Polydopamine-functionalized nanographene oxide: a versatile nanocarrier for chemotherapy and photothermal therapy.

For releasing both drug and heat to selected sites, a combination of chemotherapy and photothermal therapy in one system is a more effective way to destroy cancer cells than monotherapy. Graphene oxide (GO) with high drug-loading efficiency and near-infrared (NIR) absorbance has great potential in drug delivery and photothermal therapy, but it is difficult to load drugs with high solubility. Herein, we develop a versatile drug delivery nanoplatform based on GO for integrated chemotherapy and photothermal therapy by a facile method of simultaneous reduction and surface functionalization of GO with poly(dopamine) (PDA). Due to the excellent adhesion of PDA, both low and high solubility drugs can be encapsulated in the PDA-functionalized GO nanocomposite (rGO-PDA). The fabricated nanocomposite exhibits good biocompatibility, excellent photothermal performance, high drug loading capacity, an outstanding sustained release property, and efficient endocytosis. Moreover, NIR laser irradiation facilitates the release of loaded drugs from rGO-PDA. These features make the rGO-PDA nanocomposite achieve excellent in vivo synergistic antitumor therapeutic efficacy.

Mechanism of Self-Oxidative Copolymerization and its Application with Polydopamine-pyrrole Nano-copolymers.

Currently, the copolymer of dopamine (DA) and pyrrole (PY) via chemical and electrochemical oxidation usually requires additional oxidants, and lacks flexibility in regulating the size and morphology, thereby limiting the broad applications of DA-PY copolymer in biomedicine. Herein, the semiquinone radicals produced by the self-oxidation of DA is ingeniously utilized as the oxidant to initiate the following copolymerization with PY, and a series of quinone-rich polydopamine-pyrrole copolymers (PDAm-nPY) with significantly enhanced absorption in near-infrared (NIR) region without any additional oxidant assistance is obtained. Moreover, the morphology and size of PDAm-nPY can be regulated by changing the concentration of DA and PY, thereby optimizing nanoscale PDA0.05-0.15PY particles (≈ 150 nm) with excellent NIR absorption and surface modification activity are successfully synthesized. Such PDA0.05-0.15PY particles show effective photoacoustic (PA) imaging and photothermal therapy (PTT) against 4T1 tumors in vivo. Furthermore, other catechol derivatives can also copolymerize with PY under the same conditions. This work by fully utilizing the semiquinone radical active intermediates produced through the self-oxidation of DA reduces the dependence on external oxidants in the synthesis of composite materials and predigests the preparation procedure, which provides a novel, simple, and green strategy for the synthesis of other newly catechol-based functional copolymers.

Ferrocene-liposome-PEG: a robust ˙OH/lipid peroxide nano-converter for inducing tumor ferroptosis.

Ferroptosis induced by iron-dependent accumulation of lipid peroxides (LPOs) has received increasing attention in cancer therapy, especially chemodynamic therapy (CDT). However, the quick annihilation of hydroxyl radicals (˙OH) severely restricts the ˙OH/LPO conversion efficiency, which has become one of the key factors that influences the therapeutic efficacy of ferroptosis-based CDT. Herein, we designed a ˙OH/LPO nano-converter with a high LPO generation efficiency via loading ferrocene (Fc), a green Fenton catalyst, in the phospholipid bilayer of liposome-PEG (Fc-Lp-PEG). Under catalysis with Fc, the over-expressed H2O2 in tumors can be decomposed to ˙OH. The generated ˙OH in situ reacts with unsaturated lipids on the liposome, and is converted into LPOs, which spread the lipid peroxidation chain reaction to the remote membranes of cells and organelles, triggering efficient cancer cell ferroptosis. Systematic in vitro and in vivo therapeutic outcomes showed the high tumor inhibition ratio (74.0%) and the low side effects of Fc-Lp-PEG on 4T1 tumor-bearing mice. This novel strategy for improving the ˙OH/LPO conversion efficiency might provide new insights for the clinical development of ferroptosis-based CDT.

