Mucin-Inspired, High Molecular Weight Virus Binding Inhibitors Show Biphasic Binding Behavior to Influenza A Viruses.

Multivalent binding inhibitors are a promising new class of antivirals that prevent virus infections by inhibiting virus binding to cell membranes. The design of these inhibitors is challenging as many properties, for example, inhibitor size and functionalization with virus attachment factors, strongly influence the inhibition efficiency. Here, virus binding inhibitors are synthesized, the size and functionalization of which are inspired by mucins, which are naturally occurring glycosylated proteins with high molecular weight (MDa range) and interact efficiently with various viruses. Hyperbranched polyglycerols (hPGs) with molecular weights ranging between 10 and 2600 kDa are synthesized, thereby hitting the size of mucins and allowing for determining the impact of inhibitor size on the inhibition efficiency. The hPGs are functionalized with sialic acids and sulfates, as suggested from the structure of mucins, and their inhibition efficiency is determined by probing the inhibition of influenza A virus (IAV) binding to membranes using various methods. The largest, mucin-sized inhibitor shows potent inhibition at pm concentrations, while the inhibition efficiency decreases with decreasing the molecular weight. Interestingly, the concentration-dependent IAV inhibition shows a biphasic behavior, which is attributed to differences in the binding affinity of the inhibitors to the two IAV envelope proteins, neuraminidase, and hemagglutinin.

Blood circulation of soft nanomaterials is governed by dynamic remodeling of protein opsonins at nano-biointerface.

Nanomaterials in the blood must mitigate the immune response to have a prolonged vascular residency in vivo. The composition of the protein corona that forms at the nano-biointerface may be directing this, however, the possible correlation of corona composition with blood residency is currently unknown. Here' we report a panel of new soft single molecule polymer nanomaterials (SMPNs) with varying circulation times in mice (t1/2ß ~ 22 to 65 h) and use proteomics to probe protein corona at the nano-biointerface to elucidate the mechanism of blood residency of nanomaterials. The composition of the protein opsonins on SMPNs is qualitatively and quantitatively dynamic with time in circulation. SMPNs that circulate longer are able to clear some of the initial surface-bound common opsonins, including immunoglobulins, complement, and coagulation proteins. This continuous remodelling of protein opsonins may be an important decisive step in directing elimination or residence of soft nanomaterials in vivo.

Mega macromolecules as single molecule lubricants for hard and soft surfaces.

A longstanding goal in science and engineering is to mimic the size, structure, and functionality present in biology with synthetic analogs. Today, synthetic globular polymers of several million molecular weight are unknown, and, yet, these structures are expected to exhibit unanticipated properties due to their size, compactness, and low inter-chain interactions. Here we report the gram-scale synthesis of dendritic polymers, mega hyperbranched polyglycerols (mega HPGs), in million daltons. The mega HPGs are highly water soluble, soft, nanometer-scale single polymer particles that exhibit low intrinsic viscosities. Further, the mega HPGs are lubricants acting as interposed single molecule ball bearings to reduce the coefficient of friction between both hard and soft natural surfaces in a size dependent manner. We attribute this result to their globular and single particle nature together with its exceptional hydration. Collectively, these results set the stage for new opportunities in the design, synthesis, and evaluation of mega polymers.

Stable and compact zwitterionic polydiacetylene micelles with tumor-targeting properties.

Compact polymerized polydiacetylene-micelles with "stealth" zwitterionic surface coating were assembled and tested in a murine xenograft model of breast cancer. In vivo fluorescence imaging indicated accumulation in the tumor area and histological studies revealed predominant uptake of the micelles at the margins of the tumor, thereby allowing the delineation of its volume.

Effect of injection routes on the biodistribution, clearance, and tumor uptake of carbon dots.

The emergence of photoluminescent carbon-based nanomaterials has shown exciting potential in the development of benign nanoprobes. However, the in vivo kinetic behaviors of these particles that are necessary for clinical translation are poorly understood to date. In this study, fluorescent carbon dots (C-dots) were synthesized and the effect of three injection routes on their fate in vivo was explored by using both near-infrared fluorescence and positron emission tomography imaging techniques. We found that C-dots are efficiently and rapidly excreted from the body after all three injection routes. The clearance rate of C-dots is ranked as intravenous > intramuscular > subcutaneous. The particles had relatively low retention in the reticuloendothelial system and showed high tumor-to-background contrast. Furthermore, different injection routes also resulted in different blood clearance patterns and tumor uptakes of C-dots. These results satisfy the need for clinical translation and should promote efforts to further investigate the possibility of using carbon-based nanoprobes in a clinical setting. More broadly, we provide a testing blueprint for in vivo behavior of nanoplatforms under various injection routes, an important step forward toward safety and efficacy analysis of nanoparticles.

Crosslinked carbon dots as ultra-bright fluorescence probes.

