RESUMO
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.
Assuntos
Glicerol , Vírus da Influenza A , Mucinas , Polímeros , Ligação Viral , Animais , Antivirais/farmacologia , Membrana Celular/metabolismo , Membrana Celular/virologia , Cães , Glicerol/síntese química , Glicerol/metabolismo , Glicerol/farmacologia , Hemaglutininas Virais/metabolismo , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/metabolismo , Células Madin Darby de Rim Canino , Peso Molecular , Mucinas/química , Neuraminidase/metabolismo , Polímeros/síntese química , Polímeros/metabolismo , Polímeros/farmacologia , Ligação Viral/efeitos dos fármacosRESUMO
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.
Assuntos
Materiais Biocompatíveis/farmacocinética , Nanoestruturas/administração & dosagem , Proteínas Opsonizantes/sangue , Polímeros/metabolismo , Administração Intravenosa , Animais , Circulação Sanguínea , Feminino , Meia-Vida , Humanos , Masculino , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Proteínas Opsonizantes/química , Proteínas Opsonizantes/metabolismo , Polímeros/química , Coroa de Proteína/química , Coroa de Proteína/metabolismo , Espectrometria de Massas em Tandem , Distribuição TecidualRESUMO
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.
Assuntos
Dendrímeros/química , Glicerol/química , Lubrificantes/química , Nanotecnologia/métodos , Polímeros/química , Substâncias Macromoleculares/química , Propriedades de SuperfícieRESUMO
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.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Micelas , Polímeros/uso terapêutico , Poli-Inos/uso terapêutico , Animais , Feminino , Xenoenxertos , Camundongos , Polímero Poliacetilênico , Polímeros/química , Poli-Inos/químicaRESUMO
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.