Silver/gold nanoalloy implant coatings with antibiofilm activity via pH-triggered silver ion release.

Implant infections are a major challenge for the healthcare system. Biofilm formation and increasing antibiotic resistance of common bacteria cause implant infections, leading to an urgent need for alternative antibacterial agents. In this study, the antibiofilm behaviour of a coating consisting of a silver (Ag)/gold (Au) nanoalloy is investigated. This alloy is crucial to reduce uncontrolled potentially toxic Ag+ ion release. In neutral pH environments this release is minimal, but the Ag+ ion release increases in acidic microenvironments caused by bacterial biofilms. We perform a detailed physicochemical characterization of the nanoalloys and compare their Ag+ ion release with that of pure Ag nanoparticles. Despite a lower released Ag+ ion concentration at pH 7.4, the antibiofilm activity against Escherichia coli (a bacterium known to produce acidic pH environments) is comparable to a pure nanosilver sample with a similar Ag-content. Finally, biocompatibility studies with mouse pre-osteoblasts reveal a decreased cytotoxicity for the alloy coatings and nanoparticles.

Synthesis and Characterization of Lignin-Silver Nanoparticles.

Metal nanoparticle synthesis via environmentally friendly methods is gaining interest for their potential advantages over conventional physico-chemical approaches. Herein, we propose a robust green synthesis route for lignin-modified silver nanoparticles, utilizing the recovery of lignin as a renewable raw material and exploring its application in valuable areas. Through a systematic approach combining UV-Vis spectroscopy with AAS and DLS, we identified repeatable and scalable reaction conditions in an aqueous solution at pH 11 for homogeneous silver nanoparticles with high uniformity. The TEM median sizes ranged from 12 to 15 nm with circularity between 0.985 and 0.993. The silver nanoparticles yield exceeded 0.010 mol L-1, comparable with traditional physico-chemical methods, with a minimal loss of silver precursor ranging between 0.5 and 3.9%. Characterization by XRD and XPS revealed the presence of Ag-O bonding involving lignin functional groups on the pure face-centered cubic structure of metallic silver. Moreover, the lignin-modified silver nanoparticles generated a localized thermal effect upon near-infrared laser irradiation (808 nm), potentially allowing for targeted applications in the biomedical field. Our study showcases the potential of lignin as a renewable reducing and capping agent for silver nanoparticle synthesis, addressing some shortcomings of green synthesis approaches and contributing to the development of suitable nanomaterials.

All-Carbon Monolithic Composites from Carbon Foam and Hierarchical Porous Carbon for Energy Storage.

We designed high-volumetric-energy-density supercapacitors from monolithic composites composed of self-standing carbon foam (CF) as the conducting matrix and embedded hierarchically organized porous carbon (PICK) as the active material. Using multiprobe scanning tunneling microscopy at selected areas, we were able to disentangle morphology-dependent contributions of the heterogeneous composite to the overall conductivity. Adding PICK is found to enhance the conductivity of the monoliths by providing additional links for the CF network, enabling high and stable performance. The resulting all-carbon CF-PICK composites were used as self-standing electrodes for symmetric supercapacitors without the need for a binder, additional conducting additive, metals as a current collector, or casting/drying steps. Supercapacitors achieved a capacitance of 181 F g-1 based on the entire mass of the monolithic electrode as well as an outstanding rate capability. Our symmetrical supercapacitors also delivered a record volumetric energy density of 19.4 mW h cm-3 when using aqueous electrolytes. Excellent cycling stability with almost quantitative retention of capacitance was found after 10,000 cycles in 6.0 M KOH as the electrolyte. Furthermore, charge-discharge testing at different currents demonstrated the fast charge-discharge capability of this material system that meets the requirements for practical applications.

Mannose receptor-derived peptides neutralize pore-forming toxins and reduce inflammation and development of pneumococcal disease.

Cholesterol-dependent cytolysins (CDCs) are essential virulence factors for many human pathogens like Streptococcus pneumoniae (pneumolysin, PLY), Streptococcus pyogenes (streptolysin O, SLO), and Listeria monocytogenes (Listeriolysin, LLO) and induce cytolysis and inflammation. Recently, we identified that pneumococcal PLY interacts with the mannose receptor (MRC-1) on specific immune cells thereby evoking an anti-inflammatory response at sublytic doses. Here, we identified the interaction sites between MRC-1 and CDCs using computational docking. We designed peptides from the CTLD4 domain of MRC-1 that binds to PLY, SLO, and LLO, respectively. In vitro, the peptides blocked CDC-induced cytolysis and inflammatory cytokine production by human macrophages. Also, they reduced PLY-induced damage of the epithelial barrier integrity as well as blocked bacterial invasion into the epithelium in a 3D lung tissue model. Pre-treatment of human DCs with peptides blocked bacterial uptake via MRC-1 and reduced intracellular bacterial survival by targeting bacteria to autophagosomes. In order to use the peptides for treatment in vivo, we developed calcium phosphate nanoparticles (CaP NPs) as peptide nanocarriers for intranasal delivery of peptides and enhanced bioactivity. Co-administration of peptide-loaded CaP NPs during infection improved survival and bacterial clearance in both zebrafish and mice models of pneumococcal infection. We suggest that MRC-1 peptides can be employed as adjunctive therapeutics with antibiotics to treat bacterial infections by countering the action of CDCs.

