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As virus outbreaks continue to pose a challenge, a nonspecific viral inhibitor can provide significant benefits, especially against respiratory viruses. Polyglycerol sulfates recently emerge as promising agents that mediate interactions between cells and viruses through electrostatics, leading to virus inhibition. Similarly, hydrophobic C60 fullerene can prevent virus infection via interactions with hydrophobic cavities of surface proteins. Here, two strategies are combined to inhibit infection of SARS-CoV-2 variants in vitro. Effective inhibitory concentrations in the millimolar range highlight the significance of bare fullerene's hydrophobic moiety and electrostatic interactions of polysulfates with surface proteins of SARS-CoV-2. Furthermore, microscale thermophoresis measurements support that fullerene linear polyglycerol sulfates interact with the SARS-CoV-2 virus via its spike protein, and highlight importance of electrostatic interactions within it. All-atom molecular dynamics simulations reveal that the fullerene binding site is situated close to the receptor binding domain, within 4 nm of polyglycerol sulfate binding sites, feasibly allowing both portions of the material to interact simultaneously.
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COVID-19 , Fulerenos , Humanos , SARS-CoV-2 , Fulerenos/farmacologia , Ligação ProteicaRESUMO
The production scalability and increasing demand for nano-black phosphorus materials (nano-BPs) inevitably lead to their environmental leakage, thereby raising the risk of human exposure through inhalation, ingestion, dermal, and even intravenous pathways. Consequently, a systematic evaluation of their potential impacts on human health is necessary. This Review outlines recent progress in the understanding of various biological responses to nano-BPs. Attention is particularly given to the inconsistent toxicological findings caused by a wide variation of nano-BPs' physicochemical properties, toxicological testing methods, and cell types examined in each study. Additionally, cellular uptake and intracellular trafficking, cell death modes, immunological effects, and other biologically relevant processes are discussed in detail, providing evidence for the potential health implications of nano-BPs. Finally, we address the remaining challenges related to the health risk evaluation of nano-BPs and propose a broader range of applications for these promising nanomaterials.
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Nanoestruturas , Fósforo , Humanos , Fósforo/química , Nanoestruturas/toxicidade , Transporte BiológicoRESUMO
The remarkable progress of applied black phosphorus nanomaterials (BPNMs) is attributed to BP's outstanding properties. Due to its potential for applications, environmental release and subsequent human exposure are virtually inevitable. Therefore, how BPNMs impact biological systems and human health needs to be considered. In this comprehensive Minireview, the most recent advancements in understanding the mechanisms and regulation factors of BPNMs' endogenous toxicity to mammalian systems are presented. These achievements lay the groundwork for an understanding of its biological effects, aimed towards establishing regulatory principles to minimize the adverse health impacts.
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Nanoestruturas , Fósforo , Animais , Humanos , Nanoestruturas/toxicidade , MamíferosRESUMO
Cobalt (CoII ) ions have been an attractive candidate for the biomedical modification of orthopedic implants for decades. However, limited research has been performed into how immobilized CoII ions affect the physical properties of implant devices and how these changes regulate cellular behavior. In this study we modified biocompatible poly(vinyl alcohol) with terpyridine and catechol groups (PVA-TP-CA) to create a stable surface coating in which bioactive metal ions could be anchored, endowing the coating with improved broad-spectrum antibacterial activity against Escherichia coli and Staphylococcus aureus, as well as enhanced surface stiffness and cellular mechanoresponse manipulation. Strengthened by the addition of these metal ions, the coating elicited enhanced mechanosensing from adjacent cells, facilitating cell adhesion, spreading, proliferation, and osteogenic differentiation on the surface coating. This dual-functional PVA-TP-CA/Co surface coating offers a promising approach for improving clinical implantation outcomes.
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Polímeros , Álcool de Polivinil , Antibacterianos/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Escherichia coli , Íons/farmacologia , Osteogênese , Polímeros/farmacologia , Propriedades de Superfície , Titânio/farmacologiaRESUMO
2D nanomaterials have garnered widespread attention in biomedicine and bioengineering due to their unique physicochemical properties. However, poor functionality, low solubility, intrinsic toxicity, and nonspecific interactions at biointerfaces have hampered their application in vivo. Here, biocompatible polyglycerol units are crosslinked in two dimensions using a graphene-assisted strategy leading to highly functional and water-soluble polyglycerols nanosheets with 263 ± 53 nm and 2.7 ± 0.2 nm average lateral size and thickness, respectively. A single-layer hyperbranched polyglycerol containing azide functional groups is covalently conjugated to the surface of a functional graphene template through pH-sensitive linkers. Then, lateral crosslinking of polyglycerol units is carried out by loading tripropargylamine on the surface of graphene followed by lifting off this reagent for an on-face click reaction. Subsequently, the polyglycerol nanosheets are detached from the surface of graphene by slight acidification and centrifugation and is sulfated to mimic heparin sulfate proteoglycans. To highlight the impact of the two-dimensionality of the synthesized polyglycerol sulfate nanosheets at nanobiointerfaces, their efficiency with respect to herpes simplex virus type 1 and severe acute respiratory syndrome corona virus 2 inhibition is compared to their 3D nanogel analogs. Four times stronger in virus inhibition suggests that 2D polyglycerols are superior to their current 3D counterparts.
