formulation (fucosylated) improved the lung bioavailability 6-fold compared to intravenous administration of the same formulation at the same dose. Importantly, intranasal administration reduced systemic concentrations of the primary metabolite, N-desmethyl-bedaquiline (M2), compared with both intravenous and oral administration. This is a clinically relevant finding as the M2 metabolite is associated with a higher risk of QT-prolongation in predisposed patients. The results clearly demonstrate that a bedaquiline liposomal inhalation suspension may show enhanced antitubercular activity in the lung while reducing systemic side effects, thus meriting further nonclinical investigation.

Cold-set protein adhesives (CPAs) show great advantages in sustain- ability, eco-friendliness, and cost effectiveness but suffer from weak adhesion and poor storability as imposed by the difficulty in controlling molecular crosslinks. Here, we develop a robust, storable, and controllable CPA enabled by Pickering emulsion-templated microcapsules (PETMs). The PETMs are synthesized by leveraging highly reactive isocyanates as the core phase for cold-set adhesion, and cellulose nanofibers are densified by polyurea as a shell phase to present a responsive, adjustable, and stable nature. Also, inorganic magnesium oxide (MgO) binders are introduced to further strengthen CPA via MgO-protein complexation. Our design not only enables superior cold-set adhesion (0.98 MPa to wood) induced by pressure but also imparts the adhesive with much-improved storability (high-strength maintenance at inferior conditions). This strategy resolves the conflict between high reactivity and long storability in cold-set adhesion, offering a promising direction for the development of high-performance bio-based adhesives satisfying practical demands.

BTZ043 is an 8-nitro-1,3-benzothiazin-4-one with potency against multidrug-resistant Mycobacterium tuberculosis. Low solubility and hepatic metabolism are linked to poor oral bioavailability. Amorphous drug nanoparticles (ADN) were formulated to improve the bioavailability. Comparative pharmacokinetics of BTZ043 ADN following intranasal (2.5 mg kg(-1)) and oral administration (25 mg kg(-1)) in Balb/c mice was investigated using oral BTZ043 drug suspensions (neat; 25 mg kg(-1)) as a standard-of-care reference. Plasma exposure following oral ADN administration was 8-fold higher than for oral neat BTZ043. Intranasal ADN increased plasma exposure 18-fold compared to oral neat BTZ043 after dose normalization. BTZ043 was detectable in lung lining fluid following ADN administration, but not after oral neat BTZ043 dosing. BTZ043 was cleared faster from the lung and plasma following intranasal administration with a shorter time above the minimum inhibitory concentration (MIC) compared to oral ADN. Since time > MIC is reported to drive activity, oral ADN may represent a promising delivery strategy for BTZ043.

The electrodeposition method (EDM) has been regarded as a new technique for healing concrete microcracks in recent years due to its advantages of excellent remediation in aqueous environments. However, a flowing water environment may influence the effectiveness of the EDM. Therefore, in this paper, the effect of flowing water on the synthesis of ettringite by the EDM to heal concrete cracks was investigated through experiments and molecular dynamics simulations. The experiment results showed that the impermeability coefficient of concrete decreased from 6.41 to 5.36 and 5.18 as the flow rate increased from 0 to 1 m/d and 3 m/d after 7d. The healing products on the surface developed from a cotton-like floc structure to a gel-like morphology. At the microscopic level, with the increase in flow rate, the ettringite changed from the disordered distribution of reticulation to the orderly growth of clusters in the form of long rods. Meanwhile, the phase compositions of healing products transformed from ettringite to gypsum and calcium carbonate. In addition, combined with the molecular dynamics simulations by LAMMPS, the increase in flow rate changed the crystal characteristics of the synthesized ettringite, both the decrease in length-to-diameter ratio and crystallinity, as well as the increase in specific surface area, d-spacing, and crystallite size.

Although chlorambucil (CHL) is a long-established anticancer drug, the drug failure of CHL, mediated by the intracellular defense system consisting of glutathione (GSH) and GSH S-transferase pi (GST-pi), has significantly limited the application of CHL. To overcome this issue, we first designed a GSH-responsive small-molecule prodrug (EA-SS-CHL) by combining CHL and ethacrynic acid (EA). Subsequently, drug-loaded nanoparticles (ECPP) were formed by the self-assembly between EA-SS-CHL and amphiphilic PEG-PDLLA to improve the water solubility of the prodrug and its ability to target tumor sites. Upon exposure to high intracellular GSH concentration, EA-SS-CHL gradually degrades, leading to the release of EA and CHL. The presence of EA facilitates the depletion of GSH and inhibition of GST-pi, ultimately attenuating the detoxification of the intracellular defense system to CHL. Cytotoxicity studies and apoptosis assays demonstrate that ECPP exhibits higher therapeutic efficiency than CHL. Additionally,in vivotumor suppression effects and biocompatibility provide further evidence for the superiority of ECPP. This work presents a promising strategy to enhance the efficacy of CHL in cancer therapy.

