Redox-Active Ferrocene Quencher-Based Supramolecular Nanomedicine for NIR-II Fluorescence-Monitored Chemodynamic Therapy.

Real-time monitoring of hydroxyl radical (⋅OH) generation is crucial for both the efficacy and safety of chemodynamic therapy (CDT). Although ⋅OH probe-integrated CDT agents can track ⋅OH production by themselves, they often require complicated synthetic procedures and suffer from self-consumption of ⋅OH. Here, we report the facile fabrication of a self-monitored chemodynamic agent (denoted as Fc-CD-AuNCs) by incorporating ferrocene (Fc) into ß-cyclodextrin (CD)-functionalized gold nanoclusters (AuNCs) via host-guest molecular recognition. The water-soluble CD served not only as a capping agent to protect AuNCs but also as a macrocyclic host to encapsulate and solubilize hydrophobic Fc guest with high Fenton reactivity for in vivo CDT applications. Importantly, the encapsulated Fc inside CD possessed strong electron-donating ability to effectively quench the second near-infrared (NIR-II) fluorescence of AuNCs through photoinduced electron transfer. After internalization of Fc-CD-AuNCs by cancer cells, Fenton reaction between redox-active Fc quencher and endogenous hydrogen peroxide (H2 O2 ) caused Fc oxidation and subsequent NIR-II fluorescence recovery, which was accompanied by the formation of cytotoxic ⋅OH and therefore allowed Fc-CD-AuNCs to in situ self-report ⋅OH generation without undesired ⋅OH consumption. Such a NIR-II fluorescence-monitored CDT enabled the use of renal-clearable Fc-CD-AuNCs for efficient tumor growth inhibition with minimal side effects in vivo.

Iron-siRNA Nanohybrids for Enhanced Chemodynamic Therapy via Ferritin Heavy Chain Downregulation.

Ferrous iron (Fe2+ ) has more potent hydroxyl radical (⋅OH)-generating ability than other Fenton-type metal ions, making Fe-based nanomaterials attractive for chemodynamic therapy (CDT). However, because Fe2+ can be converted by ferritin heavy chain (FHC) to nontoxic ferric form and then sequestered in ferritin, therapeutic outcomes of Fe-mediated CDT agents are still far from satisfactory. Here we report the synthesis of siRNA-embedded Fe0 nanoparticles (Fe0 -siRNA NPs) for self-reinforcing CDT via FHC downregulation. Upon internalization by cancer cells, pH-responsive Fe0 -siRNA NPs are degraded to release Fe2+ and FHC siRNA in acidic endo/lysosomes with the aid of oxygen (O2 ). The accompanied O2 depletion causes an intracellular pH decrease, which further promotes the degradation of Fe0 -siRNA NPs. In addition to initiating chemodynamic process, Fe2+ -catalyzed ⋅OH generation facilitates endo/lysosomal escape of siRNA by disrupting the membranes, enabling FHC downregulation-enhanced CDT.

Enhancing Catalytic Activity of a Nickel Single Atom Enzyme by Polynary Heteroatom Doping for Ferroptosis-Based Tumor Therapy.

As a rising generation of nanozymes, single atom enzymes show significant promise for cancer therapy, due to their maximum atom utilization efficiency and well-defined electronic structures. However, it remains a tremendous challenge to precisely produce a heteroatom-doped single atom enzyme with an expected coordination environment. Herein, we develop an anion exchange strategy for precisely controlled production of an edge-rich sulfur (S)- and nitrogen (N)-decorated nickel single atom enzyme (S-N/Ni PSAE). In particular, sulfurized S-N/Ni PSAE exhibits stronger peroxidase-like and glutathione oxidase-like activities than the nitrogen-monodoped nickel single atom enzyme, which is attributed to the vacancies and defective sites of sulfurized nitrogen atoms. Moreover, both in vitro and in vivo results demonstrate that, compared with nitrogen-monodoped N/Ni PSAE, sulfurized S-N/Ni PSAE more effectively triggers ferroptosis of tumor cells via inactivating glutathione peroxidase 4 and inducing lipid peroxidation. This study highlights the enhanced catalytic efficacy of a polynary heteroatom-doped single atom enzyme for ferroptosis-based cancer therapy.