Trojan-Horse Diameter-Reducible Nanotheranostics for Macroscopic/Microscopic Imaging-Monitored Chemo-Antiangiogenic Therapy.

Although nanotheranostics have displayed striking potential toward precise nanomedicine, their targeting delivery and tumor penetration capacities are still impeded by several biological barriers. Besides, the current antitumor strategies mainly focus on killing tumor cells rather than antiangiogenesis. Enlightened by the fact that the smart transformable self-targeting nanotheranostics can enhance their targeting efficiency, tumor penetration, and cellular uptake, we herein report carrier-free Trojan-horse diameter-reducible metal-organic nanotheranostics by the coordination-driven supramolecular sequential co-assembly of the chemo-drug pemetrexed (PEM), transition-metal ions (FeIII), and antiangiogenesis pseudolaric acid B. Such nanotheranostics with both a high dual-drug payload efficiency and outstanding physiological stability are responsively decomposed into numerous ultra-small-diameter nanotheranostics under stimuli of the moderate acidic tumor microenvironment and then internalized into tumor cells through tumor-receptor-mediated self-targeting, synergistically enhancing tumor penetration and cellular uptake. Besides, such nanotheranostics enable visualization of self-targeting capacity under the macroscopic monitor of computed tomography/magnetic resonance imaging, thereby realizing efficient oncotherapy. Moreover, tumor microvessels are precisely monitored by optical coherence tomography angiography/laser speckle imaging during chemo-antiangiogenic therapy in vivo, visually verifying that such nanotheranostics possess an excellent antiangiogenic effect. Our work will provide a promising strategy for further tumor diagnosis and targeted therapy.

Metabolizable pH/H2O2 dual-responsive conductive polymer nanoparticles for safe and precise chemo-photothermal therapy.

Conductive polymers with high near-infrared absorbance, have attracted considerable attention in the design of intelligent nanomedicines for cancer therapy, especially chemo-photothermal therapy. However, the unknown long-term biosafety of conductive polymers in vivo due to non-degradability hinders their clinic application. Herein, a H2O2-triggered degradable conductive polymer, polyacrylic acid (PAA) stabilized poly(pyrrole-3-COOH) (PAA@PPyCOOH), is fabricated to form nanoparticles with doxorubicin (DOX) for safe and precise chemo-phototherapy. The PAA@PPyCOOH was found to be an ideal photothermal nano-agent with good dispersity, excellent biocompatibility and high photothermal conversion efficiency (56%). After further loading of doxorubicin (DOX), PAA@PPyCOOH@DOX demonstrates outstanding photothermal performance, as well as pH/H2O2 dual-responsive release of DOX in tumors with an acidic and overexpressed H2O2 microenvironment, resulting in superior chemo-photothermal therapeutic effects. The degradation mechanism of PAA@PPyCOOH is proposed to be the ring-opening reaction between the pyrrole-3-COOH unit and H2O2. More importantly, the nanoparticles can be specifically degraded by excess H2O2 in tumor, and the degradation products were confirmed to be excreted via urine and feces. In vivo therapeutic evaluation of chemo-photothermal therapy reveals tumor growth of 4T1 breast cancer model is drastically inhibited and no apparent side-effect is detected, thus indicating substantial potential in clinic application.

The role and mechanism of polydopamine and cuttlefish ink melanin carrying copper ion nanoparticles in antibacterial properties and promoting wound healing.