Tuberculosis (TB) is one of the most prevalent infectious diseases. The global TB situation is further complicated by increasing patient numbers infected with Mycobacterium tuberculosis (M.tb.) strains resistant to either one or two of the first-line therapeutics, promoted by insufficient treatment length and/or drug levels due to adverse reactions and reduced patient compliance. An intriguing approach to improve anti-TB therapy relates to nanocarrier-based drug-delivery systems, which enhance local drug concentrations at infection sites without systemic toxicity. Recently developed anti-TB antibiotics, however, are lipophilic and difficult to transport in aqueous systems. Here, the very lipophilic TB-antibiotics bedaquiline (BDQ) and BTZ (1,3-benzothiazin-4-one 043) are prepared as high-dose, amorphous nanoparticles via a solvent-antisolvent technique. The nanoparticles exhibit mean diameters of 60 ± 13 nm (BDQ) and 62 ± 44 nm (BTZ) and have an extraordinarily high drug load with 69% BDQ and >99% BTZ of total nanoparticle mass plus a certain amount of surfactant (31% for BDQ, <1% for BTZ) to make the lipophilic drugs water-dispersible. Suspensions with high drug load (4.1 mg/mL BDQ, 4.2 mg/mL BTZ) are stable for several weeks. In vitro and in vivo studies employing M.tb.-infected macrophages and susceptible C3HeB/FeJ mice show promising activity, which outperforms conventional BDQ/BTZ solutions (in DMF or DMSO) with an up to 50% higher efficacy upon pulmonary delivery. In vitro, the BDQ/BTZ nanoparticles demonstrate their ability to cross the different biological barriers and to reach the site of the intracellular mycobacteria. In vivo, high amounts of the BDQ/BTZ nanoparticles are found in the lung and specifically inside granulomas, whereas only low BDQ/BTZ-nanoparticle levels are observed in spleen or liver. Thus, pulmonary delivered BDQ/BTZ nanoparticles are promising formulations to improve antituberculosis treatment.

One of the most prominent characteristics of bisphosphonate-related osteonecrosis of the jaw(BRONJ) is its site-specificity. Osteonecrosis tends to occur specifically in maxillofacial bones, in spite of a systemic administration of the medicine. Previous studies suggested rich blood supply and fast bone turnover might be reasons for BRONJ. Yet, a sound scientific basis explaining its occurrence is still lacking. The present study aimed to explore the role of Porphyromonas gingivalis (P. gingivalis), an important oral pathogen, on the site-specificity of bisphosphonate-induced osteonecrosis and to elucidate its underlying mechanism. Mice were intraperitoneally injected with zoledronic acid (ZA) or saline for 3 weeks. In the third week, the right mandibular first molars were extracted and circular bone defects with a diameter of 1 mm were created in right femurs. After the operation, drug administration was continued, and P. gingivalis suspension was applied to the oral cavities and femur defects. The mice were killed after four or eight weeks postoperatively. The right mandibles and femurs were harvested for micro-CT and histological analyses. A poor healing of bone defects of both jaws and femurs was noted in mice injected with both ZA and P. gingivalis. Micro-CT analysis showed a decreased bone volume, and histological staining showed an increased number of empty osteocyte lacunae, a decreased collagen regeneration, an increased inflammatory infiltration and a decreased number of osteoclasts. In addition, the left femurs were collected for isolation of osteoclast precursors (OCPs). The osteoclastogenesis potential of OCPs was analyzed in vitro. OCPs extracted from mice of ZA-treated groups were shown to have a lower osteoclast differentiation potential and the expression level of related genes and proteins was declined. In conclusion, we established a mouse model of bisphosphonate-related osteonecrosis of both the jaw and femur. P. gingivalis could inhibit the healing of femur defects under the administration of ZA. These findings suggest that P. gingivalis in the oral cavity might be one of the steering compounds for BRONJ to occur.