Amplification of Lipid Peroxidation by Regulating Cell Membrane Unsaturation To Enhance Chemodynamic Therapy.

Lipid peroxidation (LPO) is one of the most damaging processes in chemodynamic therapy (CDT). Although it is well known that polyunsaturated fatty acids (PUFAs) are much more susceptible than saturated or monounsaturated ones to LPO, there is no study exploring the effect of cell membrane unsaturation degree on CDT. Here, we report a self-reinforcing CDT agent (denoted as OA@Fe-SAC@EM NPs), consisting of oleanolic acid (OA)-loaded iron single-atom catalyst (Fe-SAC)-embedded hollow carbon nanospheres encapsulated by an erythrocyte membrane (EM), which promotes LPO to improve chemodynamic efficacy via modulating the degree of membrane unsaturation. Upon uptake of OA@Fe-SAC@EM NPs by cancer cells, Fe-SAC-catalyzed conversion of endogenous hydrogen peroxide into hydroxyl radicals, in addition to initiating the chemodynamic therapeutic process, causes the dissociation of the EM shell and the ensuing release of OA that can enrich cellular membranes with PUFAs, enabling LPO amplification-enhanced CDT.

Exosomes derived from bone marrow mesenchymal stem cells reverse epithelial-mesenchymal transition potentially via attenuating Wnt/ß-catenin signaling to alleviate silica-induced pulmonary fibrosis.

Pulmonary fibrosis induced by silica dust is an irreversible, chronic, and fibroproliferative lung disease with no effective treatment at present. BMSCs-derived exosomes (BMSCs-Exo) possess similar functions to their parent cells. In this study, we investigated the therapeutic potential and underlying molecular mechanism for BMSCs-Exo in the treatment of silica-induced pulmonary fibrosis. The rat model of experimental silicosis pulmonary fibrosis was induced with 1.0 mL of one-off infusing silica suspension using the non-exposed intratracheal instillation (50 mg/mL/rat). In vivo transplantation of BMSCs-Exo effectively alleviated silica-induced pulmonary fibrosis, including a reduction in collagen accumulation, inhibition of TGF-ß1, and decreased HYP content. Treatment of BMSCs-Exo increased the expression of epithelial marker proteins including E-cadherin (E-cad) and cytokeratin19 (CK19) and reduced the expression of fibrosis marker proteins including α-Smooth muscle actin (α-SMA) after exposure to silica suspension. Furthermore, we found that BMSCs-Exo inhibited the expression of Wnt/ß-catenin pathway components (P-GSK3ß, ß-catenin, Cyclin D1) in pulmonary fibrosis tissue. BMSCs-Exo is involved in the alleviation of silica-induced pulmonary fibrosis by reducing the level of profibrotic factor TGF-ß1 and inhibiting the progression of epithelial-mesenchymal transition (EMT). Additionally, attenuation of the Wnt/ß-catenin signaling pathway closely related to EMT may be one of the mechanisms involved in anti-fibrotic effects of exosomes.

Tanshinone IIA Exerts Anti-Inflammatory and Immune-Regulating Effects on Vulnerable Atherosclerotic Plaque Partially via the TLR4/MyD88/NF-κB Signal Pathway.