Flame-Made Calcium Phosphate Nanoparticles with High Drug Loading for Delivery of Biologics.

Nanoparticles exhibit potential as drug carriers in biomedicine due to their high surface-to-volume ratio that allows for facile drug loading. Nanosized drug delivery systems have been proposed for the delivery of biologics facilitating their transport across epithelial layers and maintaining their stability against proteolytic degradation. Here, we capitalize on a nanomanufacturing process famous for its scalability and reproducibility, flame spray pyrolysis, and produce calcium phosphate (CaP) nanoparticles with tailored properties. The as-prepared nanoparticles are loaded with bovine serum albumin (model protein) and bradykinin (model peptide) by physisorption and the physicochemical parameters influencing their loading capacity are investigated. Furthermore, we implement the developed protocol by formulating CaP nanoparticles loaded with the LL-37 antimicrobial peptide, which is a biological drug currently involved in clinical trials. High loading values along with high reproducibility are achieved. Moreover, it is shown that CaP nanoparticles protect LL-37 from proteolysis in vitro. We also demonstrate that LL-37 retains its antimicrobial activity against Escherichia coli and Streptococcus pneumoniae when loaded on nanoparticles in vitro. Therefore, we highlight the potential of nanocarriers for optimization of the therapeutic profile of existing and emerging biological drugs.

Model-Based Nanoengineered Pharmacokinetics of Iron-Doped Copper Oxide for Nanomedical Applications.

The progress in nanomedicine (NM) using nanoparticles (NPs) is mainly based on drug carriers for the delivery of classical chemotherapeutics. As low NM delivery rates limit therapeutic efficacy, an entirely different approach was investigated. A homologous series of engineered CuO NPs was designed for dual purposes (carrier and drug) with a direct chemical composition-biological functionality relationship. Model-based dissolution kinetics of CuO NPs in the cellular interior at post-exposure conditions were controlled through Fe-doping for intra/extra cellular Cu2+ and biological outcome. Through controlled ion release and reactions taking place in the cellular interior, tumors could be treated selectively, in vitro and in vivo. Locally administered NPs enabled tumor cells apoptosis and stimulated systemic anti-cancer immune responses. We clearly show therapeutic effects without tumor cells relapse post-treatment with 6 % Fe-doped CuO NPs combined with myeloid-derived suppressor cell silencing.

Modeling Proteolytically Driven Tumor Lymphangiogenesis.

With the exception of a limited number of sites in the body, primary tumors infrequently lead to the demise of cancer patients. Instead, mortality and a significant degree of morbidity result from the growth of secondary tumors in distant organs. Tumor survival, growth and dissemination are associated with the formation of both new blood vessels (angiogenesis) and new lymph vessels (lymphagenesis or lymphangiogenesis). Although intensive research in tumor angiogenesis has been going on for the past four decades, experimental results in tumor lymphangiogenesis began to appear only in the last 10 years. In this chapter we expand the models proposed by Friedman, Lolas and Pepper on tumor lymphangiogenesis mediated by proteolytically and un-proteolytically processed growth factors (Friedman and Lolas G, Math Models Methods Appl Sci 15(01):95-107, 2005; Pepper and Lolas G, Selected topics in cancer modeling: genesis, evolution, immune competition, and therapy. In: The lymphatic vascular system in lymphangiogenesis invasion and metastasis a mathematical approach. Birkhäuser Boston, Boston, pp 1-22, 2008). The variables represent different cell densities and growth factors concentrations, and where possible the parameters are estimated from experimental and clinical data. The results obtained from computational simulations carried out on the model equations produce dynamic heterogeneous ("anarchic") spatio-temporal solutions. More specifically, we observed coherent masses of tumor clusters migrating around and within the lymphatic network. Our findings are in line with recent experimental evidence that associate cluster formation with the minimization of cell loss favoring high local extracellular matrix proteolysis and thus protecting cancer invading cells from an immunological assault driven by the lymphatic network.