Synthetic single-chain bolalipids with symmetrical headgroups have shown potential in various pharmaceutical applications, such as the stabilization of liposome bilayers. Despite their amphiphilic character, synthetic bolalipids have not yet been investigated for their suitability as solubilizing agents for poorly soluble drug compounds. In this study, three synthetic single-chain bolalipids with increasing alkyl chain lengths (C22, C24 and C26) were investigated. All three bolalipids were able to achieve an increased solubility of the model drug, mefenamic acid, by approximately 180% in a pH 7.4 buffer compared to only a 102-105% increase achieved by sodium dodecyl sulfate (SDS) or the non-ionic surfactant pegylated hydroxystearate (PEG-HS). Subsequently, interfacial activity of bolalipids and their ability to destabilize liposomal bilayers were investigated. The C22 bolalipid exhibited a consistently lower interfacial activity, which was consistent with its significantly lower cytotoxicity in the macrophage-like cell line, J774. A1, compared to C24 and C26 counterparts. The mean IC50 values of the bolalipids tested (0.035-0.093 mM) were approximately 4-100-fold lower than that of SDS (0.401 mM) or PEG-HS (0.922 mM), with the mechanism of toxicity linked to increased cell membrane permeability, as is expected for surfactants. In summary, evidence from this study shows that decreasing the length of the bolalipid alkyl linker from C26 to C22 resulted in a significantly decreased cytotoxicity with no loss in drug solubilization efficiency.

Ferroptosis is a novel type of regulated cell death characterized by the accumulation of lipid peroxides to lethal levels. Most tumor cells are extremely vulnerable to ferroptosis due to the high levels of reactive oxygen species (ROS) produced by their active metabolism. Therefore, tumor cells rely on glutathione (GSH) to reduce lipid peroxides catalyzed by glutathione peroxidase 4 (GPX4), and this pathway is also an important target for a variety of drugs that promote tumor cell ferroptosis. Herein, RSL3@PCA was designed to simultaneously deplete intracellular GSH and inhibit the activity of GPX4, thereby significantly promoting tumor cell ferroptosis. RSL3@PCA was successfully prepared by encapsulating a selective inhibitor of GPX4 into acidresponsive nanoparticle PCA. After being taken up by tumor cells, the acid-responsive nanoparticle gradually degraded to release cinnamaldehyde (CA) and the encapsulated RSL3. CA and RSL3 block the reduction of lipid peroxides in cells, thereby inducing ferroptosis. By a cytotoxicity assay and 4T1 cell xenotransplantation model, we confirmed that RSL3@PCA has excellent inhibition of tumor growth without significant toxicity to normal cells and tissues and still has a good therapeutic effect on tumor cells that are resistant to conventional chemotherapy drugs. This work provides new drug combinations for promoting ferroptosis in tumor cells without severe side effects in normal organs.

Ferroptosis is a novel type of regulated cell death characterized by the accumulation of lipid peroxides to lethal levels. Most tumor cells are extremely vulnerable to ferroptosis due to the high levels of reactive oxygen species (ROS) produced by their active metabolism. Therefore, tumor cells rely on glutathione (GSH) to reduce lipid peroxides catalyzed by glutathione peroxidase 4 (GPX4), and this pathway is also an important target for a variety of drugs that promote tumor cell ferroptosis. Herein, RSL3@PCA was designed to simultaneously deplete intracellular GSH and inhibit the activity of GPX4, thereby significantly promoting tumor cell ferroptosis. RSL3@PCA was successfully prepared by encapsulating a selective inhibitor of GPX4 into acid-responsive nanoparticle PCA. After being taken up by tumor cells, the acid-responsive nanoparticle gradually degraded to release cinnamaldehyde (CA) and the encapsulated RSL3. CA and RSL3 block the reduction of lipid peroxides in cells, thereby inducing ferroptosis. By a cytotoxicity assay and 4T1 cell xenotransplantation model, we confirmed that RSL3@PCA has excellent inhibition of tumor growth without significant toxicity to normal cells and tissues and still has a good therapeutic effect on tumor cells that are resistant to conventional chemotherapy drugs. This work provides new drug combinations for promoting ferroptosis in tumor cells without severe side effects in normal organs.

得益于改革开放初期我国抓住全球价值链(Global Value Chains,简称GVC)重构、产业在国际间大转移这些重要历史发展机遇,本土对外贸易规模实现了跨越式增长、产业获得了平推化发展,产生结构在一定程度上完成了优化和升级,整体经济水平实现了奇迹式增长.