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Search of new strategies for the inhibition of respiratory viruses is one of the urgent health challenges worldwide, as most of the current therapeutic agents and treatments are inefficient. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic and has taken lives of approximately two million people to date. Even though various vaccines are currently under development, virus, and especially its spike glycoprotein can mutate, which highlights a need for a broad-spectrum inhibitor. In this work, inhibition of SARS-CoV-2 by graphene platforms with precise dual sulfate/alkyl functionalities is investigated. A series of graphene derivatives with different lengths of aliphatic chains is synthesized and is investigated for their ability to inhibit SARS-CoV-2 and feline coronavirus. Graphene derivatives with long alkyl chains (>C9) inhibit coronavirus replication by virtue of disrupting viral envelope. The ability of these graphene platforms to rupture viruses is visualized by atomic force microscopy and cryogenic electron microscopy. A large concentration window (10 to 100-fold) where graphene platforms display strongly antiviral activity against native SARS-CoV-2 without significant toxicity against human cells is found. In this concentration range, the synthesized graphene platforms inhibit the infection of enveloped viruses efficiently, opening new therapeutic and metaphylactic avenues against SARS-CoV-2.
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Grafite/química , SARS-CoV-2/química , Antivirais/farmacologia , COVID-19/epidemiologia , COVID-19/virologia , Microscopia Crioeletrônica , Humanos , Microscopia de Força Atômica , Pandemias , SARS-CoV-2/efeitos dos fármacosRESUMO
While noncovalent interactions at two-dimensional nanobiointerfaces are extensively investigated, less knowledge about covalent interactions at this interface is available. In this work, boronic acid-functionalized 2D MoS2 was synthesized and its covalent multivalent interactions with bacteria and nematodes were investigated. Polymerization of glycidol by freshly exfoliated MoS2 and condensation of 2,5-thiophenediylbisboronic acid on the produced platform resulted in boronic acid-functionalized 2D MoS2. The destructive interactions between 2D MoS2 and bacteria as well as nematodes were significantly amplified by boronic acid functional groups. Because of the high antibacterial and antinematodal activities of boronic acid-functionalized 2D MoS2, its therapeutic efficacy for diabetic wound healing was investigated. The infected diabetic wounds were completely healed 10 days after treatment with boronic acid-functionalized 2D MoS2, and a normal structure for recovered tissues including different layers of skin, collagen, and blood vessels was detected.
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Ácidos Borônicos , Molibdênio , AntibacterianosRESUMO
A new method for top-down, one-pot, gram-scale production of high quality nanographene by incubating graphite in a dilute sodium hypochlorite solution at only 40 °C is reported here. The produced sheets have only 4 at% oxygen content, comparable with nanographene grown by chemical vapor deposition. The nanographene sheets are covalently functionalized using a nondestructive nitrene [2+1] cycloaddition reaction that preserves their π-conjugated system. Statistical analyses of Raman spectroscopy and X-ray photoelectron spectroscopy indicate a low number of sp3 carbon atoms on the order of 2% before and 4% after covalent functionalization. The nanographene sheets are significantly more conductive than conventionally prepared nanographene oxide, and conductivity further increases after covalent functionalization. The observed doping effects and theoretical studies suggest sp2 hybridization for the carbon atoms involved in the [2+1] cycloaddition reaction leading to preservation of the π-conjugated system and enhancing conductivity via n-type doping through the bridging N-atom. These methods are easily scalable, which opens the door to a mild and efficient process to produce high quality nanographenes and covalently functionalize them while retaining or improving their physicochemical properties.
