Tumor necrosis factor-alpha (TNF-α) specific antibodies (anti-TNF-α Ab) have been shown to be potent TNF inhibitors and effective therapeutics for a range of inflammatory diseases. Typically, these drugs are administered systemically, but systemic dosing sufficient to achieve locally effective concentrations in peripheral tissues has been associated with systemic immunosuppression and related adverse events. Here we demonstrate efficient and biologically effective MNA delivery of anti-TNF-α Ab to the intradermal microenvironment of the skin in mice and humans. These results support the development of MNA mediated antibody delivery of therapeutic antibodies for clinical applications.
This study presents a kinetic model of the chelation of iron ions by generation 4 hydroxyl-terminated polyamidoamine (PAMAM) with ethylenediamine core (G4-OH). The coordination processes of iron ions from ferric chloride, FeCl(3), and ferrous bromide, FeBr(2), to G4-OH dendrimers were analyzed using ultraviolet-visible (UV-vis) spectroscopy, proton nuclear magnetic resonance ((1)H NMR) spectroscopy, and liquid chromatography-mass spectrometry (LC-MS). In the visible region, a charge-transfer was observed when the dendrimer was added to a ferric chloride solution. This phenomenon is a ligand-to-metal charge-transfer (LMCT) between the free electron group of the dendrimer's internal amines and the dehalogenated iron ion that takes 2 h to complete at room temperature. Analysis of potential rate laws and diffusion effects led to a second-order kinetic model for this reaction. By measuring the rate coefficients as a function of temperature (22-37 °C), an apparent activation energy of 41.5 kJ/mol was obtained using the Arrhenius method. The results of this study will fuel research of PAMAM dendrimers for environmental, pharmaceutical, and materials applications.
We report a thermoresponsive chemical modification strategy of hyaluronic acid (HA) for coating onto a broad range of biomaterials without relying on chemical functionalization of the surface. Poly(di(ethylene glycol) methyl ether methacrylate) (PMEO2MA), a polymer with a lower critical solution temperature of 26 °C in water, was grafted onto HA to allow facile formation of biopolymer coatings. While the mechanism for film formation appears to involve a complex combination of homogeneous nucleation followed by heterogeneous film growth, we demonstrate that it resulted in hydrophilic coatings that significantly reduce protein adsorption despite the high fraction of hydrophobic (PMEO2MA). Structural characterization was performed using atomic force microscopy (AFM), which showed the formation of a dense, continuous coating based on 200 nm domains that were stable in protein solutions for at least 15 days. The coatings had a water contact angle of 16°, suggesting the formation of hydrophilic but not fully wetting films. Quartz crystal microbalance with dissipation monitoring (QCM-D) as well as biolayer interferometry (BLI) techniques were used to measure adsorption of bovine serum albumin (BSA), fibrinogen (Fbg), and human immunoglobulin (IgG), with results indicating that HA-PMEO2MA-coated surfaces effectively inhibited adsorption of all three serum proteins. These results are consistent with previous studies demonstrating that this degree of hydrophilicity is sufficient to generate an effectively nonfouling surface and suggest that segregation during the solubility transition resulted in a surface that presented the hydrophilic HA component of the hybrid biopolymer. We conclude that PMEO2MA-grafted HA is a versatile platform for the passivation of hydrophobic biomaterial surfaces without need for substrate functionalization.
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