H2O2 Self-Supplying and GSH-Depleting Nanocatalyst for Copper Metabolism-Based Synergistic Chemodynamic Therapy and Chemotherapy.

Chemodynamic therapy (CDT) that involves the use of Fenton catalysts to convert endogenous hydrogen peroxide (H2O2) to hydroxyl radicals (·OH) constitutes a promising strategy for cancer therapy; however, insufficient endogenous H2O2 and glutathione (GSH) overexpression render its efficiency unsatisfactory. Herein, we present an intelligent nanocatalyst that comprises copper peroxide nanodots and DOX-loaded mesoporous silica nanoparticles (MSNs) (DOX@MSN@CuO2) and can self-supply exogenous H2O2 and respond to specific tumor microenvironments (TME). Following endocytosis into tumor cells, DOX@MSN@CuO2 initially decomposes into Cu2+ and exogenous H2O2 in the weakly acidic TME. Subsequently, Cu2+ reacts with high GSH concentrations, thereby inducing GSH depletion and reducing Cu2+ to Cu+ Next, the generated Cu+ undergoes Fenton-like reactions with exogenous H2O2 to accelerate toxic ·OH production, which exhibits a rapid reaction rate and is responsible for tumor cell apoptosis, thereby enhancing CDT. Furthermore, the successful delivery of DOX from the MSNs achieves chemotherapy and CDT integration. Thus, this excellent strategy can resolve the problem of insufficient CDT efficacy due to limited H2O2 and GSH overexpression. Integrating H2O2 self-supply and GSH deletion enhances CDT, and DOX-induced chemotherapy endows DOX@MSN@CuO2 with effective tumor growth-inhibiting properties alongside minimal side effects in vivo.

Subcellular-Targeted Near-Infrared-Responsive Nanomedicine with Synergistic Chemo-photothermal Therapy against Multidrug Resistant Cancer.

Multidrug resistance (MDR) is a major obstacle to effective cancer treatment. Therefore, developing effective approaches for overcoming the limitation of MDR in cancer therapy is very essential. Chemotherapy combined with photothermal therapy (PTT) is a potential therapeutic option against MDR. Herein, we developed a subcellular-targeted near-infrared (NIR)-responsive nanomedicine (Fe3O4@PDA-TPP/S2-PEG-hyd-DOX, abbreviated as Fe3O4-ATSPD) as a new photothermal agent with improved photothermal stability and efficiency. This system demonstrates high stability in blood circulation and can be accumulated at the tumor site by magnetic targeting enhanced permeability and retention effect (EPR). Near-infrared (NIR) irradiation at the tumor site generates a photothermal effect from the photosensitizer Fe3O4@PDA, leading to a dramatic decrease in mitochondrial membrane potential. Simultaneously, the conjugated drugs released under low pH condition in endosomes or lysosomes cause nucleus DNA damage and cell apoptosis. This subcellular-targeted NIR-responsive nanomedicine with efficient integration of diagnosis and therapy could significantly enhance MDR cancer treatment by combination of chemotherapy and PTT.

Polyethylenimine functionalized magnetic nanoparticles as a potential non-viral vector for gene delivery.

Polyethylenimine (PEI) functionalized magnetic nanoparticles were synthesized as a potential non-viral vector for gene delivery. The nanoparticles could provide the magnetic-targeting, and the cationic polymer PEI could condense DNA and avoid in vitro barriers. The magnetic nanoparticles were characterized by Fourier transform infrared spectroscopy, X-ray powder diffraction, dynamic light scattering measurements, transmission electron microscopy, vibrating sample magnetometer and atomic force microscopy. Agarose gel electrophoresis was used to asses DNA binding and perform a DNase I protection assay. The Alamar blue assay was used to evaluate negative effects on the metabolic activity of cells incubated with PEI modified magnetic nanoparticles and their complexes with DNA both in the presence or absence of an external magnetic field. Flow cytometry and fluorescent microscopy were also performed to investigate the transfection efficiency of the DNA-loaded magnetic nanoparticles in A549 and B16-F10 tumor cells with (+M) or without (-M) the magnetic field. The in vitro transfection efficiency of magnetic nanoparticles was improved obviously in a permanent magnetic field. Therefore, the magnetic nanoparticles show considerable potential as nanocarriers for gene delivery.