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Due to their unique structure and properties, water-soluble fullerene derivatives are of great interest for various biomedical purposes. In this work, solution behavior, encapsulation and release properties, biocompatibility, and cellular uptake pathways of fullerene-polyglycerol amphiphiles (FPAs) with defined structures are investigated. The number of polyglycerol branches attached to the surface of fullerene affects the physicochemical properties of FPAs dramatically but not their cellular uptake. Release of encapsulated hydrophobic dyes from FPAs strongly depends on the number of their branches. Conjugation of a pH-sensitive dye to the FPAs as a probe showed that their self-assemblies are taken up through endocytotic pathways. It was observed that FPAs are able to transfer small molecules into cells both above and below their critical aggregation concentration. Taking advantage of the water solubility, biocompatibility, and transfer-ability of FPAs, they might find use as unimolecular carriers for future biomedical applications.
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A controlled, reproducible, gram-scale method is reported for the covalent functionalization of graphene sheets by a one-pot nitrene [2+1] cycloaddition reaction under mild conditions. The reaction between commercially available 2,4,6-trichloro-1,3,5-triazine and sodium azide with thermally reduced graphene oxide (TRGO) results in defined dichlorotriazine-functionalized sheets. The different reactivities of the chlorine substituents on the functionalized graphene allow stepwise post-modification by manipulating the temperature. This new method provides unique access to defined bifunctional 2D nanomaterials, as exemplified by chiral surfaces and multifunctional hybrid architectures.
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Low biodegradability of graphene derivatives and related health risks are the main limiting factors for their in vivo biomedical applications. Here, we present the synthesis of enzyme-functionalized graphene sheets with self-degrading properties under physiological conditions and their applications in tumor therapy. The synergistic enzyme cascade glucose oxidase and myeloperoxidase are covalently conjugated to the surface of graphene sheets and two-dimensional (2D) platforms are obtained that can produce sodium hypochlorite from glucose. The enzyme-functionalized graphene sheets with up to 289 nm average size are degraded into small pieces (≤40 nm) by incubation under physiological conditions for 24 h. Biodegradable graphene sheets are further loaded with doxorubicin and their ability for tumor therapy is evaluated in vitro and in vivo. The laser-triggered release of doxorubicin in combination with the enzymatic activity of the functionalized graphene sheets results in a synergistic antitumor activity. Taking advantage of their neutrophil-like activity, fast biodegradability, high photo- and chemotherapeutic effects, the novel two-dimensional nanoplatforms can be used for tumor therapeutic applications.
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Grafite , Corantes , Doxorrubicina/farmacologiaRESUMO
Implant-associated infections present severe and difficult-to-treat complications after surgery, related to implant biofilm colonization. Systemic administration of antibiotics cannot reach sufficient concentrations at the infected site and may be toxic. Here we describe how mussel-inspired dendritic material coated on a titanium surface can locally activate a prodrug of daptomycin (pro-dapto) to treat methicillin-resistant Staphylococcus aureus. The mechanism of the prodrug activation is based on bio-orthogonal click chemistry between a tetrazine (Tz) and trans-cyclooctene (TCO). The former is attached to the dendritic polymer, while the later converts daptomycin into a prodrug. Characterization of the material's properties revealed that it is hydrophobic, non-toxic, and stable for a prolonged period of time. We envision that the titanium coated dendritic material will be able to improve the treatment of implant-associated infections by concentrating systemically administered antibiotic prodrugs, thus converting them into active localized medicines.
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Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Staphylococcus aureus , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Biofilmes , Materiais Revestidos Biocompatíveis/farmacologia , Humanos , Polímeros , Infecções Estafilocócicas/tratamento farmacológico , Titânio/farmacologiaRESUMO
Biofouling constitutes a major challenge in the application of biosensors and biomedical implants, as well as for (food) packaging and marine equipment. In this work, an antifouling surface coating based on the combination of mussel-inspired dendritic polyglycerol (MI-dPG) and an amine-functionalized block copolymer of linear polyglycerol (lPG-b-OA11, OA = oligo-amine) was developed. The coating was compared to a MI-dPG surface which was postfunctionalized with commercially available amine-terminated polyethylene glycol (HO-PEG-NH2) of similar molecular weight. In the current work, these coatings were compared in their chemical stability, protein fouling characteristics, and cell fouling characteristics. The lPG-b-OA11-functionalized coating showed high chemical stability in both phosphate buffered saline (PBS) and sodium dodecyl sulfate (SDS) solutions and reduced the adhesion of fibrinogen from human plasma with 99% and the adhesion of human serum albumin with 96%, in comparison to the bare titanium dioxide substrate. Furthermore, the proliferation of human umbilical vein endothelial cells (HUVECs) was reduced with 85% when the lPG-b-OA11 system was compared to bare titanium dioxide. Additionally, a reduction of 94% was observed when the lPG-b-OA11 system was compared to tissue culture polystyrene.