Melanin and its analogue polydopamine (PDA) have attracted considerable attention in biomedical science due to their surface-rich metal binding sites, excellent adhesion and good biocompatibility. Bacterial infections at the wound site and uncontrolled bleeding are associated with a high risk of death, and the prevention of wound infections remains a major challenge. On this basis, the four nanoparticles (NPs) of melanin, PDA, copper ion-loaded melanin (Cu(ii) loaded melanin) and copper ion-loaded PDA (Cu(ii) loaded PDA) were studied in terms of antibacterial and wound healing capabilities. The in vitro experiments showed that Cu(ii) loaded PDA NPs had good blood compatibility and low cytotoxicity, showing the best antibacterial effect in comparison with other samples. Not only could the slow release of copper ions from the nanoparticles kill bacteria, but also the phenolic hydroxyl group and amine groups of PDA NPs played a synergistic role in bacterial death. In wound healing experiments, the Cu(ii) loaded PDA NPs could easily and tightly bind with biological tissue, demonstrating excellent hemostasis, antibacterial and wound healing capabilities. In summary, the excellent properties of Cu(ii) loaded PDA NPs made them a safe and effective drug for preventing wound infection and promoting healing.

Cellular uptake mechanism of molecular umbrella.

Molecular umbrella provided a promising avenue for the design of the intracellular delivery of hydrophilic therapeutic agents. However, the limited understanding of its cellular uptake would be a roadblock to its effective application. Herein, we investigate the ability and mechanism of cellular entry of a fluorescently labeled diwalled molecular umbrella, which was synthesized from cholic acid, spermine, and 5-carboxyfluorescein, into Hela cells, with the extent of uptake analyzed by confocal fluorescence microscopy and flow cytometry. It is found that the as-synthesized diwalled molecular umbrella can greatly facilitate cellular uptake of hydrophilic agent, 5-carboxyfluorescein. In vitro experiments with diffuse marker, endocytic marker, and inhibitors suggested that several distinct uptake pathways (e.g., passive diffuse, clathrin-mediated endocytosis, and caveolae/lipid-raft-dependent endocytosis) are involved in the internalization of diwalled molecular umbrella. These results, together with its low toxicity and good biocompatibility, thus demonstrate the suitability of molecular umbrella for application as vectors in drug delivery systems.

Nanowire-based polypyrrole hierarchical structures synthesized by a two-step electrochemical method.

A simple two-step electrochemical method is proposed for the synthesis of nanowire-based polypyrrole hierarchical structures. In the first step, microstructured polypyrrole films are prepared by electropolymerization. Then, polypyrrole nanowires are electrodeposited on the surface of the as-synthesized microstructured polypyrrole films. As a result, hierarchical structures of polypyrrole nanowires on polypyrrole microstructures are obtained. The surface wettabilities of the resulting nanowire-based polypyrrole hierarchical structures are examined. It is expected that this two-step method can be developed into a versatile route to produce nanowire-based polypyrrole hierarchical structures with different morphologies and surface properties.

Polynorepinephrine Nanoparticles: A Novel Photothermal Nanoagent for Chemo-Photothermal Cancer Therapy.

Novel photothermal nanoagents (PTNAs) with excellent photothermal performance, smart-responsive property, and biocompatibility are in urgent need for precise chemo-photothermal cancer therapy. Herein, polynorepinephrine nanoparticles (PNE NPs) with a high photothermal conversion efficiency (η) of 808 nm laser (67%), pH/thermal responsibility, and little to no long-term toxicity were synthesized from an endogenic neurotransmitter norepinephrine. Compared to their analogues, polydopamine NPs, a widely used PTNA, PNE NPs exhibited a higher η value (enhanced 1.63-fold) and better cellular uptake efficiency (enhanced 2.57-fold). After modifying with polyethylene glycol (PEG) and loading with doxorubicin (DOX), PNE-PEG@DOX could realize responsive release of DOX under either a cytolysosome pH microenvironment (pH 5.0) or an 808 nm laser irradiation, resulting in an enhanced chemotherapeutic efficacy of DOX. Besides, in vivo combination therapy leads to nearly complete ablation of tumor tissues, while no significant side effects were found in normal tissues. Hence, this intelligent and biocompatible nanoplatform based on PNE NPs holds great potential in promoting the clinic transformation of precise chemo-photothermal cancer therapy.