Combination chemotherapy regimens have been put forward to achieve a synergistic effect and reduce drug doses for the clinical applications of cancer treatment. One of the principal approaches for killing cancer cells involves triggering apoptotic cell death with anti-cancer drugs. Nevertheless, the efficacy of apoptosis induction in tumors is often restricted on account of intrinsic or acquired resistance of cancer cells to apoptosis. Ferroptosis, which involves reactive oxygen species (ROS), is another way to regulate cell death. Doxorubicin (DOX), a commonly used chemotherapeutic agent, can enter the nucleus and destroy tumor cells while also affecting mitochondria by producing semiquinone radicals. Therefore, a drug system combining ferroptosis and apoptosis, bridged by DOX-induced ROS, was proposed to be designed. Herein, we employed a facile and effective self-assembly method to prepare DOX-loaded nanocomplexes by DOX, Pluronic F-68, tannic acid (TA), and iron ions. TA and iron ions could not only improve the stability of nanocarrier but also facilitate achieving a ferroptotic effect. As a result, DOX@F-68/TA/Fe3+ nanocomplexes showed a strong pro-apoptotic effect as well as an increase in intracellular oxidative stress. The improved oxidative stress further resulted in the ferroptosis of tumor cells. In vivo experiments demonstrated that DOX@F-68/TA/Fe3+ efficiently targeted the tumor following intravenous injection and successfully inhibited tumor development.

改革开放以来,中国经济取得了举世瞩目的成绩.中国特色社会主义进入新时期,社会主要矛盾也发生了根本性改变.其中,产业间发展不平衡是当前我国经济社会发展中存在的重要问题之一,我国产业结构长期处于"农业发展不稳定、工业发展不够强,服务业发展相对滞后"的不合理局面,产业未充分发挥各自的比较优势,产业间有效协同融合发展的理想模式受到了制约,进而严重影响了我国经济协调稳定的发展.

It is important to achieve moderate sustained release rate for drug delivery, and so it is critical to regulate the host-guest interactions for the rational design of carrier. In this work, a nano-sized biocompatible MOF, Mg(H2TBAPy)(H2O)3·C4H8O2 (TDL-Mg), was constructed by employing π-conjugated 1,3,6,8-tetrakis(p-benzoic acid)pyrene (H4TBAPy) as ligand and used for 5-fluorouracil (5-FU) loading (28.2 wt%) and sustained slow release. TDL-Mg exhibits a 3D supramolecular architecture featuring 1D rectangle channel with a size of 6.2 × 8.1 Å2 and a BET surface area of 627 m2·g-1. Channel microenvironment analysis shows that the rigid H2TBAPy2- ligand adopts special torsion to stabilize the channels and offer rich π-binding sites; the partially deprotonated carboxyls not only participate in the formation of strong hydrogen bonds but also create a mild pH buffer environment for biological applications. Suitable host-guest interactions are generated by the synergistic effect of polydirectional hydrogen bonds, multiple π interactions and confined channels, which allows 5-FU@TDL-Mg to release 76% of loading in 72 h with a medically reasonable rate. Microcalorimetry was used to directly quantify these host-guest interactions with moderate enthalpy of 22.3 kJ·mol-1, which provides a distinctive thermodynamic interpretation for understanding the relationship between MOF design and drug release rate. Additionally, the nano-sized 5-FU@TDL-Mg can be taken up by mouse breast cancer cells (4T1 cells) for imaging based on the dramatic fluorescence change during the release of 5-FU, exhibiting potential applications in biological systems.

Background Zein-based carriers are a promising delivery system for biomedical applications. However, few studies involve systematic investigation on their in vivo biocompatibility and immunogenicity. Purpose The objective of this study was to identify the immunogenicity, type of immune response, biocompatibility and systemic recall immune response of zein nanoparticles administrated via different routes in mice. Animals and methods Female Balb/c mice were selected as the animal model in this paper. The effect of particle size, dose and inoculation routes on immunogenicity were systematically explored. The mice were challenged at week 50 via intramuscular and subcutaneous routes to investigate the systemic recall immune responses of zein nanoparticles. Hematoxylin and eosin staining was performed to investigate the biocompatibility of zein nanoparticles at injection sites. Results The administration of zein particles by parenteral routes led to a long-term systemic immune response. Particle size did not affect zein-specific IgG antibody titers. IgG antibody titers and inflammatory cell infiltration at the injection sites resulting from intramuscular zein particle injection were significantly higher than those from subcutaneous injection of the same dose. For intramuscular inoculation, dose-dependent IgG antibody titers were observed after the third inoculation, while no significant difference was found via the subcutaneous route. For both routes, IgG titer showed a time-dependent decrease at all dose levels from week 5 onward, and finally plateaued at week 28. The IgG subtype assay showed a predominant Th2-type immune response for both administration routes. Challenge with zein nanoparticles at week 50 led to a significant increase in specific IgG titer at all dose levels, indicating systemic recall immune responses. Interestingly, IgG antibody levels in the subcutaneous groups showed a delayed decrease compared to those of the intramuscular injection groups at all dose levels. Conclusion This study indicated that immunogenicity may be one of the key challenges of using zein nanoparticles as carriers via parenteral administration. Further investigation is needed to illustrate zein immunogenicity in other forms, and the possible effect of systemic recall immune response on in vivo pharmacokinetic characteristics.