Background: Tanshinone IIA (Tan IIA), a lipophilic constituent from Salvia miltiorrhiza Bunge, has shown a promising cardioprotective effect including anti-atherosclerosis. This study aims at exploring Tan IIA's anti-inflammatory and immune-regulating roles in stabilizing vulnerable atherosclerotic plaque in ApoE-deficient (ApoE-/-) mice. Methods: Male ApoE-/- mice (6 weeks) were fed with a high-fat diet for 13 weeks and then randomized to the model group (MOD) or Tan IIA groups [high dose: 90 mg/kg/day (HT), moderate dose: 30 mg/kg/day (MT), low dose: 10 mg/kg/day (LT)] or the atorvastatin group (5 mg/kg/day, ATO) for 13 weeks. Male C57BL/6 mice (6 weeks) were fed with ordinary rodent chow as control. The plaque stability was evaluated according to the morphology and composition of aortic atherosclerotic (AS) plaque in H&E staining and Movat staining sections by calculating the area of extracellular lipid, collagenous fiber, and foam cells to the plaque. The expression of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor88 (MyD88)/nuclear factor-kappa B (NF-κB) signal pathway in aorta fractions was determined by immunohistochemistry. Serum levels of blood lipid were measured by turbidimetric inhibition immunoassay. The concentrations of tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were detected by cytometric bead array. Results: Tan IIA stabilized aortic plaque with a striking reduction in the area of extracellular lipid (ATO: 13.15 ± 1.2%, HT: 12.2 ± 1.64%, MT: 13.93 ± 1.59%, MOD: 18.84 ± 1.46%, P < 0.05) or foam cells (ATO: 16.05 ± 1.26%, HT: 14.88 ± 1.79%, MT: 16.61 ± 1.47%, MOD: 22.08 ± 1.69%, P < 0.05) to the plaque, and an evident increase in content of collagenous fiber (ATO: 16.22 ± 1.91%, HT: 17.58 ± 1.33%, MT: 15.71 ± 2.26%, LT:14.92 ± 1.65%, MOD: 9.61 ± 0.7%, P < 0.05) to the plaque than that in the model group, concomitant with down-regulation of the protein expression of TLR4, MyD88, and NF-κB p65, and serum level of MCP-1 and TNF-α in a dose-dependent manner. There were no differences in serum TC, LDL, HDL, or TG levels between ApoE-/- mice and those treated with atorvastatin. Conclusions: These results suggest that Tan IIA could stabilize vulnerable AS plaque in ApoE-/- mice, and this anti-inflammatory and immune-regulating effect may be achieved via the TLR4/MyD88/NF-κB signaling pathway.

Preparation of sustained-release composite coating formed by dexamethasone and oxidated sodium alginate.

Inflammatory reaction and thrombosis are the unsolved main problems of non-coated biomaterials applied in cardiac surgery. In the present study, a series of sustained composite coating was prepared and characterized, such as in the chemical modification of polyvinyl chloride (PVC) for applications in cardiac surgery and the assessment of the biological property of modified PVC. The composite coatings were mainly formed by dexamethasone (DXM) and oxidated sodium alginate (OSA) through ionic and covalent bond methods. The biocompatibility and hemocompatibility of the coating surface were evaluated. Scanning electron microscopy analysis of the surface morphologies of the thrombus and platelets revealed that DXM-OSA coating improved the antithrombogenicity and biocompatibility of PVC circuits, which were essential for cardiac pulmonary bypass surgery. Evaluation of in vitro release revealed that the DXM on group PPC was gradually released in 8 h. Thus, DXM that covalently combined on the PVC surface showed sustained release. By contrast, DXM on groups PPI and PPD was quickly or shortly released, suggesting that groups PPI and PPD did not have sustained-release property. Overall, results indicated that the DXM-OSA composite coating may be a promising coating for the sustained delivery of DXM.

[Long-term anti-cancer implants inhibiting the activity of tumor growth in animal models].

This study was aimed to establish rat bladder tumor animal models to investigate the in viva antitumor effect of polyanhydride-pirarubicin (PAD-THP), a long-lasting anti-cancer implant, in the bladder tumor of animal models. The model of bladder cancer was set up with N-butly-N-(4 hydroxybutyl) nitrosamine (BBN) feeding into rats. The PAD-THP long-acting anti-cancer implants containing the drugs and the same dose of the THP naked drug were placed under the bladder mucosa of bladder tumor model in vivo. The pirarubicin plasma concentration was measured with high performance liquid chromatography (HPLC) detection in vivo. The effective drug concentration and lasting period were observed and compared in the animal bodies. The tumor sizes were measured before and after the treatment. The in viva antitumor effects were analyzed and compared. The results showed that more significant antitumor effect of PAD-THP implants on the local drug release characteristics were presented compared with that of the same dose of THP bare drug group and there were significant differences (P<0. 05) between the two methods. All the results indicated that the PAD-THP anti-cancer implants in the postoperative local treatment of bladder tumors would show prosperous in the future for clinical application.

Sodium alginate/heparin composites on PVC surfaces inhibit the thrombosis and platelet adhesion: applications in cardiac surgery.