Degradation of ofloxacin by potassium ferrate: kinetics and degradation pathways.

Drug residues, including various antibiotics, are being increasingly detected in aqueous environments. Ofloxacin (OFX) is one such antibiotic that is widely used in the treatment of several bacterial infections; however, chronic exposure to this antibiotic can have adverse impacts on human health. Hence, the identification of an effective OFX degradation method is essential. Thus, in this study, the degradation performance of OFX using potassium ferrate (Fe(VI)) under the influence of different initial concentrations, pH, temperature, and common ions in water was investigated. OFX degradation by Fe(VI) was directly proportional to the concentration of Fe(VI) and temperature and inversely proportional to the pH. Among the common ions in water, Fe3+ and NH4+ could significantly promote the degradation of OFX by Fe(IV), while humic acid (HA) significantly inhibited it. Under the conditions of [Fe(VI)]:[OFX] = 15:1, T = 25℃, and pH = 7.0, the removal efficiency of 8 µM OFX reached more than 90% in 4 min. Seven intermediates were identified by quadrupole time-of-flight tandem ultra-performance liquid chromatography mass spectrometry (Q-TOF LC/MS), and two possible pathways for the degradation of OFX by Fe(VI) were proposed. Overall, the results suggest that advanced oxidation technology using Fe(VI) is effective for treating wastewater containing OFX.

Yeast Template-Derived Multielectron Reaction NASICON Structure Na3MnTi(PO4)3 for High-Performance Sodium-Ion Batteries.

The sodium super ion conductor (NASICON) structure materials are essential for sodium-ion batteries (SIBs) due to their robust crystal structure, excellent ionic conductivity, and flexibility to regulate element and valence. However, the poor electronic conductivity and inferior energy density caused by the nature of these materials have always been obstacles to commercialization. Herein, using yeast as a template to derive NASICON structure Na3MnTi(PO4)3 (NMTP) materials (noted as Yeast@NMTP/C) is presented. The Yeast@NMTP/C material retains the microsphere morphology of the yeast template and not only controls the particle size (around 2 µm) to shorten the Na+ diffusion pathways but also improves the electronic conductivity to optimize the electrochemical kinetics. The Yeast@NMTP/C cathode delivers reversible multielectron redox reactions including Ti4+/3+, Mn3+/2+, and Mn4+/3+ and exhibits a high capacity of 108.5 mAh g-1 with a 79.2% capacity retention after 1000 cycles at a 2C rate. The sodium storage mechanism of Yeast@NMTP/C reveals that the addition of Ti4+/3+ redox plays a key role in improving the Na+ diffusion kinetics, and both solid-solution and two-phase reactions take place during the desodiation and sodiation process. Additionally, the high-rate and long-span cycle performance of Yeast@NMTP/C at 10C is ascribed to contribute to pseudocapacitance.

Controllably Switched Drug Release from Successively Dual-Targeted Nanoreservoirs.

The development of a nanocarrier with a capacity of releasing therapeutic agent "on demand" is of great importance for enhancing drug efficacy and reducing its side effect. Here, a multifunctional mesoporous silica nanoparticle is presented for cancer therapy. This nanoparticle can not only successively target tumor tissue and tumor cells but also has a function of controllably switching the drug release. Low molecular weight poly(ethyleneimine) segments, which are decorated on the surface of magnetic mesoporous silica nanoparticle with disulfide bonds, are chemically cross-linked, leading to the mesopores being "closed" in blood circulation but being "open" via taking off the coating in cytoplasm. As a result, the encapsulated drug can be kept in nanoparticles in the normal conditions, while be rapidly released in a reduction condition. In vivo antitumor activity demonstrates that this nanoparticle has the highest safety to body and the best therapeutic efficacy against tumors. Therefore, this work presents a good example of rational design of nanocarriers for highly effective cancer therapy.