Functionalized poly(pyrrole-3-carboxylic acid) nanoneedles for dual-imaging guided PDT/PTT combination therapy.

Herein, poly(pyrrole-3-carboxylic acid) (PPyCOOH) nanoneedles with abundant carboxyl groups were synthesized by aqueous dispersion polymerization method using pyrrole-3-carboxylic acid as conductive polymer monomer. The PPyCOOH nanoneedles not only owned good photothermal performance, but also more importantly showed enhanced tumor cell uptake efficiency (1.64 fold) compared with size and zeta-potential matched nanospheres. After loading photosensitizer aluminum phthalocyanine tetrasulfonate (AlPCS4) and modifying with poly(allylamine hydrochloride) (PAH) and poly(acrylic acid) (PAA) onto the PPyCOOH nanoneedles, novel nanoneedle complexes (AlPCS4@PPyCONH-PAH-PAA) integrating photodynamic therapy (PDT) and photothermal therapy (PTT) were successfully fabricated. The as-prepared nanoneedle complexes improved uptake efficiency of AlPCS4 both in vitro and in vivo. Moreover, the nanoneedle complexes have infrared thermal and fluorescent properties. By combined PDT/PTT under the guiding of dual modal imaging, the tumors in mice were completely eliminated and no recurrence was observed in 30 days after treatment, indicating that PPyCOOH nanoneedles have great potential as a novel drug carrier for constructing multifunctional nanoplatform used for cancer treatment.

Starch-assisted synthesis of polypyrrole nanowires by a simple electrochemical approach.

Starch, one of the most commonly used polysaccharides, has been adopted for the first time as morphology-directing agent to the electrochemical synthesis of polypyrrole (PPy) nanowires on various electrodes.

Synthesis of polypyrrole nanowires with positive effect on MC3T3-E1 cell functions through electrical stimulation.

Conducting polymer polypyrrole (PPy) possesses good biocompatibility and conductivity and has been used as functional coatings in bone tissue regeneration. In this study, a cholic acid doped PPy nanowires (PPy NWs) coating was electrochemically polymerized on the surface of titanium (Ti). The porous intertwined PPy NWs coating exhibited excellent electrical conductivity and electrochemical activity, better hydrophilicity and higher surface energy. In vitro cell experiments demonstrated that the PPy NWs coating together with a 10µA substrate-mediate electrical stimulation (ES) was capable to positive regulate the functions of MC3T3-E1 such as cell adhesion, proliferation and differentiation. Further long-term functions of cell tests including alkaline phosphatase (ALP) activity, bone-carboxyglutamic acid-containing protein (BGP) and calcium deposition were all thoroughly increased. These confirmed that the combination of PPy NWs and ES could accelerate MC3T3-E1 cells mature and osteogenesis. Hence, the PPy NWs coating was an electro bioactive coating and may have potential applications in the treatment of bone damage repairing and regeneration with ES.

Variation analysis of affinity-membrane model based on Freundlich adsorption.

The variation analysis of membrane properties including membrane thickness and pore-size was carried out theoretically by using affinity-membrane model based upon the Freundlich adsorption equation. As the percentage variation of membrane thickness and distribution of pore-size increase, we find that (1) the time of total saturation is delayed; (2) the loading capacity at the point of breakthrough are decreased; (3) solute recovery efficiency and ligand utilization efficiency is decreased; (4) the thickness of unused membrane is increased. The results show that even small variations of thickness and distribution of pore size may severely degrade the membrane performance.

Surface-modified anodic aluminum oxide membrane with hydroxyethyl celluloses as a matrix for bilirubin removal.