Thrombosis and hemocyte damage are the main problems of applied non-coated biomaterials to cardiac surgery that remain unsolved. The present study is aimed at the chemical modification of polyvinyl chloride (PVC) for applications in cardiac surgery and the biological property assessment of modified PVC. Sodium alginate (SA)/heparin (HEP) composites were covalently immobilized onto the surface of the PVC pipeline. The surface grafting density and protein adsorption were determined by ultraviolet spectrophotometry. The surface contact angles were evaluated by contact-angle measurement, whereas the surface characteristics were evaluated by Fouriertransform infrared spectroscopy. Blood coagulation time and platelet adhesion were measured using an automated blood coagulation analyzer and a hemocytometer, respectively. Surface morphologies of the thrombus and platelets were evaluated by scanning electron microscopy. The immobilization of SA/HEP reduced the contact angles of the coated surface. Protein adsorption was reduced by the immobilization of SA. The activated partial thrombin time and thrombin time of the coated PVC were significantly prolonged as compared with the non-coated PVC. Platelet adhesion and thrombus formation were all reduced by the immobilization of HEP. The results revealed that the SA/HEP coating can improve the antithrombogenicity of the PVC pipeline, as well as improve its biocompatibility and hemocompatibility, which are essential for cardiac pulmonary bypass surgery.

Reconstruction of orbital defects by implantation of antigen-free bovine cancellous bone scaffold combined with bone marrow mesenchymal stem cells in rats.

BACKGROUND: Tissue-engineering approach can result in significant bone regeneration. We aimed to reconstruct the segmental orbital rim defects with antigen-free bovine cancellous bone (BCB) scaffolds combined with bone marrow mesenchymal stem cells (BMSCs) in rats. METHODS: BCB was prepared by degreasing, deproteinization and partly decalcification. BMSCs isolated from green fluorescent protein (GFP) transgenic rats were osteogenically induced and seeded onto BCB scaffolds to construct induced BMSCs/BCB composites. An 8-mm full-thickness defect on the rat inferior-orbit rim was established. Induced BMSCs/BCB composites cultured for 5 days were implanted into the orbital defects as the experimental group. Noninduced BMSCs/BCB group, BCB group and exclusive group were set. General condition, spiral CT, 3D orbital reconstruction, histological and histomorphometric analysis were performed after implantation. RESULTS: BCB presented reticular porous structure. GFP-BMSCs adhering to BCB appeared bright green fluorescence and grew vigorously. Infection and graft dislocation were not observed. In induced BMSCs/BCB group, CT and 3D reconstruction showed perfect orbital repair situation. Histological analysis indicated BCB was mostly biodegraded; newly formed bone and complete synostosis were observed. The percentage of newly formed bone was (57.12 ± 6.28) %. In contrast, more residual BCB, less newly formed bone and nonunion were observed in the noninduced BMSCs/BCB group. Slowly absorbed BCB enwrapped by fibrous connective tissue and a small amount of new bone occurred in BCB group. Fibrous connective tissue appeared in exclusive group. CONCLUSIONS: Antigen-free bovine cancellous bone that retains natural bone porous structure and moderate mechanical strength with elimination of antigen is the ideal carrier for mesenchymal stem cells in vitro. BCB combined with BMSCs is a promising composite for tissue engineering, and can effectively reconstruct the orbit rim defects in rats.

[The study of absorbable sustained-release implants and animal experiments to prevent recurrence of bladder cancer].

This paper aims to prepare polyanhydride-Pirarubicin dose long-acting sustained-release implants for the treatment of bladder cancer and for the prevention of postoperative recurrence of bladder cancer. Pirarubicin hydrochloride (THP) and polyanhydride, in accordance with a certain proportion, were fully mixed in the agate morta and dissolved in dichloromethane, and then were cast into a film within a mold put in the dryer set at 4 degrees C. Each tablet implanted contained 5.0 mg of THP. Polyanhydride-pirarubicin sustained-release was implanted into the bladder mucosa of the rabbits, and blood and urine samples were taken at different times after the operation. The THP drug concentrations in urine and blood were determined with high-performance liquid chromatography. The THP concentration in urine was significantly higher than the THP concentration in plasma. The drug concentration in urine reached (92.5 +/- 7.4) microg/L at 250 d time after the operation. Polyanhydride-pirarubicin implants possess long-acting sustained-release level dynamics in the body. It can maintain a stable long-term drug release and can be expected to last a year and can effectively prevent recurrence of bladder cancer. The present experiments proved that the implants with sustained-release drug treatment are expected to be useful in the clinical application in prevention of bladder cancer recurrence.