Redox-responsive star-shaped magnetic micelles with active-targeted and magnetic-guided functions for cancer therapy.

UNLABELLED: Highly efficient delivery of therapeutic agents to target sites is of great importance for achieving excellent therapeutic efficacy in cancer treatment. Here, we report a redox-responsive star-shaped magnetic micelle with both active-targeted and magnetic-guided functions. The magnetic star-shaped micelles are formed by self-assembly of four-arm poly(ethylene glycol) (PEG)-poly(ε-caprolactone) (PCL) copolymers with disulfide bonds as intermediate linkers. Anticancer drug doxorubicin (DOX) and magnetic iron oxide nanoparticles (Fe3O4) are simultaneously encapsulated into the hydrophobic cores. PBA ligands are chemically conjugated to the end of the hydrophilic PEG segments, endowing the active targeting of nanocarriers. Both qualitative and quantitative analyses of the intracellular uptake of these micelles with active-targeting and dual-targeting are performed in vitro by cultured with salic acid (SA)-positive tumor cells (human liver carcinoma cell line HepG2, human cervical cancer cell line HeLa) and SA-negative tumor cells (human breast adenocarcinoma cell line MCF-7, human non-small cell lung cancer cell line A549) in the presence or absence of a permanent magnetic field. In vivo biodistribution studies with active-targeting and dual-targeting and in vivo anti-tumor effect are carried out in detail after being applied to the BALB/c mice bearing mouse H22 hepatocarcinoma cells tumor model. These in vivo results demonstrate that a great amount of dual-targeted magnetic micelles accumulate around the tumor tissues by the magnetic-guiding and in turn are taken up by the tumor cells through SA-mediated endocytosis, leading to a high therapeutic efficacy to the artificial solid tumor. STATEMENT OF SIGNIFICANCE: A redox-responsive star-shaped magnetic micelle with both active-targeted and magnetic-guided functions was developed. Both qualitative and quantitative analysis of the intracellular uptake with dual-targeting of these micelles were performed in vitro by salic acid (SA)-positive tumor cells. The in vivo results demonstrate that a great amount of dual-targeted magnetic micelles accumulated around the tumor tissues, leading to a high therapeutic efficacy to artificial solid tumor.

Precise Polymerization of a Highly Tumor Microenvironment-Responsive Nanoplatform for Strongly Enhanced Intracellular Drug Release.

The importance of achieving a high content of responsive groups of drug carriers is well-known for achieving rapid intracellular drug release; however, very little research has been published on this subject. Here, we present an entirely new strategy to synthesize a highly reduction-sensitive polymer-drug conjugate with one disulfide bond corresponding to each resultant copolymer through a precise ring-opening polymerization of ε-caprolactone that is initiated by a monoprotected cystamine. Simultaneously, the anticancer drug doxorubicin is chemically conjugated to the polymer via pH-responsive hydrazone bonds, which effectively prevent premature drug release in the blood circulation. The 3-aminophenylboronic acid (PBA) targeting ligands endow an active-targeting ability that significantly prompts the specific internalization of nanocarriers by tumor cells and thus results in excellent cytotoxicity against tumor cells. The concept of precise polymerization is put forward to achieve multifunctional nanocarriers for the first time. This study is expected to inspire the development of a highly environment-responsive nanoplatform for drug delivery in future clinical applications.

Biodegradable magnetic calcium phosphate nanoformulation for cancer therapy.

