A Drug Delivery System for Administration of Anti–TNF-α Antibody

Purpose To describe the fabrication, evaluation, and preliminary in vivo safety of a new drug delivery system (DDS) for topical anti–TNF-α antibody administration. Methods: A DDS was fabricated using inverse template fabrication of a hydrophobic three-dimensional porous scaffold (100–300 μm in diameter porosity) loaded with 10% polyvinyl alcohol hydrogel carrying 5 mg/ml (weight/volume) of anti–TNF-α antibody. Drug-loaded DDS was sterilized with 25 kGy of gamma irradiation. Long-term in vitro antibody affinity and release was evaluated at room temperature or 37°C using enzyme-linked immunosorbent assay (ELISA) and protein fluorescence. In vivo clinical and histolopathological assessment was performed by subcutaneous implantation in BALB/c mice for 3 months. Results: Gamma irradiation, repeated dry/wet cycles, and storage at room temperature for 1 year or 37°C for 1 month had no deleterious effects on antibody affinity. Anti–TNF-α release was high during the first minutes of aqueous exposure, followed by stabilization and gradual, low-dose, antibody release over the next 30 days. Histopathologic evaluation of explanted DDS showed a fibrous pseudocapsule and a myxoid acute/chronic inflammation without granuloma formation surrounding the implants. Conclusions: Sustained local delivery of anti–TNF-α antibody is feasible using the described DDS, which provides stability of the enclosed antibody for up to 1 year of storage. Preliminary results show good in vivo tolerance following subcutaneous placement for 3 months. The proposed fabrication and sterilization process opens new possibilities for the delivery of biologic agents to the anterior surface of the eye. Translational Relevance The described DDS will facilitate the treatment of ocular surface diseases amenable to biologic therapy

Amyloid and tau pathology associations with personality traits, neuropsychiatric symptoms, and cognitive lifestyle in the preclinical phases of sporadic and autosomal dominant Alzheimer’s disease

Background Major prevention trials for Alzheimer’s disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits. Methods A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression

Photophysics of 7-mercapto-4-methylcoumarin and derivatives: complementary fluorescence behaviour to 7-hydroxycoumarins

The photophysical behaviour of 7-mercapto-4-methylcoumarin (C-SH) and derivatives has been studied in different solvents. In contrast to 7-hydroxy-4-methylcoumarin, C-SH shows poor emission, but high fluorescence when the thiol is alkylated. The origin and character of the lowest singlet states are discussed, specifically proposing that the thione-like C[double bond, length as m-dash]S resonance form plays a key role in excited state deactivation in C-SH

Method to Predict Reagents in Iridium-Based Photoredox Catalysis

Visible-light photoredox catalysts with oxidizing excited states have been broadly applied in organic synthesis. Following photon absorption by the photocatalyst, electron transfer from an organic reagent is the most common mechanistic outcome for this class of reaction. Reduction potentials for organic reagents are therefore useful to predict reactivity and DFT proved to be useful as a predictive tool in this regard. Due to the complex mechanisms that follow electron transfer, kinetics play a crucial role in the success of photoredox reactions. We extend the predictive tools of DFT to estimate the electron transfer rates between an excited photocatalyst and various organic substrates. To calibrate our model, 49 electron transfer rate constants were experimentally measured in acetonitrile for the catalyst Ir[dF(CF3)ppy]2(dtbpy)+. The rate constants, kq, gave a clear predictive trend when compared to calculated ionization energies in “frozen solvent”, which was a better predictor than standard reduction potentials in our case. The calculated kq gave an average error of 17% for log(kq) values between 4 and 11. This simple method can predict the reactivity of hundreds of reagents in silico. Notably, the calculations offered unexpected insight that we could translate into success for the C-H activation of acetylacetone as a proof-of-concept

Highly Photostable and Fluorescent Microporous Solids Prepared via Solid-State Entrapment of Boron Dipyrromethene Dyes in a Nascent Metal–Organic Framework

We report a strategy to synthesize highly emissive, photostable, microporous materials by solid-state entrapment of boron dipyrromethene (BODIPY) fluorophores in a metal–organic framework. Solvent-free mechanochemistry or accelerated aging enabled quantitative capture and dispersal of the PM605 dye within the ZIF-8 framework starting from inexpensive, commercial materials. While the design of emissive BODIPY solids is normally challenged by quenching in a densely packed environment, herein reported PM605@ZIF-8 materials show excellent emissive properties and to the best of our knowledge an unprecedented ∼10-fold enhancement of BODIPY photostability. Time-resolved and steady-state fluorescence studies of PM605@ZIF-8 show that interchromophore interactions are minimal at low dye loadings, but at higher ones lead to through-pore energy transfer between chromophores and to aggregate species.Fil: Glembockyte, Viktorija. McGill University; CanadáFil: Frenette, Mathieu. Mcgill University; Canadá. Université du Québec a Montreal; CanadáFil: Mottillo, Cristina. Mcgill University; CanadáFil: Durantini, Andres Matías. Mcgill University; Canadá. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química; Argentina. Universidad Nacional de Río Cuarto. Instituto para el Desarrollo Agroindustrial y de la Salud. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto para el Desarrollo Agroindustrial y de la Salud; ArgentinaFil: Gostick, Jeff. Mcgill University; CanadáFil: Strukil, Vjekoslav. Mcgill University; Canadá. Ruđer Bošković Institute; CroaciaFil: Friščić, Tomislav. Mcgill University; Canadá. Ruđer Bošković Institute; CroaciaFil: Cosa, Gonzalo. Mcgill University; Canad

Mechanistic Evidence for a Radical-Radical Recombination Pathway of Flavin-based Photocatalytic Tyrosine Labeling

We recently introduced flavin-based photocatalysts such as riboflavin tetraacetate (RFT) as a robust platform for light- mediated protein labeling via phenoxyl radical-mediated tyrosine-biotin phenol coupling on live cells. To gain insight into this coupling reaction, we conducted detailed mechanistic analysis for RFT-photomediated activation of phenols for tyrosine labeling. Contrary to previously proposed mechanisms, we find that the initial covalent binding step between the tag and tyrosine is not radical addition, but rather radical-radical recombination. Radical addition to a phenol, while often proposed in the literature, is prohibitively unfavorable according to DFT calculations. Radical-radical recombination, followed by rearomatization, is the preferred pathway for the phenol-phenol coupling presented herein, but may also explain the mechanism of other tyrosine-tagging approaches described in the literature. Competitive kinetics experiments show that phenoxyl radicals are generated by the reaction of phenols with several reactive intermediates in the proposed mechanism: primarily with the riboflavin-photocatalyst excited state or singlet oxygen, but also possibly with the semi-reduced photocatalyst or hydroperoxyl radicals produced at key steps in the mechanism