[Preparation of the EPC and HEPC sterically stabilized doxorubicin liposomes and further studies on pharmacokinetics in rats].

In this paper, we address the preparation of the EPC and HEPC sterically stabilized doxorubicin liposomes and report the data collected from further studies on pharmacokinetics in blood for choosing a better carrier in delivering the drugs. The pharmacokinetics of EPC and HEPC sterically stabilized liposomes (EPC-SSL, and HEPC-SSL) in Wistar rats were investigated by HPLC. The results showed that the mean residence time of HEPC-SSL in blood is 23.3 h, while that of EPC-SSL is 12.0 h. In conclusion, HEPC-SSL is a better carrier in delivering the drugs to the extravascular sites when compared with EPC-SSL.

[Study on the analysis of mixed spectra of benzene homologs with Dolittle multivariate correction method].

Dolittle algorithm is a numerical analysis method with high accuracy and low cost. In the present paper, the Dolittle algorithm is introduced into chemometrics. Dolittle multivariate correction method was put forward for the first time and was applied to solve the problem of overlapped spectra of multi-components. In addition, Dolittle multivariate correction method was used to resolve the problem of spectrum of mixed system of benzene homologs. The result shows that the Dolittle multivariate correction method is superior to the K-matrix method. The relative standard deviation of the Dolittle multivariate correction method is from -6. 35% to 8. 70%, while the relative standard deviation of K-matrix is from -14. 76% to 13. 40%. It was demonstrated that Doolittle algorithm is effective in analytical chemistry.

Effect of O-4-ethoxyl-butyl-berbamine in combination with pegylated liposomal doxorubicin on advanced hepatoma in mice.

AIM: To study the synergistic effects of calmodulin (CaM) antagonist O-4-ethoxyl-butyl-berbamine (EBB) and pegylated liposomal doxorubicin (PLD) on hepatoma-22 (H(22)) in vivo. METHODS: Hepatoma model was established in 50 Balb/c mice by inoculating H(22) cells (2.5 x 10(6)) subcutaneously into the right backs of the mice. These mice were divided into 5 groups, and treated with saline only, PLD only, doxorubicin (Dox) only, PLD plus EBB and Dox plus EBB, respectively. In the treatment groups, mice were given 5 intravenous of PLD or Dox on days 0, 3, 6, 9 and 12. The first dosage of PLD or Dox was 4.5 mg/kg, the other 4 injections was 1 mg/kg. EBB (5 mg/kg) was coadministered with PLD or Dox in the corresponding groups. The effect of drugs on the life spans of hepatoma-bearing mice and tumor response to the drugs were recorded. Dox levels in the hepatoma cells were measured by a fluorescence assay. Light microscopy was performed to determine the histopathological changes in the major organs of these tumor-bearing mice. The MTT method was used to analyze the effect of Dox or PLD alone, Dox in combination with EBB, or PLD in combination with EBB on the growth of H(22) cells in an in vitro experiment. RESULTS: EBB (5 mg/kg) significantly augmented the antitumor activity of Dox or PLD, remarkably prolonged the median survival time. The median survival time was 18.2 d for control group, but 89.2 d for PLD+EBB group and 70.1 d for Dox+EBB group, respectively. However, Dox alone did not show any remarkable antitumor activity, and the median survival time was just 29.7 d. Addition of EBB to Dox or PLD significantly increased the level of Dox in H(22) cells in vivo. Moreover, EBB diminished liver toxicity of Dox and PLD. In vitro, EBB reduced the IC50 value of Dox or PLD on H(22) cells from 0.050+/-0.006 mg/L and 0.054+/-0.004 mg/L to 0.012+/-0.002 mg/L and 0.013+/-0.002 mg/L, respectively (P<0.01). CONCLUSION: EBB and liposomization could improve the therapeutic efficacy of Dox in liver cancer, while decreasing its liver toxicity.

[The synthesis of polyanhydrides and its application in biomedical field].

This paper reviews the development of the polyanhydrides as a new biodegradable polymer, and highlights the methodological and technological progress in the synthesis of the polymer. Subsequently, the future researches and developments of polyanhydrides are prospected.