We fabricated a magnetic calcium phosphate nanoformulation by the biomineralization of calcium phosphate on the surface of magnetic nanoparticles with abundant amino groups, and thus the inorganic layer of calcium phosphate can improve the biocompatibility and simultaneously the magnetic iron oxide can maintain the magnetic targeting function. Two types of anticancer drug models, doxorubicin hydrochloride and DNA, were entrapped in these nanocarriers, respectively. This delivery system displayed high pH sensitivity in drug-controlled release profile as the dissolution of CaP under acid pH condition. Magnetofection was performed to investigate the intracellular uptake and the anti-proliferative effect of tumor cells in the presence of an external magnet. The transfection of the DNA-loaded magnetic system in A549 and HepG2 tumor cells demonstrated that the magnetic nanoformulation could enhance the transfection efficiency to 30% with an applied external magnetic field.

Redox-responsive polyanhydride micelles for cancer therapy.

Biodegradable polyanhydrides possess unique features like those that they can predominantly undergo surface erosion, and the payloads can be released by a steady speed. However, there is little work that has been published to describe the polyanhydride micelles with redox-responsiveness as a nanocarrier for drug delivery. In this study, we develop one type of new amphiphilic polyanhydride copolymer containing disulfide bonds between the hydrophilic and hydrophobic segments. The copolymer can self-assemble into stable micelles with well-defined core-shell structure and a uniform size distribution with an average diameter of 69 nm. The disassembly behaviors of the micelles triggered by glutathione are evaluated from the changes of the micellar size, morphology and molecular weight. An approximate zero-order in vitro drug release mode with a fast speed can be achieved in a reducing and acid environment similar with that of tumor cells. In vitro cytotoxicity analysis demonstrate that the Cur-loaded micelles are of great efficiency in inhibiting the growth of cancer cells due to the rapidly intracellular delivery of therapeutic agent. Both the qualitative and quantitative results of the antitumor activity in 4T1 tumor-bearing BALB/c mice reveal that the redox-responsive micelles have a more significant therapeutic effect to artificial solid tumor compared to the redox-insensitive micelles. This study provides a new insight into the biomedical application of polyanhydrides in drug delivery.

Quantitative control of active targeting of nanocarriers to tumor cells through optimization of folate ligand density.

The active targeting delivery system has been widely studied in cancer therapy by utilizing folate (FA) ligands to generate specific interaction between nanocarriers and folate receptors (FRs) on tumor cell. However, there is little work that has been published to investigate the influence of the definite density of the FA ligands on the active targeting of nanocarriers. In this study, we have combined magnetic-guided iron oxide nanoparticles with FA ligands, adjusted the FA ligand density and then studied the resulting effects on the active targeting ability of this dual-targeting drug delivery system to tumor cells. We have also optimized the FA ligand density of the drug delivery system for their active targeting to FR-overexpressing tumor cells in vitro. Prussian blue staining, semi-thin section of cells observed with transmission electron microscopy (TEM) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) have shown that the optimal FA density is from 2.3 × 10(18) to 2.5 × 10(18) per gram nanoparticles ((g·NPs)(-1)). We have further tried to qualitatively and quantitatively control the active targeting and delivering of drugs to tumors on 4T1-bearing BALB/c mice. As expected, the in vivo experimental results have also demonstrated that the FA density of the magnetic nanoparticles (MNPs) could be optimized for a more easily binding to tumor cells via the multivalent linkages and more readily internalization through the FR-mediated endocytosis. Our study can provide a strategy to quantitatively control the active targeting of nanocarriers to tumor cells for cancer therapy.

Actively targeted delivery of anticancer drug to tumor cells by redox-responsive star-shaped micelles.

In cancer therapy nanocargos based on star-shaped polymer exhibit unique features such as better stability, smaller size distribution and higher drug capacity in comparison to linear polymeric micelles. In this study, we developed a multifunctional star-shaped micellar system by combination of active targeting ability and redox-responsive behavior. The star-shaped micelles with good stability were self-assembled from four-arm poly(ε-caprolactone)-poly(ethylene glycol) copolymer. The redox-responsive behaviors of these micelles triggered by glutathione were evaluated from the changes of micellar size, morphology and molecular weight. In vitro drug release profiles exhibited that in a stimulated normal physiological environment, the redox-responsive star-shaped micelles could maintain good stability, whereas in a reducing and acid environment similar with that of tumor cells, the encapsulated agent was promptly released. In vitro cellular uptake and subcellular localization of these micelles were further studied with confocal laser scanning microscopy and flow cytometry against the human cervical cancer cell line HeLa. In vivo and ex vivo DOX fluorescence imaging displayed that these FA-functionalized star-shaped micelles possessed much better specificity to target solid tumor. Both the qualitative and quantitative results of the antitumor effect in 4T1 tumor-bearing BALB/c mice demonstrated that these redox-responsive star-shaped micelles have a high therapeutic efficiency to artificial solid tumor. Therefore, the multifunctional star-shaped micelles are a potential platform for targeted anticancer drug delivery.