As the direct entrapment of camptothecin (CPT) into conventionally used polymeric materials is extremely difficult due to its high crystallization property, CPT-derived prodrugs are widely used to increase drug-polymer compatibility. However, the rapid CPT conversion from prodrugs is still a challenge due to the high steric hindrance around the hydroxyl of CPT. To address this, we reported here a fragile lactyl carbonate (LC) linker, which could be instantly cleaved to release CPT from LC-linked lipophilic prodrugs under physiological conditions. Furthermore, such instantly-cleaved CPT prodrugs could be stably encapsulated in methoxy poly(ethylene glycol)-block-poly(actic acid) (mPEG-PLA) micelles, thus to achieve indirect CPT entrapment with a potent in vitro cytotoxicity as a result of the rapid CPT conversion. The strategy of entrapping instantly-cleaved prodrugs in polymeric micelles displayed an excellent potential to broaden the scope of application of polymeric materials in drug delivery.

Several vanadium chlorides bearing bis(arylimino)-acenaphthene (BIAN) ligands, (2,6-Me2C6H3-BIAN)V (THF)Cl-3 (1), (2,6-Et2C6H3-BIAN)V(THF)Cl-3 (2), (2,6-(Pr2C6H3)-Pr-i-BIAN)V(THF)Cl-3 (3), [3,5-(CF3)(2)C6H3-BIAN] V(THF)Cl-3 (4), [4-OMe-C6H4-BIAN]V(THF)Cl-3 (5), and [2,6-(Ph2CH)(2)-4-OMeC6H2-BIAN]V. (THF)Cl-3 (6) were synthesized by direct reaction of VCl3(THF)(3) with corresponding BIAN ligands. All these complexes were characterized by elemental analyses, and FT-IR spectroscopy. The molecular structures of 1, 2, and 4 were identified by X-ray crystallography, in which the six-coordinated vanadium metal centers were in distorted octahedral geometry with the oxygen atom of the coordinated THF, two nitrogen atoms of the diimine ligand and one chlorine atom in the same plane. When activated with AlEt2Cl these vanadium complexes showed high catalytic activities for ethylene polymerization affording linear polyethylene with high molecular weight. However, when MAO was used as co-catalyst, ultra high molecular-weight polymers were obtained albeit with decreased activity. (C) 2019 Elsevier Ltd. All rights reserved.

A reactivity pattern for C3-arylation of 9-MeO-phenanthrene has been established for the first time by using 2-naphthyl amines as coupling partners. A series of phenanthrene- and naphthalene-based multifunctionalized polycyclic aromatic hydrocarbons have been obtained in good to excellent yields. Alternative C10-arylation of 9-MeO-phenanthrene has also been accomplished, using 2-naphthalenol derivatives as coupling partners. Trifluoroacetic acid is found crucial for the regioselectivity. Density functional theory calculations and electrochemical analyses have been performed to rationalize the reaction mechanism.

Herein, a pH and redox dual-sensitive core-crosslinked targeting nanocarrier was prepared and used for co-delivery of doxorubicin (DOX) and tariquidar (TQR). The nanocarrier not only had excellent stability but also prevented the leakage of the drug in the normal physiological environment efficiently. Meanwhile, the targeting function of nanocarriers could also be suppressed in the normal physiological environment, protecting nanocarriers from being captured by RAW264.7 cells. Under mild acidic conditions, the targeting function was regained, leading to an effective tumor cell uptake of the nanocarrier. Furthermore, reduction-responsive drug release would occur in the cytoplasm due to the collapse of the reduction-sensitive crosslinked structure in the nanocarrier. By means of ligand-receptor mediated endocytosis and TQR-mediated glycoprotein (P-gp) inhibition, the IC50 value of DOX to MCF-7/ADR cells reduced from more than 100 μg mL-1 to 8.55 μg mL-1, exhibiting great potential in overcoming drug resistance.