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As resistance to traditional drugs emerges for treatment of virus infections, the need for new methods for virus inhibition increases. Graphene derivatives with large surface areas have shown strong activity against different viruses. However, the inability of current synthetic protocols to accurately manipulate the structure of graphene sheets in order to control their antiviral activity remains a major challenge. In this work, a series of graphene derivatives with defined polyglycerol sulfate and fatty amine functionalities have been synthesized and their interactions with herpes simplex virus type 1 (HSV-1) are investigated. While electrostatic interactions between polyglycerol sulfate and virus particles trigger the binding of graphene to virus, alkyl chains induce a high antiviral activity by secondary hydrophobic interactions. Among graphene sheets with a broad range of alkyl chains, (C3-C18), the C12-functionalized sheets showed the highest antiviral activity, indicating the optimum synergistic effect between electrostatic and hydrophobic interactions, but this derivative was toxic against the Vero cell line. In contrast, sheets functionalized with C6- and C9-alkyl chains showed low toxicity against Vero cells and a synergistic inhibition of HSV-1. This study shows that antiviral agents against HSV-1 can be obtained by controlled and stepwise functionalization of graphene sheets and may be developed into antiviral agents for future biomedical applications.
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Thermoresponsive polymer coatings can facilitate cell sheet fabrication under mild conditions by promoting cell adhesion and proliferation at 37 °C. At lower temperatures the detachment of confluent cell sheets is triggered without enzymatic treatment. Thus, confluent cell sheets with intact extracellular matrix for regenerative medicine or tissue engineering applications become available. Herein, we applied the previously identified structural design parameters of functional, thermoresponsive poly(glycidyl ether) brushes on gold to the more application-relevant substrate glass via the self-assembly of a corresponding block copolymer (PGE-AA) with a short surface-reactive, amine-presenting anchor block. Both, physical and covalent immobilization on glass via either multivalent ionic interactions of the anchor block with bare glass or the coupling of the anchor block to a polydopamine (PDA) adhesion layer on glass resulted in stable coatings. Atomic force microscopy revealed a high degree of roughness of covalently attached coatings on the PDA adhesion layer, while physically attached coatings on bare glass were smooth and in the brush-like regime. Cell sheets of primary human dermal fibroblasts detached reliably (86%) and within 20 ± 10 min from physically tethered PGE-AA coatings on glass when prepared under cloud point grafting conditions. The presence of the laterally inhomogeneous PDA adhesion layer, however, hindered the spontaneous temperature-triggered cell detachment from covalently grafted PGE-AA, decreasing both detachment rate and reliability. Despite being only physically attached, self-assembled monolayer brushes of PGE-AA block copolymers on glass are functional and stable thermoresponsive coatings for application in cell sheet fabrication of human fibroblasts as determined by X-ray photoelectron spectroscopy.
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Graphene and its derivatives have recently attracted much attention for sensing and deactivating pathogens. However, the mechanism of multivalent interactions at the graphene-pathogen interface is not fully understood. Since different physicochemical parameters of graphene play a role at this interface, control over graphene's structure is necessary to study the mechanism of these interactions. In this work, different graphene derivatives and also zwitterionic graphene nanomaterials (ZGNMs) were synthesized with defined exposure, in terms of polymer coverage and functionality, and isoelectric points. Then, the switchable interactions of these nanomaterials with E. coli and Bacillus cereus were investigated to study the validity of the generally proposed "trapping" and "nano-knives" mechanisms for inactivating bacteria by graphene derivatives. It was found that the antibacterial activity of graphene derivatives strongly depends on the accessible area, i.e. edges and basal plane of sheets and tightness of their agglomerations. Our data clearly confirm the authenticity of "trapping" and "nano-knives" mechanisms for the antibacterial activity of graphene sheets.
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Antibacterianos/química , Bacillus cereus/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Grafite/química , Nanoestruturas/química , PolímerosRESUMO
A novel surface coating with durable broad-spectrum antibacterial ability was prepared based on mussel-inspired dendritic polyglycerol (MI-dPG) embedded with copper nanoparticles (Cu NPs). The functional surface coating is fabricated via a facile dip-coating process followed by in situ reduction of copper ions with a MI-dPG coating to introduce Cu NPs into the coating matrix. This coating has been demonstrated to possess efficient long-term antibacterial properties against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and kanamycin-resistant E. coli through an "attract-kill-release" strategy. The synergistic antibacterial activity of the coating was shown by the combination of two functions of the contact killing, reactive oxygen species production and Cu ions released from the coating. Furthermore, this coating inhibited biofilm formation and showed good compatibility to eukaryotic cells. Thus, this newly developed Cu NP-incorporated MI-dPG surface coating may find potential application in the design of antimicrobial coating, such as implantable devices.