Microporous anodic aluminum oxide (AAO) membranes were modified by 3-glycidoxypropyltrimethoxysilane to produce terminal epoxy groups. These were used to covalently link hydroxyethyl celluloses (HEC) to amplify reactive groups of AAO membrane. The hydroxyl groups of HEC-AAO composite membrane were further modified with 1,4-butanediol diglycidyl ether to link arginine as an affinity ligand. The contents of HEC and arginine of arginine-immobilized HEC-AAO membrane were 52.1 and 19.7mg/g membrane, respectively. As biomedical adsorbents, the arginine-immobilized HEC-AAO membranes were tested for bilirubin removal. The non-specific bilirubin adsorption on the unmodified HEC-AAO composite membranes was 0.8mg/g membrane. Higher bilirubin adsorption values, up to 52.6mg/g membrane, were obtained with the arginine-immobilized HEC-AAO membranes. Elution of bilirubin showed desorption ratio was up to 85% using 0.3M NaSCN solution as the desorption agent. Comparisons equilibrium and dynamic capacities showed that dynamic capacities were lower than the equilibrium capacities. In addition, the adsorption mechanism of bilirubin and the effects of temperature, initial concentration of bilirubin, albumin concentration and ionic strength on adsorption were also investigated.

Multifunctional ZnPc-loaded mesoporous silica nanoparticles for enhancement of photodynamic therapy efficacy by endolysosomal escape.

The cellular uptake and localization of photosensitizer-loaded nanoparticles have significant impact on photodynamic therapy (PDT) efficacy due to short lifetime and limited action radius of singlet oxygen. Herein, we develop poly(ethylene glycol) (PEG)- and polyethylenimine (PEI)-functionalized zinc(II) phthalocyanine (ZnPc)-loaded mesoporous silica nanoparticles (MSNs), which are able to distribute in the cytosol by endolysosomal escape. In this photosensitizer-carrier system (PEG-PEI-MSNs/ZnPc), ZnPc is a PDT agent; MSNs are the nanocarrier for encapsulating ZnPc; PEI facilitates endosomal escape; and PEG enhances biocompatibility. The as-synthesized PEG-PEI-MSNs/ZnPc have a high escape efficiency from the lysosome to the cytosol due to the "proton sponge" effect of PEI. Compared with the ZnPc-loaded MSNs, the phototoxicity of the PEG-PEI-MSNs/ZnPc is greatly enhanced in vitro. By measuring the mitochondrial membrane potential, a significant loss of >80% Δψm after treatment with PEG-PEI-MSNs/ZnPc-PDT is observed. It is further demonstrated that the ultra-efficient passive tumor targeting and excellent PDT efficacy are achieved in tumor-bearing mice upon intravenous injection of PEG-PEI-MSNs/ZnPc and the followed light exposure. We present here a strategy for enhancement of PDT efficacy by endolysosomal escape and highlight the promise of using multifunctional MSNs for cancer therapy.

An albumin-fixed membrane for the removal of protein-bound toxins.

Established methods for kidney dialysis do not work for liver failure because kidney dialysis removes only water-soluble toxins, while the liver normally removes albumin-bound toxins. In the present study, a polysulfone dialysis membrane with a -OH reactive group was prepared by hydrolyzing the chloromethylated polysulfone membrane, and the bovine serum albumin molecules were fixed into the membrane with 1,1'-carbonyldiimidazole activation. The content of albumin of the albumin-fixed membrane was 121.3 mg (g membrane)(-1). The albumin-fixed dialysis membranes were used to remove protein-bound toxins, bilirubin, from the bilirubin-albumin solution. The transfer rate of bilirubin of the albumin-fixed membrane was obviously higher compared to the normal dialysis membrane. The clearance of bilirubin with the albumin-fixed membrane was 49.8%. The albumin-fixed membrane can easily be regenerated by the bovine serum albumin and NaOH solution. Regeneration of the membrane suggested good mechanical and chemical stability, as well as good clearance of bilirubin. In addition, the effects of membrane thickness and bilirubin initial concentration on the removal of bilirubin were discussed.