Thermo-triggered drug release from actively targeting polymer micelles.

How to deliver the drug to the target area at the right time and at the right concentration is still a challenge in cancer therapy. In this study, we present a facile strategy to control drug release by precisely controlling the thermo-sensitivity of the nanocarriers to the variation of environmental temperature. One type of thermoresponsive Pluronic F127-poly(d,l-lactic acid) (F127-PLA, abbreviated as FP) copolymer micelles was developed and decorated with folate (FA) for active targeting. FP100 micelles assembled from FP with PLA segment having polymerization degree of 100 had a low critical solution temperature of 39.2 °C close to body temperature. At 37 °C, little amount of encapsulated anticancer drug DOX is released from the FP100 micelles, while at a slightly elevated temperature (40 °C), the shrinkage of thermoresponsive segments causes a rapid release of DOX and instantly increases the drug concentration locally. The cytocompatibility analysis and cellular uptake efficiency were characterized with the fibroblast cell line NIH 3T3 and human cervix adenocarcinoma cell line HeLa. The results demonstrate that this copolymer has excellent cytocompatibility, and FA-decorated FP100 micelles present much better efficiency of cellular uptake and higher cytotoxicity to folate receptor (FR)-overexpressed HeLa cells. In particular, under hyperthermia (40 °C) the cytotoxicity of DOX-loaded FA-FP100 micelles against HeLa cells was significantly more obvious than that upon normothermia (37 °C). Therefore, these temperature-responsive micelles have great potential as a drug vehicle for cancer therapy.

Magnetic micelles as a potential platform for dual targeted drug delivery in cancer therapy.

The magnetic nanomicelles as a potential platform for dual targeted (folate-mediated and magnetic-guided) drug delivery were developed to enhance the efficiency and veracity of drug delivering to tumor site. The magnetic nanocarriers were synthesized based on superparamagnetic iron oxide nanoparticles (SPIONs), biocompatible Pluronic F127 and poly(dl-lactic acid) (F127-PLA) copolymer chemically conjugated with tumor-targeting ligand-folic acid (FA) via a facile chemical conjugation method. Doxorubicin hydrochloride (DOX·HCl) was selected as a model anticancer drug to investigate the in vitro drug release and antiproliferative effect of tumor cells in vitro and in vivo in the presence or absence of an external magnetic filed (MF) with strength of 0.1T. The Alamar blue assay exhibited that these magnetic nanomicelles possessed remarkable cell-specific targeting in vitro. Additionally this smart system enabling folate receptor-mediated uptake into tumor cells, showed strong responsiveness to MF. The primary in vivo tumor model study, which was carried out in VX2 tumor-bearing male New Zealand white rabbits, demonstrated that the nanomicelles could be guided into tumor site more efficiently by application of MF, and further represented significant therapeutic efficiency to solid tumor.

Synthesis of multifunctional Fe3O4 core/hydroxyapatite shell nanocomposites by biomineralization.

Superparamagnetic nanoparticles with surface functional groups (-OH, -COOH and -NH(2)) were modified by in situ deposition of hydroxyapatite (HA) on the materials' surface through the biomineralization process to form Fe(3)O(4) core/hydroxyapatite shell nanocomposites. They possess potential applications as targeted carriers for antitumor drugs and as bone tissue engineering scaffolds by integrating multiple functions into a single nanosystem.