Carbon dots (surface-passivated small carbon nanoparticles) are crosslinked to result in fluorescence probes containing one or multiple dots. For the single-dot probes, the crosslinking further stabilizes the dot structure, while for those packed with multiple dots, the individual probe imaging results demonstrate that the fluorescence properties are additive, with more dots for higher emission intensities in a proportional fashion, thus enabling the preparation of ultra-bright fluorescence probes.

Cellular uptake and trafficking of polydiacetylene micelles.

Polydiacetylene (PDA) micelles coated with either carboxylate-, ammonium-, or methoxy-polyethyleneglycol (PEG) chains were assembled and loaded with a fluorescent dye (DiO). Their interaction with MCF-7 human breast tumor cells was investigated by epi-fluorescence microscopy and fluorescence-activated cell sorting (FACS) to determine their internalization pathway and intracellular fate. It was found that the ionic character of the micelles influenced their internalization kinetics through a caveolae-mediated pathway and that all micelle types behaved somewhat similarly inside cells.

Carbon dots of different composition and surface functionalization: cytotoxicity issues relevant to fluorescence cell imaging.

Nanoscale carbon particles have emerged as versatile precursors for a new class of highly fluorescent nanomaterials that resemble semiconductor quantum dots. The surface-passivated fluorescent carbon nanoparticles, dubbed 'carbon dots', were already demonstrated for their potential optical bioimaging applications in vitro and in vivo. In this study, we conducted a systematic cytotoxicity evaluation on the carbon dots prepared by various combinations of precursor carbon nanoparticles and molecules for the particle surface functionalization. The results suggested that the cytotoxicity of carbon dots was dependent on the selection of surface passivation molecules. Those dots showing more significant cytotoxicity at higher concentrations were also evaluated for their effects on the fluorescence imaging of live cells. The implications of the results on the eventual use of carbon dots as cell imaging agents are discussed.

Carbon nanoparticles as chromophores for photon harvesting and photoconversion.

Carbon nanomaterials have generated a tremendous amount of attention in the scientific community. While most of the research and development efforts have been on fullerenes, carbon nanotubes, and graphene sheets, carbon nanoparticles (which are often considered as impurities or unwanted complications in the other carbon nanomaterials) have recently emerged as a unique class of highly fluorescent nano-dots. However, little or no attention has been paid to potential uses of carbon nanoparticles as chromophores in photochemical reactions or for photon harvesting and photoconversion in general. In the study reported herein we demonstrate the chromophore-equivalent functions of aqueous-suspended small carbon nanoparticles in harvesting visible photons for the reductive coating of the nanoparticles with silver and gold and, as a result, the preparation of unique carbon-noble-metal core-shell nanostructures.

Graphene oxides dispersing and hosting graphene sheets for unique nanocomposite materials.

Graphene oxides (GOs), beyond their widely reported use as precursors for single-layer graphene sheets, are in fact excellent materials themselves (polymers in two-dimension, polyelectrolyte-like, aqueous solubility and biocompatibility, etc.). In this reported work we used aqueous GOs to effectively disperse few-layer graphene sheets (GNs) in suspension for facile wet-processing into nanocomposites of GNs embedded in GOs (as the polymeric matrix). The resulting lightweight and plastic-like nanocomposite materials remained mechanically flexible even at high loadings of GNs, and they were found to be highly efficient in thermal transport, with the experimentally determined thermal diffusivity competitive to those typically observed only in well-known thermally conductive metals such as aluminum and copper. As demonstrated, GOs apparently represent a unique class of two-dimensional polymeric materials for potentially "all-carbon" nanocomposites, among others, which may find technological applications independent of those widely proclaimed for graphene sheets.

Carbon nanoparticles as visible-light photocatalysts for efficient CO2 conversion and beyond.

Increasing atmospheric CO(2) levels have generated much concern, driving the ongoing carbon sequestration effort. A compelling CO(2) sequestration option is its photocatalytic conversion to hydrocarbons, for which the use of solar irradiation represents an ultimate solution. Here we report a new strategy of using surface-functionalized small carbon nanoparticles to harvest visible photons for subsequent charge separation on the particle surface in order to drive the efficient photocatalytic process. The aqueous solubility of the catalysts enables photoreduction under more desirable homogeneous reaction conditions. Beyond CO(2) conversion, the nanoscale carbon-based photocatalysts are also useful for the photogeneration of H(2) from water under similar conditions.

Toward quantitatively fluorescent carbon-based "quantum" dots.

Carbon-based "quantum" dots (or "carbon dots") are generally defined as surface-passivated small carbon nanoparticles that are brightly fluorescent. Apparently, the carbon particle surface passivation in carbon dots is critical to their fluorescence performance. An effective way to improve the surface passivation is to dope the surface of the precursor carbon nanoparticles with an inorganic salt, followed by the typical functionalization with organic molecules. In this work we passivated small carbon nanoparticles by a combination of the surface-doping with nanoscale semiconductors and the organic functionalization, coupled with gel column fractionation to harvest the most fluorescent carbon dots, which exhibited fluorescence emission quantum yields of up to 78%. Experimental and mechanistic issues relevant to potentially further improve the performance of carbon dots toward their being quantitatively fluorescent are discussed.